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19 Apr 2021 at 01:31
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Bibliography on: Alzheimer Disease — Treatment


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RJR: Recommended Bibliography 19 Apr 2021 at 01:31 Created: 

Alzheimer Disease — Treatment

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. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: alzheimer[TIAB] AND treatment[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2021-04-16

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

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

ACS chemical neuroscience [Epub ahead of print].

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

RevDate: 2021-04-14

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

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

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

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

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

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

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

RevDate: 2021-04-14

Grunenwald A, LT Roumenina (2021)

The Benefits of Complement Measurements for the Clinical Practice.

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

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

RevDate: 2021-04-15

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

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

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

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

RevDate: 2021-04-13

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

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

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

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

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

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

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

RevDate: 2021-04-14

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

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

Frontiers in aging neuroscience, 13:647990.

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

RevDate: 2021-04-13

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

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

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

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

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

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

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

RevDate: 2021-04-15

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

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

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

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

RevDate: 2021-04-13

Leinenga G, Koh WK, J Götz (2021)

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

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

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

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

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

RevDate: 2021-04-06

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

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

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

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

RevDate: 2021-04-05

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

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

ACS chemical neuroscience [Epub ahead of print].

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

RevDate: 2021-04-06

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

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

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

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

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

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

RevDate: 2021-04-08

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

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

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

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

RevDate: 2021-04-08

Jain AP, G Sathe (2021)

Proteomics Landscape of Alzheimer's Disease.

Proteomes, 9(1):.

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

RevDate: 2021-04-13

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

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

Brain sciences, 11(3):.

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

RevDate: 2021-04-15

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

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

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

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

RevDate: 2021-04-03

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

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

Frontiers in aging neuroscience, 13:591735.

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

RevDate: 2021-04-06

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

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

Scientific reports, 11(1):7289.

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

RevDate: 2021-03-27

Zhao J, Li T, J Wang (2021)

Association between psoriasis and dementia: A systematic review.

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

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

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

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

RevDate: 2021-03-26

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

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

Neuropathology and applied neurobiology [Epub ahead of print].

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

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

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

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

RevDate: 2021-04-15

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

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

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

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

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

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

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

RevDate: 2021-03-23

KÖylÜ A, Altunkaynak BZ, B DelİbaŞ (2021)

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

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

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

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

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

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

RevDate: 2021-03-22

Miranda A, Montiel E, Ulrich H, et al (2021)

Selective Secretase Targeting for Alzheimer's Disease Therapy.

Journal of Alzheimer's disease : JAD pii:JAD201027 [Epub ahead of print].

Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

RevDate: 2021-04-09

Van Dyk K, Zhou X, Small BJ, et al (2021)

Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.

JNCI cancer spectrum, 5(2):pkab013.

Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.

Methods: We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.

Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.

Conclusions: APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.

RevDate: 2021-04-05

Haeckert J, Brendel M, Beyer L, et al (2021)

Effective Valproic Acid Treatment in a Patient With Delusional Parasitosis Due to Corticobasal Syndrome and Alzheimer Disease.

Journal of clinical psychopharmacology pii:00004714-900000000-98332 [Epub ahead of print].

RevDate: 2021-03-16

Duez H, B Pourcet (2021)

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway.

Frontiers in endocrinology, 12:630536.

The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.

RevDate: 2021-03-15

Zhan-Qiang H, Hai-Hua Q, Chi Z, et al (2021)

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.

Neurologia (Barcelona, Spain) pii:S0213-4853(21)00022-0 [Epub ahead of print].

INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1-42.

METHODS: To create a model of AD, SH-SY5Y cells were treated with Aβ1-42 and mice received intracerebroventricular injections of Aβ1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.

RESULTS: Aβ1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1-42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.

CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.

RevDate: 2021-03-14

Shamsipour S, Sharifi G, F Taghian (2021)

An 8-Week Administration of Bifidobacterium bifidum and Lactobacillus plantarum Combined with Exercise Training Alleviates Neurotoxicity of Aβ and Spatial Learning via Acetylcholine in Alzheimer Rat Model.

Journal of molecular neuroscience : MN [Epub ahead of print].

This study aimed to determine the effects of 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training on neurotoxicity of Aβ, spatial learning, acetylcholine (ACH), and vascular endothelial growth factor (VEGF) in Alzheimer rats. Twenty-five Wistar rats were randomly divided into 5 groups (n = 5 in each): (1) healthy control (control), (2) Alzheimer disease (AD), (3) AD with treadmill exercise (AD + Exe), (4) AD with probiotic (combined administration of Bifidobacterium bifidum and Lactobacillus plantarum) treatment (AD + Pro), and (5) AD with treadmill exercise and probiotic treatment (AD + Exe + Pro). AD was induced by intra-cerebroventricular injection of Aβ1-42 peptide. Then, the training groups exercised on treadmill for 8 weeks, 5 days per weeks. The rats were treated daily with probiotic supplements via gavage for 8 weeks. The Morris water maze (MWM) test was administered to measure spatial learning. Then, the animals were sacrificed and Vegf and ACH were analyzed using the qPCR and immunohistochemistry (IHC) methods, respectively. Results showed that the β-amyloid plaques were significantly increased in the brains of the AD group compared with the control group (p < 0.001). The combined use of probiotics and exercise training significantly increased the time spent in the target quadrant after removing the platform, compared with the AD group in the Morris water maze test (p < 0.001). Crystal violet analysis showed that sole (p < 0.01) and combined exercise training and probiotic supplementation (p < 0.001) significantly reduced the number of dead cells in the brains of rats compared with the AD group. AD significantly decreased Vegf mRNA and ACH in the CA1 area of the hippocampus (p < 0.001). However, mono and combined therapy (exercise and probiotics) significantly increased ACH in the rats' brain compared with the AD group. Overall, 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training can improve spatial learning impairment in the AD rats. Exercise and probiotics seem to offer potential benefits to AD patients by upregulating ACH.

RevDate: 2021-03-13

Sharma S, Tiarks G, Haight J, et al (2021)

Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy.

Frontiers in molecular neuroscience, 14:612073.

Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.

RevDate: 2021-04-15

Bigarré IM, Trombetta BA, Guo YJ, et al (2021)

IGF2R circular RNA hsa_circ_0131235 expression in the middle temporal cortex is associated with AD pathology.

Brain and behavior, 11(4):e02048.

OBJECTIVE: To identify circular RNAs as candidates for differential expression in the middle temporal (MT) cortex in a well-characterized cohort with contrasting Alzheimer disease (AD) pathology and cognition. Top screen candidates were assessed for proof of circularity and then quantified by qPCR in a larger number of samples.

METHODS: An initial RNA sequencing screen was performed on n = 20 frozen human tissue samples. Filters were applied to select candidate circular RNAs for further investigation. Frozen human tissue samples were selected for global AD pathology burden and global cognition scores (n = 100). Linear and divergent primers were used to assess circularity using RNaseR digestion. RT-qPCR was performed to quantify relative hsa_circ_0131235 abundance.

RESULTS: Eleven circular RNAs were selected for further investigation. Four candidates produced circular RNA primers with appropriate efficiencies for qPCR. RNaseR treatment and analysis by both basic PCR and qPCR confirmed hsa_circ_0131235 circularity. There was a significant main effect of AD pathology on hsa_circ_0131235 expression.

CONCLUSIONS: Elevated hsa_circ_0131235 expression in the MT cortex was significantly associated with AD pathology.

RevDate: 2021-03-13

Raket LL (2020)

Statistical Disease Progression Modeling in Alzheimer Disease.

Frontiers in big data, 3:24.

Background: The characterizing symptom of Alzheimer disease (AD) is cognitive deterioration. While much recent work has focused on defining AD as a biological construct, most patients are still diagnosed, staged, and treated based on their cognitive symptoms. But the cognitive capability of a patient at any time throughout this deterioration reflects not only the disease state, but also the effect of the cognitive decline on the patient's pre-disease cognitive capability. Patients with high pre-disease cognitive capabilities tend to score better on cognitive tests that are sensitive early in disease relative to patients with low pre-disease cognitive capabilities at a similar disease stage. Thus, a single assessment with a cognitive test is often not adequate for determining the stage of an AD patient. Repeated evaluation of patients' cognition over time may improve the ability to stage AD patients, and such longitudinal assessments in combinations with biomarker assessments can help elucidate the time dynamics of biomarkers. In turn, this can potentially lead to identification of markers that are predictive of disease stage and future cognitive decline, possibly before any cognitive deficit is measurable. Methods and Findings: This article presents a class of statistical disease progression models and applies them to longitudinal cognitive scores. These non-linear mixed-effects disease progression models explicitly model disease stage, baseline cognition, and the patients' individual changes in cognitive ability as latent variables. Maximum-likelihood estimation in these models induces a data-driven criterion for separating disease progression and baseline cognition. Applied to data from the Alzheimer's Disease Neuroimaging Initiative, the model estimated a timeline of cognitive decline that spans ~15 years from the earliest subjective cognitive deficits to severe AD dementia. Subsequent analyses demonstrated how direct modeling of latent factors that modify the observed data patterns provides a scaffold for understanding disease progression, biomarkers, and treatment effects along the continuous time progression of disease. Conclusions: The presented framework enables direct interpretations of factors that modify cognitive decline. The results give new insights to the value of biomarkers for staging patients and suggest alternative explanations for previous findings related to accelerated cognitive decline among highly educated patients and patients on symptomatic treatments.

RevDate: 2021-03-10

Piao Z, Song L, Yao L, et al (2021)

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons.

Pharmacology pii:000507818 [Epub ahead of print].

INTRODUCTION: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer's disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders.

OBJECTIVE: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons.

METHODS: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1-42 (Aβ1-42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1-42 oligomer-treated neurons.

RESULTS AND CONCLUSIONS: Our findings indicated that schisandrin significantly alleviated the Aβ1-42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

RevDate: 2021-03-29

Stroup TS, Olfson M, Huang C, et al (2021)

Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia.

JAMA psychiatry [Epub ahead of print].

Importance: People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy.

Objective: To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI).

This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020.

Main Outcomes and Measures: Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria.

Results: The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age.

Conclusions and Relevance: In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.

RevDate: 2021-03-29

Shaw C, Hayes-Larson E, Glymour MM, et al (2021)

Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model.

JAMA network open, 4(3):e211001.

Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence.

Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence.

This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020.

Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender.

Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival.

Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women).

Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.

RevDate: 2021-03-15

Roca-Agujetas V, Barbero-Camps E, de Dios C, et al (2021)

Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.

Molecular neurodegeneration, 16(1):15.

BACKGROUND: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer's disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.

METHODS: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.

RESULTS: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.

CONCLUSIONS: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

RevDate: 2021-03-29

Nasrallah IM, Gaussoin SA, Pomponio R, et al (2021)

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.

JAMA neurology [Epub ahead of print].

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control.

Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers.

This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020.

Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317).

Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle.

Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy.

Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

RevDate: 2021-03-06

Elmorsy E, Elsharkawy E, Alhumaydhi FA, et al (2021)

The protective effect of Indian Catechu methanolic extract against aluminum chloride-induced neurotoxicity, A rodent model of Alzheimer's disease.

Heliyon, 7(2):e06269.

Alzheimer's disease (AD) is the commonest neurodegenerative disorder with a wide array of manifestations, courses, and contributing causes. Despite being clinically characterized a long time ago; no treatment has been developed that could improve the pathology or slow down the disease manifestation- so far. Indian Catechu methanolic extract (ICME) has proved to have multiple beneficial effects that support its use in several disorders- especially those with complex etiology. In the present study, we evaluated the neuroprotective effect of ICME in a rat model of AD using Aluminum Chloride (AlCl3). The results showed that ICME could have a positive impact on the course of AD through its anticholinesterase effect and significant antioxidant effect which was reflected on the animals both on behavioral tests as well as hallmark pathological findings.

RevDate: 2021-03-19

Schnier C, Janbek J, Williams L, et al (2021)

Antiherpetic medication and incident dementia: Observational cohort studies in four countries.

European journal of neurology [Epub ahead of print].

BACKGROUND AND PURPOSE: Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype.

METHODS: A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time-dependent covariates.

RESULTS: Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk.

CONCLUSIONS: Short-term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.

RevDate: 2021-04-04

Guzmán-Ruiz MA, Herrera-González A, Jiménez A, et al (2021)

Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1-42 rat model.

BMC neuroscience, 22(1):14.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aβ) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aβ neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aβ rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1-42 (Aβ1-42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aβ rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot.

RESULTS: We observed that the i.c.v injection of Aβ decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aβ-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aβ rats, which was prevented by the APN treatment.

CONCLUSION: The present study describes the olfactory impairment of Aβ treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aβ1-42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.

RevDate: 2021-04-06
CmpDate: 2021-04-06

Librizzi D, Cabanel N, Zavorotnyy M, et al (2021)

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia.

Molecules (Basel, Switzerland), 26(5):.

PET of β-Amyloid plaques (Aβ) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.

RevDate: 2021-03-01

Reiss AB, Montufar N, DeLeon J, et al (2021)

Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.

The neurologist, 26(2):52-61 pii:00127893-202103000-00006.

BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-β and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered.

REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway.

CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

RevDate: 2021-03-04

Watt JA, Veroniki AA, Tricco AC, et al (2021)

Using a distribution-based approach and systematic review methods to derive minimum clinically important differences.

BMC medical research methodology, 21(1):41.

BACKGROUND: Clinical interpretation of changes measured on a scale is dependent on knowing the minimum clinically important difference (MCID) for that scale: the threshold above which clinicians, patients, and researchers perceive an outcome difference. Until now, approaches to determining MCIDs were based upon individual studies or surveys of experts. However, the comparison of meta-analytic treatment effects to a MCID derived from a distribution of standard deviations (SDs) associated with all trial-specific outcomes in a meta-analysis could improve our clinical understanding of meta-analytic treatment effects.

METHODS: We approximated MCIDs using a distribution-based approach that pooled SDs associated with baseline mean or mean change values for two scales (i.e. Mini-Mental State Exam [MMSE] and Alzheimer Disease Assessment Scale - Cognitive Subscale [ADAS-Cog]), as reported in parallel randomized trials (RCTs) that were included in a systematic review of cognitive enhancing medications for dementia (i.e. cholinesterase inhibitors and memantine). We excluded RCTs that did not report baseline or mean change SD values. We derived MCIDs at 0.4 and 0.5 SDs of the pooled SD and compared our derived MCIDs to previously published MCIDs for the MMSE and ADAS-Cog.

RESULTS: We showed that MCIDs derived from a distribution-based approach approximated published MCIDs for the MMSE and ADAS-Cog. For the MMSE (51 RCTs, 12,449 patients), we derived a MCID of 1.6 at 0.4 SDs and 2 at 0.5 SDs using baseline SDs and we derived a MCID of 1.4 at 0.4 SDs and 1.8 at 0.5 SDs using mean change SDs. For the ADAS-Cog (37 RCTs, 10,006 patients), we derived a MCID of 4 at 0.4 SDs and 5 at 0.5 SDs using baseline SDs and we derived a MCID of 2.6 at 0.4 SDs and 3.2 at 0.5 SDs using mean change SDs.

CONCLUSION: A distribution-based approach using data included in a systematic review approximated known MCIDs. Our approach performed better when we derived MCIDs from baseline as opposed to mean change SDs. This approach could facilitate clinical interpretation of outcome measures reported in RCTs and systematic reviews of interventions. Future research should focus on the generalizability of this method to other clinical scenarios.

RevDate: 2021-02-27

Chen C, Liu P, Wang J, et al (2020)

Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease.

Frontiers in cell and developmental biology, 8:624339.

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. No effective therapy is available for this disease. In this study, we investigated the potential therapeutic effects of dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid, on AD, and found that DAU administration significantly improved cognitive impairments in 3xTg-AD mice by decreasing Aβ plaques and hyperphosphorylated tau and increasing the hippocampal ATP level. Proteomic and western blot analyses revealed that DAU treatment mainly modified the expression of proteins involved in mitochondrial energy metabolism, such as Aco2, Ndufs1, Cox5a, and SDHB, and that of synapse-related proteins such as Syn1 and Syn2. Pathway analysis revealed that DAU modulated the tricarboxylic acid cycle, synaptic vesicle cycle, glycolysis, and gluconeogenesis in 3xTg-AD mice. Our study suggests that DAU may be a potential drug for the treatment of AD.

RevDate: 2021-03-01
CmpDate: 2021-03-01

Yamazaki K, Yoshimura A, Miyahara S, et al (2021)

Evaluation of cerebral blood flow in the hippocampus, thalamus, and basal ganglia and the volume of the hippocampus in dogs before and during treatment with prednisolone.

American journal of veterinary research, 82(3):230-236.

OBJECTIVE: To examine whether glucocorticoid (GC) administration alters hippocampal cerebral blood flow (CBF) or volume in dogs.

ANIMALS: 6 clinically normal adult Beagles.

PROCEDURES: Each dog underwent CT and MRI to measure the CBF in the hippocampus, basal ganglia, thalamus, and cerebral cortex and the volume of the hippocampus in each hemisphere of the brain before (day 0) and during (days 7 and 21) a 21-day treatment with prednisolone (1.0 mg/kg, PO, q 24 h) and famotidine (0.5 mg/kg, PO, q 12 h). Results for hippocampal volume, anesthesia-related variables, and semiquantitative measurements of CBF (hemisphere-specific ratios of the CBF in the hippocampus, basal ganglia, and thalamus relative to the CBF in the ipsilateral cerebral cortex and the left cerebral cortex CBF-to-right cerebral cortex CBF ratio) were compared across assessment time points (days 0, 7, and 21).

RESULTS: The ratios of CBF in the right hippocampus and right thalamus to that in the right cerebral cortex on day 21 were significantly lower than those on day 0. No meaningful differences were detected in results for the hippocampal volume in either hemisphere or for the anesthesia-related variables across the 3 time points.

Results indicated that GC administration reduced CBF in the hippocampus and thalamus in dogs of the present study, similar to that which occurs in humans. Research on GC-related brain alteration in dogs could potentially contribute to advancements in understanding Alzheimer disease in humans and neurodegenerative conditions in dogs.

RevDate: 2021-02-27

Feng X, Li T, Song X, et al (2020)

Bayesian Scalar on Image Regression With Nonignorable Nonresponse.

Journal of the American Statistical Association, 115(532):1574-1597.

Medical imaging has become an increasingly important tool in screening, diagnosis, prognosis, and treatment of various diseases given its information visualization and quantitative assessment. The aim of this article is to develop a Bayesian scalar-on-image regression model to integrate high-dimensional imaging data and clinical data to predict cognitive, behavioral, or emotional outcomes, while allowing for nonignorable missing outcomes. Such a nonignorable nonresponse consideration is motivated by examining the association between baseline characteristics and cognitive abilities for 802 Alzheimer patients enrolled in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1), for which data are partially missing. Ignoring such missing data may distort the accuracy of statistical inference and provoke misleading results. To address this issue, we propose an imaging exponential tilting model to delineate the data missing mechanism and incorporate an instrumental variable to facilitate model identifiability followed by a Bayesian framework with Markov chain Monte Carlo algorithms to conduct statistical inference. This approach is validated in simulation studies where both the finite sample performance and asymptotic properties are evaluated and compared with the model with fully observed data and that with a misspecified ignorable missing mechanism. Our proposed methods are finally carried out on the ADNI1 dataset, which turns out to capture both of those clinical risk factors and imaging regions consistent with the existing literature that exhibits clinical significance. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

RevDate: 2021-02-23

Mooko T, Bala A, Tripathy S, et al (2021)

Cannabis Sativa L. Flower and Bud Extracts inhibited In vitro Cholinesterases and b-Secretase Enzymes Activities: Possible Mechanisms of Cannabis use in Alzheimer Disease.

Endocrine, metabolic & immune disorders drug targets pii:EMIDDT-EPUB-114436 [Epub ahead of print].

BACKGROUND: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer's disease, but there is lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer's disease.

AIM: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and β-secretase enzyme activity as one of the possible mechanisms of Alzheimer's disease.

METHODS: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and β-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts.

RESULTS: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards β-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure.

CONCLUSION: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.

RevDate: 2021-02-23

Fahanik-Babaei J, Baluchnejadmojarad T, M Roghani (2020)

Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.

Basic and clinical neuroscience, 11(4):517-524.

Introduction: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD.

Methods: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway.

Results: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters.

Conclusion: Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.

RevDate: 2021-02-23

Fahimi Truski F, Ghotbeddin Z, Tabandeh MR, et al (2020)

Crocin Treatment after Maternal Hypoxia Attenuates Spatial Memory Impairment and Expression of BACE1 and HIF-1α in Rat Offspring Brain.

Basic and clinical neuroscience, 11(4):499-506.

Introduction: Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1α, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia.

Methods: Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14-28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.

Results: Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1α and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes.

Conclusion: According to our results, down-regulation of HIF-1α and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory.

RevDate: 2021-03-05

Liu MN, Liou YJ, Wang WC, et al (2021)

Group Music Intervention Using Percussion Instruments to Reduce Anxiety Among Elderly Male Veterans with Alzheimer Disease.

Medical science monitor : international medical journal of experimental and clinical research, 27:e928714.

BACKGROUND This study aimed to assess the impact of a group music intervention on anxiety and depression of elderly male veterans with dementia. MATERIAL AND METHODS In total, 50 elderly men with Alzheimer disease were randomly divided into intervention and control groups. Patients in the intervention group attended a 60-minute group music session that used percussion instruments with familiar music in the morning once a week for 12 weeks, whereas those in the control group received a rest and reading session at the same intervals and under the same conditions. The Hamilton Anxiety Rating Scale and Geriatric Depression Scale were used to assess anxiety and depression at baseline, week 6, and week 12. The Primary Measures of Music Audiation (PMMA) was used to assess musical aptitude at the baseline. RESULTS A significant reduction in the anxiety level following the 12-week music sessions was observed in the intervention group (P<.001), but there was no significant change in the control group. However, the change in depressive symptoms between the 2 groups was nonsignificant. In the intervention group, when stratifying patients based on music aptitude determined through PMMA assessment, patients with high PMMA scores had significantly reduced anxiety symptoms over time compared with those with low scores. CONCLUSIONS For elderly male veterans with dementia, participating in a group music intervention reduced anxiety symptoms. In patients with high musical aptitude, the treatment effects on anxiety reduction were satisfactory. Measures of music aptitude may provide valuable information regarding patients' response to music intervention.

RevDate: 2021-03-10

Vasconcelos-Filho FSL, da Rocha-E-Silva RC, Martins JER, et al (2020)

Neuroprotector Effect of Daily 8-Minutes of High-Intensity Interval Training in Rat Aβ1-42 Alzheimer Disease Model.

Current Alzheimer research, 17(14):1320-1333.

BACKGROUND: Alzheimer's disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD.

OBJECTIVE: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model.

METHODS: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer's) untrained group, and Aβ1-42 (Alzheimer's) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation.

RESULTS: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed.

CONCLUSION: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.

RevDate: 2021-03-10

Siafaka PI, Mutlu G, NÜ Okur (2020)

Alzheimer's Disease and its Related Dementia Types: A Review on Their Management Via Nanotechnology Based Therapeutic Strategies.

Current Alzheimer research, 17(14):1239-1261.

BACKGROUND: Dementia and its related types such as Alzheimer's disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of dementia is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain.

OBJECTIVE: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being discussed.

METHODS: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer's disease, vascular dementia and mixed dementia was performed. Moreover, nanotheranostics as possible imaging markers for such dementias were also reported.

RESULTS: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nanotherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer's disease targeting; thus, nanocarriers for other types of dementia should be developed.

CONCLUSION: To conclude, understanding the mechanism of neurodegeneration and reviewing the current drug delivery systems for Alzheimer's disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.

RevDate: 2021-04-15

Ghotbeddin Z, Tabandeh MR, Pourmahdi Borujeni M, et al (2021)

Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.

Brain and behavior, 11(4):e02078.

INTRODUCTION: Brain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia-inducible factor-1 (HIF-1). Crocin by anti-amyloidogenic property inhibits β-amyloid formation. However, the molecular mechanism associated with anti-amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF-1α and β-secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.

MATERIAL AND METHODS: Pregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1-H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT-PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF-1α genes in the brain tissues.

RESULTS: Animal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF-1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF-1α and BACE1 in the brains of neonate rat.

CONCLUSIONS: It was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.

RevDate: 2021-03-30

Yu E, Liao Z, Fan W, et al (2021)

The Economic Burden of Alzheimer's Disease in Zhejiang Province.

Journal of Alzheimer's disease : JAD, 80(2):539-553.

BACKGROUND: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province.

OBJECTIVE: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province.

METHODS: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity.

RESULTS: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province's GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity.

CONCLUSION: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.

RevDate: 2021-02-12

Ratto F, Franchini F, Musicco M, et al (2021)

A narrative review on the potential of tomato and lycopene for the prevention of Alzheimer's disease and other dementias.

Critical reviews in food science and nutrition [Epub ahead of print].

Oxidative stress is a major factor in aging and is implicated in the pathogenesis of tumors, diabetes mellitus, cardiovascular and neurodegenerative diseases, including Alzheimer Disease (AD). Bioactive constituents of tomato as polyphenols and carotenoids, among which lycopene (LYC) are effective in reducing markers of oxidative stress, and appear to have a protective modulator role on the pathogenetic mechanisms, cognitive symptoms and behavioral manifestations of these diseases in cell cultures and animal models. Epidemiological evidence indicates a consistent association between the intake of tomatoes and reduced cardiovascular and neoplastic risk. LYC deficiency is common in elders and AD patients and it is strongly predictive of mortality and poor cardiovascular (CV) outcomes. Dietary intake of tomatoes seems to be more effective than tomato/LYC supplementation. Limited evidence from human intervention trials suggests that increasing tomato intake, besides improving CV markers, enhances cognitive performances. In this narrative review, we analyze the existing evidence on the beneficial effects of tomatoes on AD-related processes or risk factors. Results support the development of promising nutritional strategies to increase the levels of tomato consumption for the prevention or treatment of AD and other dementias. Extensive well-structured research, however, is mandatory to confirm the neuroprotective effects of tomato/LYC in humans.

RevDate: 2021-02-14

Garad M, Edelmann E, V Leßmann (2021)

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques.

International journal of molecular sciences, 22(3):.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

RevDate: 2021-02-11

Saleem U, Akhtar R, Anwar F, et al (2021)

Neuroprotective potential of Malva neglecta is mediated via down-regulation of cholinesterase and modulation of oxidative stress markers.

Metabolic brain disease [Epub ahead of print].

Alzheimer's disease affects daily routine due to loss of memory and decline in cognition. In vitro data showed acetylcholine esterase inhibition activity of Malva neglecta but no in vivo evidence is available. The current study aims to investigate the anti-Alzheimer's activity of Malva neglecta methanolic extract in the AlCl3-induced Alzheimer disease rats' model. Thirty Wistar rats were divided into six groups and respective doses were given orally for 21 days. Behavioural observations were recorded and biochemical analysis was performed on brain homogenate. Improvement in memory and cognition was noted in treated rats as compared to disease control. A dose-dependent decrease (0.530 ± 0.009 at 200 mg/kg, 0.212 ± 0.007 at 400 mg/kg, 0.173 ± 0.005 at 600 mg/kg) in AChE activity was noted in the treatment groups with reference to disease control value (1.572 ± 0.013). This decrease in AChE activity is linked with an increase in acetylcholine in the brain which plays a key role in retaining memory. Oxidative stress biomarkers; GSH (66.77 ± 0.01 at 600 mg/kg), SOD (26.60 ± 0.10 at 600 mg/kg), CAT (21.46 ± 0.01 at 600 mg/kg) levels were increased with a decrease in MDA (103.33 ±0.49 at 600 mg/kg) level in a dose-dependently manner in the treatment groups as compared to disease control respective values. It is concluded that Malva neglecta could ameliorate Alzheimer's symptoms possibly by decreasing AChE activity and oxidative stress.

RevDate: 2021-04-02

Kawas CH, Legdeur N, MM Corrada (2021)

What have we learned from cognition in the oldest-old.

Current opinion in neurology, 34(2):258-265.

PURPOSE OF REVIEW: People over 90 are the fastest growing segment of the population with the highest rates of dementia. This review highlights recent findings that provide insight to our understanding of dementia and cognition at all ages.

RECENT FINDINGS: Risk factors for Alzheimer's disease (AD) and dementia differ by age, with some factors, like the development of hypertension, actually becoming protective in the oldest-old. At least half of all dementia in this age group is due to non AD pathologies, including microinfarcts, hippocampal sclerosis and TDP-43. The number of pathologic changes found in the brain is related to both risk and severity of dementia, but many people in this age group appear to be 'resilient' to these pathologies. Resilience to Alzheimer pathology, in part, may be related to absence of other pathologies, and imaging and spinal fluid biomarkers for AD have limited utility in this age group.

SUMMARY: Studies of dementia in the oldest-old are important for our understanding and eventual treatment or prevention of dementia at all ages.

RevDate: 2021-04-09

Vernerová A, Kujovská Krčmová L, Melichar B, et al (2021)

Non-invasive determination of uric acid in human saliva in the diagnosis of serious disorders.

Clinical chemistry and laboratory medicine, 59(5):797-812 pii:cclm-2020-1533.

This review summarizes and critically evaluates the published approaches and recent trends in sample pre-treatment, as well as both separation and non-separation techniques used for the determination of uric acid (UA) in saliva. UA is the final product of purine nucleotide catabolism in humans. UA concentrations in biological fluids such as serum, plasma, and urine represent an important biomarker of diseases including gout, hyperuricemia, or disorders associated with oxidative stress. Previous studies reported correlation between UA concentrations detected in saliva and in the blood. The interest in UA has been increasing during the past 20 years from a single publication in 2000 to 34 papers in 2019 according to MEDLINE search using term "uric acid in saliva". The evaluation of salivary UA levels can contribute to non-invasive diagnosis of many serious diseases. Increased salivary UA concentration is associated with cancer, HIV, gout, and hypertension. In contrast, low UA levels are associated with Alzheimer disease, progression of multiple sclerosis, and mild cognitive impairment.

RevDate: 2021-03-23

Donoso A, González-Durán J, Muñoz AA, et al (2021)

"Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials".

Pharmacological research, 166:105479.

Astaxanthin is a natural C40 carotenoid with numerous reported biological functions, most of them associated with its antioxidant and anti-inflammatory activity, standing out from other antioxidants as it has shown the highest oxygen radical absorbance capacity (ORAC), 100-500 times higher than ⍺-tocopherol and a 10 times higher free radical inhibitory activity than related antioxidants (α-tocopherol, α-carotene, β -carotene, lutein and lycopene). In vitro and in vivo studies have associated astaxanthin's unique molecular features with several health benefits, including neuroprotective, cardioprotective and antitumoral properties, suggesting its therapeutic potential for the prevention or co-treatment of dementia, Alzheimer, Parkinson, cardiovascular diseases and cancer. Benefits on skin and eye health promotion have also been reported, highlighting its potential for the prevention of skin photo-aging and the treatment of eye diseases like glaucoma, cataracts and uveitis. In this review, we summarize and discuss the currently available evidence on astaxanthin benefits, with a particular focus on human clinical trials, including a brief description of the potential mechanisms of action responsible for its biological activities.

RevDate: 2021-04-01

Domingues R, Pereira C, Cruz MT, et al (2021)

Therapies for Alzheimer's disease: a metabolic perspective.

Molecular genetics and metabolism, 132(3):162-172.

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. Currently, there are over 50 million cases of dementia worldwide and it is expected that it will reach 136 million by 2050. AD is described as a neurodegenerative disease that gradually compromises memory and learning capacity. Patients often exhibit brain glucose hypometabolism and are more susceptible to develop type 2 diabetes or insulin resistance in comparison with age-matched controls. This suggests that there is a link between both pathologies. Glucose metabolism and the tricarboxylic acid cycle are tightly related to mitochondrial performance and energy production. Impairment of both these pathways can evoke oxidative damage on mitochondria and key proteins linked to several hallmarks of AD. Glycation is also another type of post-translational modification often reported in AD, which might impair the function of proteins that participate in metabolic pathways thought to be involved in this illness. Despite needing further research, therapies based on insulin treatment, usage of anti-diabetes drugs or some form of dietary intervention, have shown to be promising therapeutic approaches for AD in its early stages of progression and will be unveiled in this paper.

RevDate: 2021-03-09
CmpDate: 2021-03-09

Thiyagalingam S, Kulinski AE, Thorsteinsdottir B, et al (2021)

Dysphagia in Older Adults.

Mayo Clinic proceedings, 96(2):488-497.

Dysphagia, which is a geriatric syndrome affecting 10% to 33% of older adults, is commonly seen in older adults who have experienced a stroke or neurodegenerative diseases such as Alzheimer or Parkinson disease. Patients diagnosed as having dysphagia can experience malnutrition, pneumonia, and dehydration. Patients can also experience increased rates of mortality and long-term care admission. Providers can identify the specific type of dysphagia for treatment in approximately 80% of patients by asking 5 questions in the patient's history: What happens when you try to swallow? Do you have trouble chewing? Do you have difficulty swallowing solids, liquids, or both? Describe the symptom onset, duration, and frequency? What are the associated symptoms? Providers can then request a videofluoroscopic swallow study or a fiberoptic endoscopic evaluation of swallowing for further evaluation of oropharyngeal dysphagia. If providers are diagnosing esophageal dysphagia, barium esophagraphy or esophagogastroduodenoscopy (EGD) can be used as part of the assessment. Patients can be treated for oropharyngeal dysphagia by using compensatory interventions, including behavioral changes, oral care, dietary modification, or rehabilitative interventions such as exercises and therapeutic oral trials. Providers often address treatment of esophageal dysphagia by managing the underlying etiology, which could include removal of caustic medications or using EGD as a therapeutic modality for esophageal rings. High-quality, large research studies are necessary to further manage the diagnosis and appropriate treatment of this growing geriatric syndrome.

RevDate: 2021-03-09
CmpDate: 2021-03-09

Hsiao SH, Hwang TJ, Lin FJ, et al (2021)

The Association Between the Use of Cholinesterase Inhibitors and Cardiovascular Events Among Older Patients With Alzheimer Disease.

Mayo Clinic proceedings, 96(2):350-362.

OBJECTIVE: To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD).

PATIENTS AND METHODS: This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005-2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs.

RESULTS: The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96).

CONCLUSION: The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.

RevDate: 2021-02-06

Živković L, Bajić V, Čabarkapa-Pirković A, et al (2021)

Strawberry (Fragaria ananassa duch.) Alba extract attenuates DNA damage in lymphocytes of patients with Alzheimer's disease.

Journal of food biochemistry [Epub ahead of print].

Increased levels of oxidative stress and oxidative DNA damage are common features in the pathology of Alzheimer's disease (AD) found in neurons and peripheral cells like peripheral blood lymphocytes (PBL). Natural products such as strawberry cultivar Alba are an important source of bioactive nutrients that could help in lowering both the oxidative stress and DNA damage levels. The objective was to estimate the effects of Alba extract on DNA damage in peripheral blood lymphocytes of sporadic AD (aged 60-84 years) patients, and healthy elderly (aged 69-83 years) and young (aged 21-30 years) individuals in in vitro conditions. Comet assay was used as a sensitive technique for the evaluation of PBL DNA damage levels. Reduction of basal DNA damage level in PBL was shown in the young group after the incubation with Alba extract ranging from 25 to 200 μg/ml, with 100 μg/ml being the most effective concentration. Selected Alba extract of 100 μg/ml was further used for PBL treatment of AD and healthy elderly age matched group, displaying potential to significantly attenuate DNA damage levels in both groups (p < .05). Alba extract displayed biological activity against oxidative DNA damage, suggesting that its functional ingredients may have beneficial health effects. PRACTICAL APPLICATIONS: The data obtained in this preliminary study displayed that strawberry Alba extract is efficient against DNA damage induced by endogenous and exogenous oxidative stress in peripheral blood lymphocytes of Alzheimer`s disease in vitro. An active area of future research of Alba cultivar should be to determine the trials in in vivo systems. Our findings also suggest that Alba cultivar's functional ingredients potentially may have beneficial health effects in AD.

RevDate: 2021-02-06

Salobrar-García E, López-Cuenca I, Sánchez-Puebla L, et al (2020)

Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F .

Frontiers in aging neuroscience, 12:625642.

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.

RevDate: 2021-03-16

Fragoso-Morales LG, Correa-Basurto J, MC Rosales-Hernández (2021)

Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer's Disease Murine Models.

Antioxidants (Basel, Switzerland), 10(2):.

Alzheimer's disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.

RevDate: 2021-02-06

Pereira AKDS, Santos IA, da Silva WW, et al (2021)

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?.

Pharmacological reports : PR [Epub ahead of print].

BACKGROUND: Chikungunya fever is an endemic disease caused by the Chikungunya virus (CHIKV) to which there is no vaccine or effective antiviral drug treatment so far. Our study aimed to evaluate the potential anti-CHIKV activity of memantine hydrochloride (mtnH), a drug from the class of the aminoadamantanes approved for the treatment of Alzheimer´s disease, as a possible drug to be repurposed to the treatment of Chikungunya fever.

METHODS: MtnH antiviral activity against CHIKV was determined by infecting BHK-21 cells with CHIKV-nanoluc, a virus carrying the marker nanoluciferase reporter, in the presence or absence of mtnH at concentrations ranging from 500 to 1.45 µM. The effective concentration of 50% inhibition (EC50) was calculated. Cell viability assay (determination of CC50) was also performed employing BHK-21 cells. Mutagenic assays were performed by the Salmonella Typhimurium/microsome assay (Ames test).

RESULTS: MtnH presented a CC50 of 248.4 ± 31.9 µM and an EC50 of 32.4 ± 4 µM against CHIKV in vitro. The calculated selectivity index (SI) was 7.67. MtnH did not induce genetic mutation in Salmonella strains with or without an external metabolizing system.

CONCLUSION: With the data herein presented, it is possible to hypothesize mtnH as a viable candidate to be repurposed as an anti-CHIKV drug. Clinical assays are, therefore, encouraged due to the promising in vitro results. The drug memantine hydrochloride is herein personified with a doubt: as a prior regulated drug against Alzheimer, could it follow the path against Chikungunya virus too?

RevDate: 2021-02-10

Munir R, Zia-Ur-Rehman M, Murtaza S, et al (2021)

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach.

Molecules (Basel, Switzerland), 26(3):.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

RevDate: 2021-02-02
CmpDate: 2021-02-02

Arsenault-Lapierre G, Godard-Sebillotte C, Sourial N, et al (2020)


Sante publique (Vandoeuvre-les-Nancy, France), 32(4):375-380.

Many countries have answered the call from the World Health Organization, and developed or implemented Alzheimer Plans. Some plans anchored the majority of the care for persons living with dementia in specialized care settings, while others anchored it in primary care. In this article we present the Quebec Alzheimer Plan, which is being implemented in Family Medicine Groups, primary care interdisciplinary clinics, across the Canadian province. The Quebec Alzheimer Plan aims to enable primary healthcare teams of physicians, nurses and/or social workers to provide access to personalized, coordinated assessment and treatment services for people living with dementia and their caregivers. The Quebec Alzheimer Plan enables and empowers primary care clinicians to detect, diagnose, treat and follow-up the vast majority of patients/caregivers. A major strength of the Quebec Alzheimer Plan strategy is the embedded evaluation to inform implementation and its flexibility to allow local adaptations. We are discussing that it is feasible and advantageous to anchor dementia care in an interprofessional primary care setting.

RevDate: 2021-02-28

Lin CH, Chiu CC, HY Lane (2021)

Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease.

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 19(1):135-144.

Objective: Melatonin has been considered to have an essential role in the pathophysiology of Alzheimer's disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn't show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits.

Methods: We enrolled 270 elder individuals (consisting four groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment.

Results: In the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort.

Conclusion: This study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.

RevDate: 2021-04-13

Yuan Q, Lin ZX, Wu W, et al (2020)

Huperzine A in treatment of amyloid-β-associated neuropathology in a mouse model of Alzheimer disease: abridged secondary publication.

Hong Kong medical journal = Xianggang yi xue za zhi, 26 Suppl 8(6):34-37.

RevDate: 2021-01-27

Rezaei Rad F, Ghahvechi Akbari M, Zamani M, et al (2021)

Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer's Disease.

Molecular neurobiology [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I β chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.

RevDate: 2021-03-11

Bektašević M, Politeo O, I Carev (2021)

Comparative Study of Chemical Composition, Cholinesterase Inhibition and Antioxidant Potential of Mentha pulegium L. Essential Oil.

Chemistry & biodiversity, 18(3):e2000935.

Perennial plant Mentha pulegium L. (pennyroyal, Lamiaceae) can be found in Europe and Mediterranean. In areas where it thrives, M. pulegium is used in nutrition and as medicinal plant. Essential oil of M. pulegium is also a frequent constituent of foods and fragrances, because of mint-like odor. Regarding the use of M. pulegium in traditional medicine and nutrition, as well as fact that essential oils are potential sources of bioactive components, this study was conducted to examine the chemical composition of essential oil of M. pulegium wild growing in Bosnia and Herzegovina and its biological activity. The chemical profile testing was made using GC/MS and GC/FID technique. Potential of cholinesterase inhibition was tested by Ellman's assay. The antioxidant activity was tested by DPPH and FRAP assay. The dominant components in analyzed oil were pulegone 54.4 %, p-menthone 14.0 % and piperitenone 12.8 %. Good antioxidant activity and moderate cholinesterase inhibition potential of tested essential oil indicates to possibility of its use in treatment of diseases related to free radicals, Alzheimer disease and as lipid protecting antioxidant.

RevDate: 2021-01-27

Anonymous (2021)

Clinical Consensus Statement: Association of Anticholinergic Medication Use and Cognition in Women With Overactive Bladder.

Female pelvic medicine & reconstructive surgery, 27(2):69-71.

ABSTRACT: Overactive bladder affects a significant portion of the overall population and has substantial impact on daily activities and quality of life. First-line treatment of overactive bladder includes behavioral therapies, which may be combined with pharmacologic management as indicated. Anticholinergic medications and β-3 agonists are often used as initial pharmacologic therapy, but caution should be taken in prescribing anticholinergic medications in frail or cognitively impaired patients. Recently, additional concerns have emerged regarding prolonged use of anticholinergic medications and the associated risk of cognitive impairment, dementia, and Alzheimer disease in the general population. Given the available evidence, which has shown significant associations between anticholinergic medication use and increased risk of cognitive impairment and dementia, providers should counsel on the associated risks, prescribe the lowest effective dose, and consider alternative medications in patients at risk.

RevDate: 2021-04-11

Joseph-Mathurin N, Wang G, Kantarci K, et al (2021)

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

Neurology, 96(12):e1632-e1645.

OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).

CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.

RevDate: 2021-01-26

Saha S, Pal D, SB Nimse (2021)

Recent Advances in the Discovery of GSK-3 Inhibitors from Synthetic Origin in the Treatment of Neurological Disorders.

Current drug targets pii:CDT-EPUB-113483 [Epub ahead of print].

BACKGROUND: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase enzyme which controlled the neuronal functions such as neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. The enzyme has two subunits as GSK-3α and GSK-3β. 4ACC, 1Q3D, 3AFG, 1UV5, 1Q5K are the important GSK-3 receptors isolated from Homo sapiens and Mus musculus. This enzyme mainly phosphorylates Tau protein with increased amount in neuronal fibres altogether with beta-amyloid plaques cause neuronal defects like Alzheimer, Parkinson's and many more.

OBJECTIVE: We investigated the developments of various synthetic GSK-3 inhibitors responsible for the prevention and treatment of neurological disorders like Alzheimer disease, bipolar disorders, antidepressant, neuroprotective etc. Results and Conclusion: It was observed that structures of the GSK-3 inhibitors comprised of benzopyridine, benzthiazole, pyrazole, pyrazine, dioxolo-benzoxazin, oxadiazole, benzimidazole in the skeletal with cyclopropylamide, phenyl carbamothioate, 3-[(propan-2-yl)oxy]propan-1-amine in side chain. The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin dependent kinase, and phosphodiesterase-4 along with tail suspension test, forced swim test, percent neuronal survival and other cognitive behaviour. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson's depression, psychosis and other forms of neurological disorders.

RevDate: 2021-01-27

Ross SM (2021)

Coconut Oil: Effects of Medium-Chain Triglycerides for Prevention and Treatment of Alzheimer Disease.

Holistic nursing practice, 35(1):49-50.

RevDate: 2021-01-26

Kikuchi H, Harata K, Madhyastha H, et al (2021)

Ellagic acid and its fermentative derivative urolithin A show reverse effects on the gp91-phox gene expression, resulting in opposite alterations in all-trans retinoic acid-induced superoxide generating activity of U937 cells.

Biochemistry and biophysics reports, 25:100891.

Ellagitannins (esters composed of glucose and ellagic acid) are hydrolyzed to generate ellagic acid in gut followed by conversion of ellagic acid to urolithins such as urolithin A by intestinal bacteria. Since urolithins are absorbed by gut easier than ellagitannins and ellagic acid, and show various physiological activities (e.g. anti-cancer, anti-cardiovascular disease, anti-diabetes mellitus, anti-obesity and anti-Alzheimer disease activities), they are expected as excellent health-promoting phytochemicals. Here, using human monoblast U937 cells, we investigated the effect of ellagic acid and urolithin A on the superoxide anion (O2-)-generating system of phagocytes, which is consisted of five specific protein factors (membrane proteins: p22-phox and gp91-phox, cytosolic proteins: p40-phox, p47-phox and p67-phox). Twenty micromolar of urolithin A enhanced the all-trans retinoic acid (ATRA)-induced O2--generating activity (to ~175%) while 20 μM ellagic acid inhibited the ATRA-induced O2--generating activity (to ~70%). Semiquantitative RT-PCR showed that transcription level of gp91-phox was certainly decreased (to ~70%) in ATRA plus ellagic acid-treated cells, while that of gp91-phox was significantly increased (to ~160%) in ATRA plus urolithin A-treated cells. Chromatin immunoprecipitation assay suggested that urolithin A enhanced acetylations of Lys-9 residues of histone H3 within chromatin surrounding the promoter region of gp91-phox gene, but ellagic acid suppressed the acetylations. Immunoblotting also revealed that ATRA plus urolithin A-treatment up-regulated protein levels of p22-phox (to ~160%) and gp91-phox (to ~170%) although ATRA plus ellagic acid-treatment down-regulated protein levels of p22-phox (to ~70%) and gp91-phox (to ~60%). These results suggested that conversion of ellagic acid to urolithin A in gut may bring about reverse effects on the gp91-phox gene expression, resulting in opposite alterations in O2--generating activity of intestinal macrophages.

RevDate: 2021-02-18

Turkez H, Cacciatore I, Marinelli L, et al (2021)

Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.

Biomolecules, 11(1):.

So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.

RevDate: 2021-01-26

Nieraad H, de Bruin N, Arne O, et al (2021)

Effects of Alzheimer-Like Pathology on Homocysteine and Homocysteic Acid Levels-An Exploratory In Vivo Kinetic Study.

International journal of molecular sciences, 22(2):.

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer's disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.

RevDate: 2021-03-15

Mani S, Swargiary G, R Chadha (2021)

Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.

Mitochondrion, 57:270-293.

Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.

RevDate: 2021-01-22

Nagy EN, Ali AY, Behiry ME, et al (2021)

Impact of Combined Photo-Biomodulation and Aerobic Exercise on Cognitive Function and Quality-of-Life in Elderly Alzheimer Patients with Anemia: A Randomized Clinical Trial.

International journal of general medicine, 14:141-152.

Purpose: Few data are available on the positive impact of photo-biomodulation (PBM) using low-level laser therapy as a complementary treatment for improving the cognitive function and optimizing the hemoglobin (Hb) level and oxygen carrying capacity in anemic elderly patients and consequently improving the quality-of-life. The present study aimed to evaluate a new, safe, and easy therapeutic approach to improve Alzheimer's disease-related symptoms that interfere with the whole life activities and social interaction of elderly patients.

Patients and Methods: In this placebo-controlled clinical trial, 60 elderly patients suffering from anemia and mild cognitive dysfunction were randomly assigned into two equal groups to receive active or placebo low-level laser in addition to a moderate-intensity aerobic exercise over a 12-week period. Hb level as well as cognitive and functional tests were reassessed for any change after 12 weeks of intervention.

Results: By the end of this study, both groups showed significant improvements in Hb level, Montreal Cognitive Assessment Scale (MoCa - B basic), Quality-of-Life for Alzheimer's Disease scale, and Berg Balance scale scores along with significant reduction in body mass index (BMI) and waist-hip ratio (WHR) (P<0.0001). The experimental group which received active low-level laser in addition to moderate-intensity aerobic exercise showed more significant results compared to the control group which received placebo low-level laser in addition to moderate-intensity aerobic exercise in all the measured outcomes (P<0.001).

Conclusion: Combined low-level laser therapy and moderate-intensity aerobic exercises are more effective in improving the cognitive function and quality-of-life of Alzheimer's disease patients.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04496778.

RevDate: 2021-03-09
CmpDate: 2021-01-29

Guan X, Zhang L, Li X, et al (2021)

Effectiveness comparisons of acupuncture treatments for vascular dementia: A protocol for systematic review and network meta-analysis.

Medicine, 100(2):e24079.

BACKGROUND: Vascular dementia (VD) is the second most common form of dementia in the world. Acupuncture therapy has been widely used in clinical treatment. Based on the available evidence, we will rank different acupuncture therapy to determine the most effective acupuncture therapy.

METHODS: We will search the following database, including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database and Chinese Scientific Journals Database database, in order to collect randomized controlled trials on acupuncture in the treatment of VD. We will use Stata 14.2 and WinBUGS 1.4.3 software for Bayesian network meta-analysis and finally evaluated the level of evidence of the results.

RESULTS: This study will compare and rank the effectiveness of acupuncture in the treatment of vascular dementia. Outcome indicators included Alzheimer Disease Assessment Scale-Cognitive section and Mini-mental State Examination, Activity of Daily Living, Blessed dementia scale, Hastgawa Dementia Scale, and adverse events.

CONCLUSION: Our study will provide support for clinical practice.


RevDate: 2021-03-12

Sperling R, Henley D, Aisen PS, et al (2021)

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

JAMA neurology, 78(3):293-301.

Importance: Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).

Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.

Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment.

Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185).

Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study.

Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups.

Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.

Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

RevDate: 2021-03-31

Liss JL, Seleri Assunção S, Cummings J, et al (2021)

Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

Journal of internal medicine [Epub ahead of print].

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

RevDate: 2021-01-15

Tabrizian K, Amelinia F, Belaran M, et al (2021)

Tadalafil Reversed H-89 - and Scopolamine - Induced Spatial Learning Impairments in Male Rats.

Drug research [Epub ahead of print].

Accumulated evidence shows that the cAMP and cGMP signaling pathway plays an important role in memory function and neuronal plasticity. Phosphodiesterase 5 (PDE5) is a hopeful therapeutic target in AD (Alzheimer disease), and PDE5 inhibition may be a good therapeutic strategy for the treatment of AD. In the present study, the four-day bilateral intra-hippocampal infusion of H-89 as a protein kinase AII inhibitor (10 µM/side) and intra-peritoneal injections of tadalafil (20 mg/kg) and scopolamine (0.5 mg/kg) alone and also on combination on spatial learning in Morris water maze (MWM) were investigated. DMSO and saline were used as controls for H-89 and other mentioned drugs, respectively. Rats were trained for 4 days; each day included one block of four trials. Post- training probe trial tests were performed on day 5. Administration of H-89 and scopolamine led to a significant impairment in spatial learning compared to their related controls. But, combination of tadalafil/H-89 or tadalafil/scopolamine reversed H-89 or scopolamine- induced spatial learning deficits in MWM. Taken together, these results showed the probable regulatory effects of cGMP on cholinergic and cAMP/PKA signaling pathways in co-administrations of these mentioned drugs on spatial learning in MWM.

RevDate: 2021-02-16
CmpDate: 2021-02-16

Wang C, Zhang M, Garcia G, et al (2021)

ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.

Cell stem cell, 28(2):331-342.e5.

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

RevDate: 2021-01-25

Hashimoto Y, Kusakari S, Nawa M, et al (2021)

Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.

Translational psychiatry, 11(1):44.

Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer's disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE9 double transgenic mice (APP/PS1 mice). Despite the anticipated role of CLSP as an AD-suppressing factor, it remains unanswered whether the insufficiency of the CLSP activity is linked to the AD pathogenesis. In this study, we first show that adiponectin, a CLSP potentiator/protector, dominantly determines the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin. We next show that both the levels of brain adiponectin and the intraneuronal levels of SH3BP5, an important effector of the CLSP signal, are reduced in both AD patients and APP/PS1 mice. Finally, the restoration of the CLSP activity by subcutaneous injection of a hybrid peptide named CLSPCOL consisting of CLSP(1-61) and the collagen-homologous region of adiponectin, which has more potent neuroprotective activity than CLSP, is insensitive to the suppression by the CLSP inhibitors, and is efficiently recruited into brains, alleviates dementia and synaptic loss in the aged APP/PS1 mice. Collectively, these results suggest that the reduction in the CLSP activity, likely caused by the reduction in the levels of adiponectin, leads to the insufficient protection of neurons from neurotoxicity in the AD brains and the restoration of the CLSP activity is a promising strategy for the treatment of AD.

RevDate: 2021-01-14

Yao X, Sun C, Fan B, et al (2021)

Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines.

Journal of orthopaedic translation, 26:74-83.

Background/objective: Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI.

Method: NTP was intraperitoneally administered to adult female Wistar rats subjected to contusion-induced SCI. Functional recovery was evaluated with behavioural scores and electrophysiological examinations. Tissue recovery was assessed with magnetic resonance imaging as well as histological staining with haematoxylin and eosin and Luxol Fast Blue. Neuronal survival and gliosis were observed after NeuN and glial fibrillary acidic protein immunofluorescence. Levels of apoptosis were demonstrated with TdT-mediated dUTP nick-end labeling (TUNEL) staining, Caspase-3 and B-cell lymphoma-2 (Bcl-2) Western blot, and Annexin V/propidium iodide flow cytometry. A protein antibody chip analysis was performed to evaluate the expression levels of 67 rat cytokines.

Results: NTP treatment improved the hindlimb locomotor recovery of the injured animals as well as their electrophysiological outcomes after SCI. A dosage of 50 NTP units/kg was found to optimize the efficacy of NTP. Magnetic resonance imaging revealed that lesion sizes decreased after NTP treatment. The haematoxylin and eosin and Luxol Fast Blue staining showed significant increases in the amount of spared tissue. The NeuN and glial fibrillary acidic protein immunofluorescence revealed that NTP treatment increased neuronal survival and reduced gliosis in tissue samples obtained from the lesion's epicentre. That NTP inhibited apoptosis was confirmed by the decreased number of TUNEL-positive cells, level of Caspase-3 expression, and number of Annexin V/propidium iodide-positive cells, as well as the increased level of Bcl-2 expression. The protein array analysis identified 28 differentially expressed proteins in the NTP group, and the gene ontology (GO) analysis showed that the enriched differentially expressed proteins implicate janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathways. The expression levels of proinflammatory cytokines such as interleukin 6, thymus chemokine-1(TCK-1), and lipopolysaccharide-induced CXC chemokine (LIX) decreased after NTP treatment, whereas the levels of prorepair cytokine hepatocyte growth factor and adiponectin increased.

Conclusion: Our research provides evidence that NTP can improve functional outcomes and alleviate secondary injury after SCI by inhibiting apoptosis and modulating cytokines.

The multicomponent NTP might have broad target spectra in SCI pathophysiology and halt the secondary injury cascade. As a safe drug that features sixty years of clinical use as an analgesic, translating this demonstrated efficacy of NTP to addressing SCI in human patients may potentially be accelerated.

RevDate: 2021-04-09

Moscoso A, Grothe MJ, Ashton NJ, et al (2021)

Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease.

JAMA neurology, 78(4):396-406.

Importance: Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear.

Objective: To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury.

This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol.

Exposures: Plasma p-tau181 and NfL measured with single-molecule array technology.

Main Outcomes and Measures: Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020.

Results: Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = -0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = -0.05, P = .48; CImp: r = -0.27, P < .001) and gray matter volume (CU: r = -0.19, P < .001; CImp: r = -0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β-positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β-negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures.

Conclusions and Relevance: Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.

RevDate: 2021-01-09

Jalili-Baleh L, Nadri H, Forootanfar H, et al (2021)

Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities.

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences [Epub ahead of print].

PURPOSE: Alzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.

METHODS: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.

RESULTS: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.

CONCLUSION: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.

RevDate: 2021-02-25

Tan MS, Yang YX, Xu W, et al (2021)

Associations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.

Alzheimer's research & therapy, 13(1):15.

BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration.

METHODS: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model.

RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process.

CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

RevDate: 2021-01-27

Moussavi Z, Rutherford G, Lithgow B, et al (2021)

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

JMIR research protocols, 10(1):e25144.

BACKGROUND: Alzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia.

OBJECTIVE: The objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment.

METHODS: We have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention.

RESULTS: As of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect.

CONCLUSIONS: This protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.


RevDate: 2021-01-27

Herr M, Ankri J, Diard C, et al (2021)

Removal of Drugs for Alzheimer's Disease from the List of Reimbursable Drugs in France: Analysis of Change in Drug Use, Disease Management and Cognition Using the National Alzheimer Data Bank (BNA).

Drugs & aging, 38(1):63-74.

BACKGROUND: Because of insufficient data about their benefit-risk ratio in real life, drugs used for Alzheimer's disease (AD; cholinesterase inhibitors and memantine) were withdrawn from the list of reimbursable drugs in France on 1 August 2018.

OBJECTIVES: In this context, this study aimed to investigate the effects of the removal of AD drugs from the list of reimbursed drugs among patients followed in memory centres in France, in terms of prevalence and factors associated with drug discontinuation and evolution of disease management and cognition after drug discontinuation.

METHODS: This is an observational study based on data from the National Alzheimer Data Bank ('Banque Nationale Alzheimer' [BNA]), which centralizes information about patients consulting in memory centres. The drug discontinuation rate was estimated among patients receiving AD drugs at the last visit before the end of reimbursement. Factors associated with drug discontinuation were investigated among sociodemographic and disease characteristics, as well as among the use of healthcare resources before the end of reimbursement. We compared the evolution of disease management (psychotropic drugs and non-pharmacological interventions) and Mini-Mental State Examination (MMSE) score during the year following the end of reimbursement among patients with a diagnosis of AD.

RESULTS: Among the 19,380 patients of the study sample (62.5% females, mean age 81 years, 86.8% with a diagnosis of AD), 19.5% discontinued their treatment after the end of reimbursement. The main factors associated with drug discontinuation were the type of dementia and lower MMSE level. Compared with patients with a diagnosis of AD, those with vascular dementia were more likely to stop their treatment, whereas those with dementia with Lewy bodies were less likely to discontinue. Among patients with a diagnosis of AD, drug discontinuation was associated with increased use of psychotropic medications, especially antidepressants, and non-pharmacological interventions afterwards, but there was no difference regarding the evolution of MMSE score.

CONCLUSION: This study provides real-life information about the use of AD drugs after they were withdrawn from reimbursement in France and shows that drug discontinuation was limited among patients followed in memory centres and accompanied by increased use of other healthcare resources.

RevDate: 2021-01-19

Wani A, Al Rihani SB, Sharma A, et al (2021)

Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.

Autophagy [Epub ahead of print].

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.

RevDate: 2021-01-06

Taudte N, Linnert M, Rahfeld JU, et al (2021)

Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis.

The Journal of biological chemistry pii:RA120.016836 [Epub ahead of print].

The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.

RevDate: 2021-04-09

Jonathan MC, Adrián SH, A Gonzalo (2021)

Type II nuclear receptors with potential role in Alzheimer disease.

Molecular aspects of medicine, 78:100940.

Nuclear receptors are ligand-activated transcription factors that can modulated cellular processes involved in the development, homeostasis, cell proliferation, metabolism, and reproduction through the control of the specific genetic and molecular program. In the central nervous system, they are key regulators of neural stem cell fate decisions and can modulate the physiology of different brain cells. Over the past decades, a large body of evidence has supported that nuclear receptors are potential therapeutic targets for the treatment of neurodegenerative disorders such as Alzheimer's disease, the most common dementia worldwide, and the main cause of disability in later life. This disease is characterized by the progressive accumulation of amyloid-beta peptides and hyperphosphorylated tau protein that can explain alterations in synaptic transmission and plasticity; loss of dendritic spines; increased in reactive microglia and inflammation; reduction of neuronal stem cells number; myelin and vascular alterations that finally leads to increased neuronal death. Here, we present a review of type II no steroidal nuclear receptors that form obligatory heterodimers with the Retinoid X Receptor (RXR) and its potential in the therapeutic of AD. Activation of type II nuclear receptor by synthetic agonist leads to transcriptional regulation of specific genes that acts counteracting against the detrimental effects of amyloid-beta peptides and hyperphosphorylated tau in neuronal cells recovering the functionality of the synapses. But also, activation of type II nuclear receptor leads to modifications in APP metabolism, repression of inflammatory cascade and inductors of the generation of neuronal stem cells and progenitor cells supporting its potential therapeutics role for Alzheimer's disease.

RevDate: 2021-01-12

Fernández-Fierro A, Funes SC, Rios M, et al (2020)

Immune Modulation by Inhibitors of the HO System.

International journal of molecular sciences, 22(1):.

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

RevDate: 2021-01-05

Zhou Y, Chen Y, Xu C, et al (2020)

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment.

Frontiers in neuroscience, 14:602508.

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)-a key component of the innate immune system-in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.

RevDate: 2021-03-21

Taleski G, Schuhmacher D, Su H, et al (2020)

Disturbances in PP2A methylation and one-carbon metabolism compromise Fyn distribution, neuritogenesis and APP regulation.

The Journal of biological chemistry [Epub ahead of print].

The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylation are implicated in cancer and Alzheimer disease (AD). Here, we tested the hypothesis that the methylation state of PP2A catalytic subunit, which influences PP2A subunit composition and substrate specificity, can affect Fyn regulation and function. Using N2a neuroblastoma cell models, we first show that methylated PP2A holoenzymes containing the Bα subunit co-immunoprecipitate and co-purify with Fyn in membrane rafts. PP2A methylation status regulates Fyn distribution and Fyn-dependent neuritogenesis, likely in part by affecting actin dynamics. A methylation incompetent PP2A mutant fails to interact with Fyn. It perturbs the normal partitioning of Fyn and amyloid precursor protein (APP) in membrane microdomains, which governs Fyn function and APP processing. This correlates with enhanced amyloidogenic cleavage of APP, a hallmark of AD pathogenesis. Conversely, enhanced PP2A methylation promotes the nonamyloidogenic cleavage of APP in a Fyn-dependent manner. Disturbances in one-carbon metabolic pathways that control cellular methylation are associated with AD and cancer. Notably, they induce a parallel loss of membrane-associated methylated PP2A and Fyn enzymes in N2a cells and acute mouse brain slices. One-carbon metabolism also modulates Fyn-dependent process outgrowth in N2a cells. Thus, our findings identify a novel methylation dependent PP2A/Fyn signaling module. They highlight the underestimated importance of crosstalks between essential metabolic pathways and signaling scaffolds that are involved in normal cell homeostasis and currently being targeted for cancer and AD treatment.

RevDate: 2020-12-29

Yang H, Han W, H Li (2020)

Efficacy and safety of MAO-B inhibitor versus donepezil in Chinese elderly stroke patients with Alzheimer disease: A potential therapeutic option.

Pakistan journal of pharmaceutical sciences, 33(3(Special)):1349-1354.

This pilot study designed to evaluate the efficacy and safety of MAO-B inhibitor in comparison with Donepezil (DNP) in elderly Chinese patients with Alzheimer disease (AD). In the present clinical trial, Chinese elderly patients aged ≥65 years with a confirmed diagnosis of AD were enrolled. The patients received MAO-B inhibitor (Selegiline 5 mg) or DNP 10 mg daily (reference) for 6 months. The efficacy and safety data were collected from 120 patients (60 patients in each group) every 3 weeks until 6 months. The primary endpoints were to assess the change in cognitive score from baseline in both the treatment group. The result of the present study showed that the patients treated with MAO-B inhibitor and DNP have similar efficacy and safety profile Considering the clinical benefit, mean (SD) improvement in sign and symptoms was numerically greater in DNP-treated patients as compared to MAO-B inhibitor at endpoint visit (SIB: 12.3 (3.7) vs 11.3 (4.2); AD severity: 14.2 (3.5); CIBIS+/CIBIC: 10.2 (2.7) vs 9.4 (3.2); ADCS-ADL: 14.3 (4.2) vs 13.2 (3.4); MMSE: 14.3 (3.7) vs 12.2 (3.2), P>0.05 respectively for each comparison). However, a statistical difference in terms of clinical benefit was similar between both the treatment groups (p>0.05). Overall, both the study drugs were found comparable in relieving the symptoms of AD (severity score after end of treatment: 14.2 vs 13.4 respectively; p >0.05). This indicates that MAO-B inhibitor is a potential target for the treatment of AD in China. The results of the present study may help to design a large clinical trial to evaluate the efficacy and safety of MAO-B inhibitor in comparison with DNP in AD patients.


RJR Experience and Expertise


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


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


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


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


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


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


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


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

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

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