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30 Mar 2023 at 01:35
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Bibliography on: Alzheimer Disease — Treatment


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RJR: Recommended Bibliography 30 Mar 2023 at 01:35 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: 2023-03-29

Knight E, Geetha T, Broderick TL, et al (2023)

The Role of Dietary Antioxidants and Their Potential Mechanisms in Alzheimer's Disease Treatment.

Metabolites, 13(3): pii:metabo13030438.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and characterized by amyloid-β plaques and neurofibrillary tau tangles. Although AD's exact pathophysiology remains unclear, oxidative stress is known to play a role in the neurodegenerative process. Since no curative treatment exists, antioxidants represent a potential treatment for AD due to their ability to modulate oxidative stress. Therefore, this review aims to examine the impact of antioxidant supplementation and its potential mechanisms on cognitive function. The review primarily discusses research articles published between 2012 and 2022 reporting the results of clinical trials involving antioxidant supplementation on cognitive function in individuals with AD. Antioxidant supplementation included probiotics, selenium, melatonin, resveratrol, rosmarinic acid, carotenoids, curcumin, vitamin E, and coenzyme Q. While the studies included in this review did not provide much evidence for the beneficial role of antioxidant supplements on cognitive function in AD, the results varied from antioxidant to antioxidant and among trials examining the same antioxidant. Furthermore, many of the studies' findings face several limitations, including short trial durations, small sample sizes, and a lack of diversity among study participants. As a result, more research is required to examine the impact of antioxidant supplementation on cognitive function in AD.

RevDate: 2023-03-29

Numakawa T, R Kajihara (2023)

Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer's Disease.

Life (Basel, Switzerland), 13(3): pii:life13030647.

The involvement of the changed expression/function of neurotrophic factors in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), has been suggested. AD is one of the age-related dementias, and is characterized by cognitive impairment with decreased memory function. Developing evidence demonstrates that decreased cell survival, synaptic dysfunction, and reduced neurogenesis are involved in the pathogenesis of AD. On the other hand, it is well known that neurotrophic factors, especially brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB, have multiple roles in the central nervous system (CNS), including neuronal maintenance, synaptic plasticity, and neurogenesis, which are closely linked to learning and memory function. Thus, many investigations regarding therapeutic approaches to AD, and/or the screening of novel drug candidates for its treatment, focus on upregulation of the BDNF/TrkB system. Furthermore, current studies also demonstrate that GDNF, IGF1, and bFGF, which play roles in neuroprotection, are associated with AD. In this review, we introduce data demonstrating close relationships between the pathogenesis of AD, neurotrophic factors, and drug candidates, including natural compounds that upregulate the BDNF-mediated neurotrophic system.

RevDate: 2023-03-29

Wang C, Zou Q, Pu Y, et al (2023)

Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.

International journal of molecular sciences, 24(6): pii:ijms24065896.

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1-Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

RevDate: 2023-03-29

Li H, Huynh TN, Duong MT, et al (2023)

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia.

International journal of molecular sciences, 24(6): pii:ijms24065616.

Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and cholesterol loading. However, the mediators involved in transmitting the effects of A1B in immune cells is unknown. Microglial Acat1/Soat1 expression is elevated in many neurodegenerative diseases and in acute neuroinflammation. We evaluated LPS-induced neuroinflammation experiments in control vs. myeloid-specific Acat1/Soat1 knockout mice. We also evaluated LPS-induced neuroinflammation in microglial N9 cells with and without pre-treatment with K-604, a selective ACAT1 inhibitor. Biochemical and microscopy assays were used to monitor the fate of Toll-Like Receptor 4 (TLR4), the receptor at the plasma membrane and the endosomal membrane that mediates pro-inflammatory signaling cascades. In the hippocampus and cortex, results revealed that Acat1/Soat1 inactivation in myeloid cell lineage markedly attenuated LPS-induced activation of pro-inflammatory response genes. Studies in microglial N9 cells showed that pre-incubation with K-604 significantly reduced the LPS-induced pro-inflammatory responses. Further studies showed that K-604 decreased the total TLR4 protein content by increasing TLR4 endocytosis, thus enhancing the trafficking of TLR4 to the lysosomes for degradation. We concluded that A1B alters the intracellular fate of TLR4 and suppresses its pro-inflammatory signaling cascade in response to LPS.

RevDate: 2023-03-29

Fei Z, Pei R, Pan B, et al (2023)

Antibody Assay and Anti-Inflammatory Function Evaluation of Therapeutic Potential of Different Intravenous Immunoglobulins for Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065549.

Alzheimer's disease (AD) is a common neurodegenerative disease that currently has no known cure. Intravenous immunoglobulin (IVIG), which contains AD-related antibodies and has anti-inflammatory properties, has shown potential as a treatment for AD. However, the efficacy of clinical trials involving AD patients treated with IVIG has been inconsistent. Our previous study found that different IVIGs had significantly varied therapeutic effects on 3xTg-AD mice. In order to investigate the relationship between the composition and function of IVIG and its efficacy in treating AD, we selected three IVIGs that showed notable differences in therapeutic effects. Then, the concentrations of specific antibodies against β-amyloid (Aβ)42, tau, and hyperphosphorylated tau (p-tau) in three IVIGs, as well as their effects on systemic inflammation induced by lipopolysaccharide (LPS) in Balb/c mice, were analyzed and compared in this study. The results indicated that these IVIGs differed greatly in anti-Aβ42/tau antibody concentration and anti-p-tau ratio, and improved LPS-stimulated peripheral inflammation, liver and kidney injury, and neuroinflammation in Balb/c mice to varying degrees. Combined with our previous results, the efficacy of IVIG against AD may be positively correlated with its level of AD-related antibodies and anti-inflammatory ability. AD-related antibody analysis and functional evaluation of IVIG should be given sufficient attention before clinical trials, as this may greatly affect the therapeutic effect of AD treatment.

RevDate: 2023-03-29

Penke B, Szűcs M, F Bogár (2023)

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer's Disease.

International journal of molecular sciences, 24(6): pii:ijms24065383.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60-80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research.

RevDate: 2023-03-29

Tautou M, Descamps F, Larchanché PE, et al (2023)

A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP[Swe]/PSEN1[ΔE9] Mice Model of Amyloid Pathology.

International journal of molecular sciences, 24(6): pii:ijms24065285.

The progress in Alzheimer's disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive β-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aβ plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aβ plaque load, and inflammatory processes in APP[Swe]/PSEN1[ΔE9] PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process.

RevDate: 2023-03-29

Zhou W, Lei B, Yang C, et al (2023)

Artemisia annua Extract Improves the Cognitive Deficits and Reverses the Pathological Changes of Alzheimer's Disease via Regulating YAP Signaling.

International journal of molecular sciences, 24(6): pii:ijms24065259.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the occurrence of cognitive deficits. With no effective treatments available, the search for new effective therapies has become a major focus of interest. In the present study, we describe the potential therapeutic effect of Artemisia annua (A. annua) extract on AD. Nine-month-old female 3xTg AD mice were treated with A. annua extract for three months via oral administration. Animals assigned to WT and model groups were administrated with an equal volume of water for the same period. Treated AD mice significantly improved the cognitive deficits and exhibited reduced Aβ accumulation, hyper-phosphorylation of tau, inflammatory factor release and apoptosis when compared with untreated AD mice. Moreover, A. annua extract promoted the survival and proliferation of neural progenitor cells (NPS) and increased the expression of synaptic proteins. Further assessment of the implicated mechanisms revealed that A. annua extract regulates the YAP signaling pathway in 3xTg AD mice. Further studies comprised the incubation of PC12 cells with Aβ1-42 at a concentration of 8 μM with or without different concentrations of A. annua extract for 24 h. Obtained ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis and assessment of the signaling pathways involved was performed using western blot and immunofluorescence staining. The obtained results showed that A. annua extract significantly reversed the Aβ1-42-induced increase in ROS levels, caspase-3 activity and neuronal cell apoptosis in vitro. Moreover, either inhibition of the YAP signaling pathway, using a specific inhibitor or CRISPR cas9 knockout of YAP gene, reduced the neuroprotective effect of the A. annua extract. These findings suggest that A. annua extract may be a new multi-target anti-AD drug with potential use in the prevention and treatment of AD.

RevDate: 2023-03-29

Panizzutti B, Skvarc D, Lin S, et al (2023)

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.

International journal of molecular sciences, 24(6): pii:ijms24065250.

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

RevDate: 2023-03-29

Chakraborty D, Zhuang Z, Xue H, et al (2023)

Deep Learning-Based Feature Extraction with MRI Data in Neuroimaging Genetics for Alzheimer's Disease.

Genes, 14(3): pii:genes14030626.

The prognosis and treatment of patients suffering from Alzheimer's disease (AD) have been among the most important and challenging problems over the last few decades. To better understand the mechanism of AD, it is of great interest to identify genetic variants associated with brain atrophy. Commonly, in these analyses, neuroimaging features are extracted based on one of many possible brain atlases with FreeSurf and other popular software; this, however, may cause the loss of important information due to our incomplete knowledge about brain function embedded in these suboptimal atlases. To address the issue, we propose convolutional neural network (CNN) models applied to three-dimensional MRI data for the whole brain or multiple, divided brain regions to perform completely data-driven and automatic feature extraction. These image-derived features are then used as endophenotypes in genome-wide association studies (GWASs) to identify associated genetic variants. When we applied this method to ADNI data, we identified several associated SNPs that have been previously shown to be related to several neurodegenerative/mental disorders, such as AD, depression, and schizophrenia.

RevDate: 2023-03-29

Yamasaki T (2023)

Preventive Strategies for Cognitive Decline and Dementia: Benefits of Aerobic Physical Activity, Especially Open-Skill Exercise.

Brain sciences, 13(3): pii:brainsci13030521.

As there is no curative treatment for dementia, including Alzheimer's disease (AD), it is important to establish an optimal nonpharmaceutical preventive intervention. Physical inactivity is a representative modifiable risk factor for dementia, especially for AD in later life (>65 years). As physical activity and exercise are inexpensive and easy to initiate, they may represent an effective nonpharmaceutical intervention for the maintenance of cognitive function. Several studies have reported that physical activity and exercise interventions are effective in preventing cognitive decline and dementia. This review outlines the effects of physical activity and exercise-associated interventions in older adults with and without cognitive impairment and subsequently summarizes their possible mechanisms. Furthermore, this review describes the differences between two types of physical exercise-open-skill exercise (OSE) and closed-skill exercise (CSE)-in terms of their effects on cognitive function. Aerobic physical activity and exercise interventions are particularly useful in preventing cognitive decline and dementia, with OSE exerting a stronger protective effect on cognitive functions than CSE. Therefore, the need to actively promote physical activity and exercise interventions worldwide is emphasized.

RevDate: 2023-03-29

Giulietti MV, Spatuzzi R, Fabbietti P, et al (2023)

Effects of Mindfulness-Based Interventions (MBIs) in Patients with Early-Stage Alzheimer's Disease: A Pilot Study.

Brain sciences, 13(3): pii:brainsci13030484.

Bachground In this study, we hypothesize that mindfulness-based interventions (MBIs) may improve well-being and the related outcomes in Alzheimer's dementia patients (AD-P) at an early stage. MBIs consist of the practice of consciously observing the psychic contents in the present moment (thoughts, sensations, feelings, and other events). This attention allows one to become aware of the psychic contents and integrate them, thus favoring the quality of life and an increase in the mood of practitioners. Methods The randomized controlled study enrolled 22 AD-P at an early stage (age ≥ 60 years) treated with MBIs and 22 patients without treatment (six months of MBI training). Tests (T0-T1 six months): Mini-Mental State Examination (MMPI); Spiritual Well-Being (SWB); Beck Depression Inventory (BDI); SF36. Test-Caregiver: Everyday Cognition scales (ECOG). Results AD-P with mindfulness: Improvement of ECOG (p = 0.026), quality of life (p < 0.001), spiritual well-being (p < 0.001); decrease in depression BDI (p < 0.001). The MMSE remains unchanged. The control group of untreated patients showed a significant worsening in all these dimensions. Conclusions MBI training is effective in increasing quality of life and preventing worsening in patients with early-stage Alzheimer's dementia.

RevDate: 2023-03-29

Gandla K, Babu AK, Unnisa A, et al (2023)

Carotenoids: Role in Neurodegenerative Diseases Remediation.

Brain sciences, 13(3): pii:brainsci13030457.

Numerous factors can contribute to the development of neurodegenerative disorders (NDs), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Oxidative stress (OS), a fairly common ND symptom, can be caused by more reactive oxygen species being made. In addition, the pathological state of NDs, which includes a high number of protein aggregates, could make chronic inflammation worse by activating microglia. Carotenoids, often known as "CTs", are pigments that exist naturally and play a vital role in the prevention of several brain illnesses. CTs are organic pigments with major significance in ND prevention. More than 600 CTs have been discovered in nature, and they may be found in a wide variety of creatures. Different forms of CTs are responsible for the red, yellow, and orange pigments seen in many animals and plants. Because of their unique structure, CTs exhibit a wide range of bioactive effects, such as anti-inflammatory and antioxidant effects. The preventive effects of CTs have led researchers to find a strong correlation between CT levels in the body and the avoidance and treatment of several ailments, including NDs. To further understand the connection between OS, neuroinflammation, and NDs, a literature review has been compiled. In addition, we have focused on the anti-inflammatory and antioxidant properties of CTs for the treatment and management of NDs.

RevDate: 2023-03-29

Lee IS, Choi GY, Sreelatha I, et al (2023)

Effect of Sinapic Acid on Scopolamine-Induced Learning and Memory Impairment in SD Rats.

Brain sciences, 13(3): pii:brainsci13030427.

The seriousness of the diseases caused by aging have recently gained attention. Alzheimer's disease (AD), a chronic neurodegenerative disease, accounts for 60-80% of senile dementia cases. Continuous research is being conducted on the cause of Alzheimer's disease, and it is believed to include complex factors, such as genetic factors, the accumulation of amyloid beta plaques, a tangle of tau protein, oxidative stress, cholinergic dysfunction, neuroinflammation, and cell death. Sinapic acid is a hydroxycinnamic acid found in plant families, such as oranges, grapefruit, cranberry, mustard seeds, and rapeseeds. It exhibits various biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, and anti-depressant effects. Sinapic acid is an acetylcholine esterase inhibitor that can be applied to the treatment of dementia caused by Alzheimer's disease and Parkinson's disease. However, electrophysiological studies on the effects of sinapic acid on memory and learning must still be conducted. Therefore, it was confirmed that sinapic acid was effective in long-term potentiation (LTP) using organotypic hippocampal segment tissue. In addition, the effect on scopolamine-induced learning and memory impairment was measured by oral administration of sinapic acid 10 mg/kg/day for 14 days, and behavioral experiments related to short-term and long-term spatial memory and avoidance memory were conducted. Sinapic acid increased the activity of the field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after TBS, and restored fEPSP activity in the CA1 region suppressed by scopolamine. The scopolamine-induced learning and memory impairment group showed lower results than the control group in the Y-maze, Passive avoidance (PA), and Morris water maze (MWM) experiments. Sinapic acid improved avoidance memory, short and long-term spatial recognition learning, and memory. In addition, sinapic acid weakened the inhibition of the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and the activation of prostaglandin-endoperoxide synthase 2 (COX-2) and interleukin 1 beta (IL-1β) induced by scopolamine in the hippocampus. These results show that sinapic acid is effective in restoring LTP and cognitive impairment induced by the cholinergic receptor blockade. Moreover, it showed the effect of alleviating the reduction in scopolamine-induced BDNF and TrkB, and alleviated neuroinflammatory effects by inhibiting the increase in COX-2 and IL-1β. Therefore, we showed that sinapic acid has potential as a treatment for neurodegenerative cognitive impairment.

RevDate: 2023-03-29

Li M, Qin Z, Chen H, et al (2023)

Effects of Combined Intervention of rTMS and Neurotransmitter Drugs on the Brain Functional Networks in Patients with Cognitive Impairment.

Brain sciences, 13(3): pii:brainsci13030419.

Alzheimer's disease (AD) causes extensive neural network dysfunction. Memantine and donepezil are commonly used as monotherapy or in combination with non-drug interventions, such as repetitive transcranial magnetic stimulation (rTMS), for its treatment. However, no studies have reported any differences between the effects of combined neurotransmitter and rTMS interventions versus rTMS alone on the brain networks of patients with cognitive impairment. Therefore, it is crucial to explore the advantages of different intervention methods to guide clinical practice. We used resting-state functional magnetic resonance imaging (rs-fMRI) to investigate the impact of neurotransmitter superimposed rTMS and rTMS alone on the brain functional network of patients with cognitive impairment. We divided patients with cognitive impairment who had received rTMS into two groups based on whether they received neurotransmitters: the combined intervention group and the rTMS-alone intervention group. We conducted rs-fMRI scans and comprehensively assessed cognitive function in these patients. To examine the effects of the superimposed interventions, we utilized independent component analysis to evaluate the functional connectivity of brain networks in these patients. Compared to the rTMS-alone intervention group, co-intervention of neurotransmitter drugs and rTMS exhibited potential for cognitive enhancement via the reconstructed inter-network connectivity of the cerebellum and the enhanced intra-network connectivity of the frontal-parietal regions in these patients with cognitive impairment. We hypothesized that the combination of neurotransmitter drugs and rTMS intervention could have greater clinical benefits than rTMS intervention alone, leading to improved cognitive function in patients with cognitive impairment.

RevDate: 2023-03-29

Campisi A, Sposito G, Grasso R, et al (2023)

Effect of Astaxanthin on Tissue Transglutaminase and Cytoskeletal Protein Expression in Amyloid-Beta Stressed Olfactory Ensheathing Cells: Molecular and Delayed Luminescence Studies.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030750.

Astaxanthin, a natural compound of Haematococcus pluvialis, possesses antioxidant, anti-inflammatory, anti-tumor and immunomodulatory activities. It also represents a potential therapeutic in Alzheimer's disease (AD), that is related to oxidative stress and agglomeration of proteins such as amyloid-beta (Aβ). Aβ is a neurotoxic protein and a substrate of tissue transglutaminase (TG2), an ubiquitary protein involved in AD. Herein, the effect of astaxanthin pretreatment on olfactory ensheathing cells (OECs) exposed to Aβ(1-42) or by Aβ(25-35) or Aβ(35-25), and on TG2 expression were assessed. Vimentin, GFAP, nestin, cyclin D1 and caspase-3 were evaluated. ROS levels and the percentage of cell viability were also detected. In parallel, delayed luminescence (DL) was used to monitor mitochondrial status. ASTA reduced TG2, GFAP and vimentin overexpression, inhibiting cyclin D1 levels and apoptotic pathway activation which induced an increase in the nestin levels. In addition, significant changes in DL intensities were particularly observed in OECs exposed to Aβ toxic fragment (25-35), that completely disappear when OECs were pre-incubated in astaxantin. Therefore, we suggest that ASTA pre-treatment might represent an innovative mechanism to contrast TG2 overexpression in AD.

RevDate: 2023-03-29

Han S, He Z, Hu X, et al (2023)

Inhibiting NLRP3 Inflammasome Activation by CY-09 Helps to Restore Cerebral Glucose Metabolism in 3×Tg-AD Mice.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030722.

The reduction of the cerebral glucose metabolism is closely related to the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in Alzheimer's disease (AD); however, its underlying mechanism remains unclear. In this paper, [18]F-flurodeoxyglucose positron emission tomography was used to trace cerebral glucose metabolism in vivo, along with Western blotting and immunofluorescence assays to examine the expression and distribution of associated proteins. Glucose and insulin tolerance tests were carried out to detect insulin resistance, and the Morris water maze was used to test the spatial learning and memory ability of the mice. The results show increased NLRP3 inflammasome activation, elevated insulin resistance, and decreased glucose metabolism in 3×Tg-AD mice. Inhibiting NLRP3 inflammasome activation using CY-09, a specific inhibitor for NLRP3, may restore cerebral glucose metabolism by increasing the expression and distribution of glucose transporters and enzymes and attenuating insulin resistance in AD mice. Moreover, CY-09 helps to improve AD pathology and relieve cognitive impairment in these mice. Although CY-09 has no significant effect on ferroptosis, it can effectively reduce fatty acid synthesis and lipid peroxidation. These findings provide new evidence for NLRP3 inflammasome as a therapeutic target for AD, suggesting that CY-09 may be a potential drug for the treatment of this disease.

RevDate: 2023-03-29

Jadhav R, YA Kulkarni (2023)

The Combination of Baicalein and Memantine Reduces Oxidative Stress and Protects against β-amyloid-Induced Alzheimer's Disease in Rat Model.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030707.

Alzheimer's disease (AD) is a neuronal condition causing progressive loss of memory and cognitive dysfunction particularly in elders. An upsurge in the global old age population has led to a proportionate increase in the prevalence of AD. The current treatments for AD are symptomatic and have debilitating side effects. A literature review and current research have directed scientists to explore natural products with better safety and efficacy profiles as new treatment options for AD. Baicalein, belonging to the flavone subclass of flavonoids, has been reported for its anti-oxidant, anti-inflammatory, AChE enzyme inhibitory activity and anti-amyloid protein aggregation activity, which collectively demonstrates its benefits as a neuroprotective agent. Presently, memantine, a NMDAR antagonist, is one of the important drugs used for treatment of Alzheimer's disease. The current study aims to investigate the effect of baicalein in combination with memantine in β-amyloid-induced AD in albino Wistar rats. Baicalein (10 mg/kg) alone, 5 mg/kg and 10 mg/kg in combination with memantine (20 mg/kg) was administered for 21 days. Treatment with baicalein in combination with memantine showed significant improvement in behavioural studies. The combination treatment decreased oxidative stress, β-amyloid plaque formation and increased the expression of brain-derived neurotrophic factor (BDNF) in the brain. From the results, it can be concluded that treatment with baicalein and memantine could be beneficial for reducing the progression of neurodegeneration in rats. Baicalein has an additive effect in combination with memantine, making it a potential option for the treatment of AD.

RevDate: 2023-03-29

Zhang ZH, Peng JY, Chen YB, et al (2023)

Different Effects and Mechanisms of Selenium Compounds in Improving Pathology in Alzheimer's Disease.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030702.

Owing to the strong antioxidant capacity of selenium (Se) in vivo, a variety of Se compounds have been shown to have great potential for improving the main pathologies and cognitive impairment in Alzheimer's disease (AD) models. However, the differences in the anti-AD effects and mechanisms of different Se compounds are still unclear. Theoretically, the absorption and metabolism of different forms of Se in the body vary, which directly determines the diversification of downstream regulatory pathways. In this study, low doses of Se-methylselenocysteine (SMC), selenomethionine (SeM), or sodium selenate (SeNa) were administered to triple transgenic AD (3× Tg-AD) mice for short time periods. AD pathology, activities of selenoenzymes, and metabolic profiles in the brain were studied to explore the similarities and differences in the anti-AD effects and mechanisms of the three Se compounds. We found that all of these Se compounds significantly increased Se levels and antioxidant capacity, regulated amino acid metabolism, and ameliorated synaptic deficits, thus improving the cognitive capacity of AD mice. Importantly, SMC preferentially increased the expression and activity of thioredoxin reductase and reduced tau phosphorylation by inhibiting glycogen synthase kinase-3 beta (GSK-3β) activity. Glutathione peroxidase 1 (GPx1), the selenoenzyme most affected by SeM, decreased amyloid beta production and improved mitochondrial function. SeNa improved methionine sulfoxide reductase B1 (MsrB1) expression, reflected in AD pathology as promoting the expression of synaptic proteins and restoring synaptic deficits. Herein, we reveal the differences and mechanisms by which different Se compounds improve multiple pathologies of AD and provide novel insights into the targeted administration of Se-containing drugs in the treatment of AD.

RevDate: 2023-03-29

Melrose J (2023)

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030663.

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood-brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

RevDate: 2023-03-29

Balakrishnan R, Park JY, Cho DY, et al (2023)

AD-1 Small Molecule Improves Learning and Memory Function in Scopolamine-Induced Amnesic Mice Model through Regulation of CREB/BDNF and NF-κB/MAPK Signaling Pathway.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030648.

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of AD-1 small molecule, we here explored the possible underlying mechanisms of the protective effect of AD-1 small molecule against scopolamine-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, scopolamine administration resulted in increased AChE activity, MDA levels, and decreased antioxidant enzymes, as well as the downregulation of the antioxidant response proteins of Nrf2 and HO-1 expression; however, treatment with AD-1 small molecule mitigated the generation of oxidant factors while restoring the antioxidant enzymes status, in addition to improving antioxidant protein levels. Similarly, AD-1 small molecule significantly increased the protein expression of neuroprotective markers such as BDNF and CREB and promoted memory processes in scopolamine-induced mice. Western blot analysis showed that AD-1 small molecule reduced activated microglia and astrocytes via the attenuation of iba-1 and GFAP protein expression. We also found that scopolamine enhanced the phosphorylation of NF-κB/MAPK signaling and, conversely, that AD-1 small molecule significantly inhibited the phosphorylation of NF-κB/MAPK signaling in the brain regions of hippocampus and cortex. We further found that scopolamine promoted neuronal loss by inducing Bax and caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, AD-1 small molecule significantly decreased the levels of apoptotic markers and increased neuronal survival. Furthermore, AD-1 small molecule ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. These findings revealed that AD-1 small molecule attenuated scopolamine-induced cognitive and memory dysfunction by ameliorating AChE activity, oxidative brain damage, neuroinflammation, and neuronal apoptosis.

RevDate: 2023-03-29

Rodríguez-Periñán G, de la Encarnación A, Moreno F, et al (2023)

Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions.

Antioxidants (Basel, Switzerland), 12(3): pii:antiox12030581.

Loss-of-function (LOF) mutations in GRN gene, which encodes progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). FTLD-TDP is one of the most common forms of early onset dementia, but its pathogenesis is not fully understood. Mitochondrial dysfunction has been associated with several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Here, we have investigated whether mitochondrial alterations could also contribute to the pathogenesis of PGRN deficiency-associated FTLD-TDP. Our results showed that PGRN deficiency induced mitochondrial depolarization, increased ROS production and lowered ATP levels in GRN KD SH-SY5Y neuroblastoma cells. Interestingly, lymphoblasts from FTLD-TDP patients carrying a LOF mutation in the GRN gene (c.709-1G > A) also demonstrated mitochondrial depolarization and lower ATP levels. Such mitochondrial damage increased mitochondrial fission to remove dysfunctional mitochondria by mitophagy. Interestingly, PGRN-deficient cells showed elevated mitochondrial mass together with autophagy dysfunction, implying that PGRN deficiency induced the accumulation of damaged mitochondria by blocking its degradation in the lysosomes. Importantly, the treatment with two brain-penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27), known for preventing the phosphorylation and cytosolic accumulation of TDP-43, rescued mitochondrial function in PGRN-deficient cells. Taken together, these results suggest that mitochondrial function is impaired in FTLD-TDP associated with LOF GRN mutations and that the TDP-43 pathology linked to PGRN deficiency might be a key mechanism contributing to such mitochondrial dysfunction. Furthermore, our results point to the use of drugs targeting TDP-43 pathology as a promising therapeutic strategy for restoring mitochondrial function in FTLD-TDP and other TDP-43-related diseases.

RevDate: 2023-03-28

Liu T, Su K, Cai W, et al (2023)

Therapeutic potential of puerarin against cerebral diseases: From bench to bedside.

European journal of pharmacology pii:S0014-2999(23)00206-6 [Epub ahead of print].

The incidence of cerebral diseases is rapidly increasing worldwide, and they have become an important challenge for modern medicine. Most of the available chemical drugs used in the treatment of cerebral diseases are highly toxic and single-targeted. Therefore, novel drugs from natural resources have attracted much attention for their potential to manage cerebral diseases. Puerarin is a natural isoflavone isolated from the roots of Pueraria species such as P. lobata (Willd) Ohwi, P. thomsonii, and P. mirifica. Several authors have reported the beneficial effects of puerarin in cerebral ischemic disease, intracerebral hemorrhage, vascular dementia, Alzheimer's disease, Parkinson's disease, depression, anxiety, and traumatic brain injury. This review summarizes the brain pharmacokinetics, brain drug delivery system, clinical use (in cerebral diseases), toxicity, and the adverse clinical reactions of puerarin. We have systematically presented the pharmacological actions and the molecular mechanisms of puerarin in various cerebral diseases to provide a direction for future research on the therapeutic use of puerarin in cerebral diseases.

RevDate: 2023-03-28

Makarov M, E Korkotian (2023)

Differential Role of Active Compounds in Mitophagy and Related Neurodegenerative Diseases.

Toxins, 15(3): pii:toxins15030202.

Neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, significantly reduce the quality of life of patients and eventually result in complete maladjustment. Disruption of the synapses leads to a deterioration in the communication of nerve cells and decreased plasticity, which is associated with a loss of cognitive functions and neurodegeneration. Maintaining proper synaptic activity depends on the qualitative composition of mitochondria, because synaptic processes require sufficient energy supply and fine calcium regulation. The maintenance of the qualitative composition of mitochondria occurs due to mitophagy. The regulation of mitophagy is usually based on several internal mechanisms, as well as on signals and substances coming from outside the cell. These substances may directly or indirectly enhance or weaken mitophagy. In this review, we have considered the role of some compounds in process of mitophagy and neurodegeneration. Some of them have a beneficial effect on the functions of mitochondria and enhance mitophagy, showing promise as novel drugs for the treatment of neurodegenerative pathologies, while others contribute to a decrease in mitophagy.

RevDate: 2023-03-28

Riordan R, Rong W, Yu Z, et al (2023)

Effect of Nrf2 loss on senescence and cognition of tau-based P301S mice.

GeroScience [Epub ahead of print].

Cellular senescence may contribute to chronic inflammation involved in the progression of age-related diseases such as Alzheimer's disease (AD), and its removal prevents cognitive impairment in a model of tauopathy. Nrf2, the major transcription factor for damage response pathways and regulators of inflammation, declines with age. Our previous work showed that silencing Nrf2 gives rise to premature senescence in cells and mice. Others have shown that Nrf2 ablation can exacerbate cognitive phenotypes of some AD models. In this study, we aimed to understand the relationship between Nrf2 elimination, senescence, and cognitive impairment in AD, by generating a mouse model expressing a mutant human tau transgene in an Nrf2 knockout (Nrf2KO) background. We assessed senescent cell burden and cognitive decline of P301S mice in the presence and absence of Nrf2. Lastly, we administered 4.5-month-long treatments with two senotherapeutic drugs to analyze their potential to prevent senescent cell burden and cognitive decline: the senolytic drugs dasatinib and quercetin (DQ) and the senomorphic drug rapamycin. Nrf2 loss accelerated the onset of hind-limb paralysis in P301S mice. At 8.5 months of age, P301S mice did not exhibit memory deficits, while P301S mice without Nrf2 were significantly impaired. However, markers of senescence were not elevated by Nrf2 ablation in any of tissues that we examined. Neither drug treatment improved cognitive performance, nor did it reduce expression of senescence markers in brains of P301S mice. Contrarily, rapamycin treatment at the doses used delayed spatial learning and led to a modest decrease in spatial memory. Taken together, our data suggests that the emergence of senescence may be causally associated with onset of cognitive decline in the P301S model, indicate that Nrf2 protects brain function in a model of AD through mechanisms that may include, but do not require the inhibition of senescence, and suggest possible limitations for DQ and rapamycin as therapies for AD.

RevDate: 2023-03-28

Drucker DJ, JJ Holst (2023)

The expanding incretin universe: from basic biology to clinical translation.

Diabetologia [Epub ahead of print].

Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet β-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification.

RevDate: 2023-03-29

Yang H, Zhang Q, Zhang B, et al (2023)

Potential Active Marine Peptides as Anti-Aging Drugs or Drug Candidates.

Marine drugs, 21(3): pii:md21030144.

Aging is an irreversible physiological process in the human body, and the aging characteristics of the body that accompany this process also lead to many other chronic diseases, such as neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease, cardiovascular diseases, hypertension, obesity, cancer, and so on. The marine environment is highly biodiverse, the natural active products of these organisms constitute a vast treasure trove of marine drugs or drug candidates that play an essential role in disease prevention and treatment, and the active peptide products among them have received special attention because of their unique chemical properties. Therefore, the development of marine peptide compounds as anti-aging drugs is emerging as an important research area. This review highlights the currently available data on marine bioactive peptides with anti-aging potential from 2000 to 2022 by analyzing the prevalent aging mechanisms, critical aging metabolic pathways and well-established multi-omics aging characteristics, as well as grouping different bioactive and biological species lines of peptides from marine organisms and discussing their research modalities and functional characteristics. Active marine peptides is a promising topic to explore and to develop their potential as anti-aging drugs or drug candidates. We expect this review to be instructive for future marine drug development and to reveal new directions for future biopharmaceuticals.

RevDate: 2023-03-28

Gotla S, S Matysiak (2023)

Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan.

Physical chemistry chemical physics : PCCP [Epub ahead of print].

Neurodegeneration related to Alzheimer's disease has long been linked to the accumulation of abnormal aggregates of amyloid-β (Aβ) peptides. Pre-fibrillar oligomeric intermediates of Aβ aggregation are considered the primary drivers of neurotoxicity, however, their targetting remains an unresolved challenge. In response, the effects of macromolecular components of the blood-brain barrier, artificial extracellular matrix mimics, and polymeric drug delivery particles, on the aggregation of Aβ peptides are gaining interest. Multiple experimental studies have demonstrated the potential of one such macromolecule, chitosan (CHT) - a polysaccharide with acid induced cationicity (pKa 6.5) - to inhibit the aggregation of Aβ, and reduce the associated neurotoxic effects. However, the mechanistic details of this inhibitory action, and the structural details of the emergent Aβ complexes are not understood. In this work, we probed how CHT modulated the aggregation of Aβ's central hydrophobic core fragment, K16LVFFAE22, using coarse-grained molecular dynamics simulations. CHT was found to bind and sequester Aβ peptides, thus limiting their ultimate aggregation numbers. The intensity of this inhibitory action was enhanced by CHT concentration, as well as CHT's pH-dependent degree of cationicity, corroborating experimental observations. Furthermore, CHT was found to reshape the conformational landscapes of Aβ peptides, enriching collapsed peptides at near-physiological conditions of pH 7.5, and extended peptides at slightly acidic conditions of pH 6.5, where the charge profile of K16LVFFAE22 peptides remained unchanged. These conformational changes were limited to peptides in direct contact in CHT, thus emphasizing the influence of local environments on Aβ conformations. These findings add to basic knowledge of the aggregation behaviour of Aβ peptides, and could potentially guide the development of advanced CHT-based materials for the treatment of Alzheimer's disease.

RevDate: 2023-03-28

Kumar Singh N, B Bhushan (2023)

Preclinical Evidence-based Neuroprotective Potential of Silibinin.

Current drug research reviews pii:CDRR-EPUB-130376 [Epub ahead of print].

Neurodegeneration is an elucidating feature of many neuronal disorders including Alz- heimer's, disease, Parkinson's disease, and cerebral ischemia. These neurodegenerative disorders are a major public health concern with high mortality and morbidity rates around the world. Pres- ently, researchers have concentrated their efforts on determining the neuroprotective activity of natural products for the management of neurological manifestation associated with neurodegener- ation or aging. Silibinin, an active component of the plant Silybum marianum (family: Asteraceae) was used for the treatment of liver diseases from ancient times. Recently several preclinical stud- ies provide supportive evidence for the neuroprotective activity of silibinin in experimental ani- mals. Besides its antioxidant effect, silibinin exhibits neuroprotective activities by altering several cellular and molecular signaling pathways like BDNF, ER/PI3/Akt, NfκB, JNK, IR & IGF-IR, mTOR, and many more against brain-related neurotoxicity. This review provided a comprehen- sive summary of the chemistry, pharmacokinetics, side effects, and pharmacological effects of silibinin against various neurodegenerative disorders with a prominent cellular and molecular mechanism. The literature reviews and preclinical studies demonstrated that silibinin could be an alternate candidate for the management of neurodegenerative disorders. Thus, there is a scope for further preclinical and clinical research to introduce this phytoconstituent as a therapeutic alterna- tive candidate.

RevDate: 2023-03-29
CmpDate: 2023-03-29

Bleibel M, El Cheikh A, Sadier NS, et al (2023)

The effect of music therapy on cognitive functions in patients with Alzheimer's disease: a systematic review of randomized controlled trials.

Alzheimer's research & therapy, 15(1):65.

BACKGROUND: The use of music interventions as a non-pharmacological therapy to improve cognitive and behavioral symptoms in Alzheimer's disease (AD) patients has gained popularity in recent years, but the evidence for their effectiveness remains inconsistent.

OBJECTIVES: To summarize the evidence of the effect of music therapy (alone or in combination with pharmacological therapies) on cognitive functions in AD patients compared to those without the intervention.

METHODS: A systematic literature search was performed in PubMed, Cochrane library, and HINARI for papers published from 1 January 2012 to 25 June 2022. All randomized controlled trials that compared music therapy with standard care or other non-musical intervention and evaluation of cognitive functions are included. Cognitive outcomes included: global cognition, memory, language, speed of information processing, verbal fluency, and attention. Quality assessment and narrative synthesis of the studies were performed.

RESULTS: A total of 8 studies out of 144 met the inclusion criteria (689 participants, mean age range 60.47-87.1). Of the total studies, 4 were conducted in Europe (2 in France, 2 in Spain), 3 in Asia (2 in China, 1 in Japan), and 1 in the USA. Quality assessment of the retrieved studies revealed that 6 out of 8 studies were of high quality. The results showed that compared to different control groups, there is an improvement in cognitive functions after music therapy application. A greater effect was shown when patients are involved in the music making when using active music intervention (AMI).

CONCLUSION: The results of this review highlight the potential benefits of music therapy as a complementary treatment option for individuals with AD and the importance of continued investigation in this field. More research is needed to fully understand the effects of music therapy, to determine the optimal intervention strategy, and to assess the long-term effects of music therapy on cognitive functions.

RevDate: 2023-03-29
CmpDate: 2023-03-29

Alamro H, Thafar MA, Albaradei S, et al (2023)

Exploiting machine learning models to identify novel Alzheimer's disease biomarkers and potential targets.

Scientific reports, 13(1):4979.

We still do not have an effective treatment for Alzheimer's disease (AD) despite it being the most common cause of dementia and impaired cognitive function. Thus, research endeavors are directed toward identifying AD biomarkers and targets. In this regard, we designed a computational method that exploits multiple hub gene ranking methods and feature selection methods with machine learning and deep learning to identify biomarkers and targets. First, we used three AD gene expression datasets to identify 1/ hub genes based on six ranking algorithms (Degree, Maximum Neighborhood Component (MNC), Maximal Clique Centrality (MCC), Betweenness Centrality (BC), Closeness Centrality, and Stress Centrality), 2/ gene subsets based on two feature selection methods (LASSO and Ridge). Then, we developed machine learning and deep learning models to determine the gene subset that best distinguishes AD samples from the healthy controls. This work shows that feature selection methods achieve better prediction performances than the hub gene sets. Beyond this, the five genes identified by both feature selection methods (LASSO and Ridge algorithms) achieved an AUC = 0.979. We further show that 70% of the upregulated hub genes (among the 28 overlapping hub genes) are AD targets based on a literature review and six miRNA (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, hsa-mir-26a-5p, hsa-mir-93-5p, hsa-mir-155-5p) and one transcription factor, JUN, are associated with the upregulated hub genes. Furthermore, since 2020, four of the six microRNA were also shown to be potential AD targets. To our knowledge, this is the first work showing that such a small number of genes can distinguish AD samples from healthy controls with high accuracy and that overlapping upregulated hub genes can narrow the search space for potential novel targets.

RevDate: 2023-03-27

Kim MG, Ooi SL, Kim GW, et al (2023)

Effectiveness and Safety of Pattern Identification-Based Herbal Medicine for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Journal of integrative and complementary medicine [Epub ahead of print].

Objective: Alzheimer's disease (AD), the most common cause of dementia, has only symptomatic treatments in conventional Western medicine (WM). Disease-modifying drugs are still under development. This study evaluated the efficacy and safety of herbal medicine (HM) based on pattern identification (PI) as a whole system practice for treating AD. Methods: Thirteen databases were searched from inception to August 31, 2021. Twenty-seven randomized controlled trials (RCTs) with 2069 patients were included in the evidence synthesis. Results: The meta-analysis showed that, compared with WM, HM prescription based on PI, either alone or in combination with WM, could significantly improve the cognitive functions of AD patients (Mini-Mental State Examination [MMSE]-HM vs. WM: mean difference [MD] = 1.96, 95% confidence intervals [CIs]: 0.28-3.64, N = 981, I[2] = 96%; HM+WM vs. WM: MD = 1.33, 95% CI: 0.57-2.09, N = 695, I[2] = 68%) and their ability to perform activities of daily living (ADL-HM vs. WM: standardized mean difference [SMD] = 0.71, 95% CI: 0.04-1.38, N = 639, I[2] = 94%; HM+WM vs. WM: SMD = 0.60, 95% CI: 0.27-0.93, N = 669, I[2] = 76%). Duration-wise, 12 weeks of HM+WM were superior to 12 weeks of WM and 24 weeks of HM were superior to 24 weeks of WM. None of the included studies found any severe safety concerns. The odds of mild-to-moderate adverse events were marginally lower in HM than in WM (odds ratio = 0.34, 95% CI: 0.11-1.02, N = 689, I[2] = 55%). Conclusion: Hence, prescribing PI-based HM is a safe and effective therapeutic option for AD, either as first-line therapy or adjuvant treatment. However, most of the included studies have a high or uncertain risk of bias. Thus, well-designed RCTs with proper blinding and placebo controls are needed.

RevDate: 2023-03-27

Nada H, Sivaraman A, Lu Q, et al (2023)

Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure-Activity Relationships and Molecular Docking.

Journal of medicinal chemistry [Epub ahead of print].

Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

RevDate: 2023-03-27

Fitzgerald GS, Chuchta TG, EC McNay (2023)

Insulin-like growth factor-2 is a promising candidate for the treatment and prevention of Alzheimer's disease.

CNS neuroscience & therapeutics [Epub ahead of print].

Alzheimer's disease (AD) is the most common form of dementia. Current AD treatments slow the rate of cognitive decline, but do not restore lost function. One reason for the low efficacy of current treatments is that they fail to target neurotrophic processes, which are thought to be essential for functional recovery. Bolstering neurotrophic processes may also be a viable strategy for preventative treatment, since structural losses are thought to underlie cognitive decline in AD. The challenge of identifying presymptomatic patients who might benefit from preventative treatment means that any such treatment must meet a high standard of safety and tolerability. The neurotrophic peptide insulin-like growth factor-2 (IGF2) is a promising candidate for both treating and preventing AD-induced cognitive decline. Brain IGF2 expression declines in AD patients. In rodent models of AD, exogenous IGF2 modulates multiple aspects of AD pathology, resulting in (1) improved cognitive function; (2) stimulation of neurogenesis and synaptogenesis; and, (3) neuroprotection against cholinergic dysfunction and beta amyloid-induced neurotoxicity. Preclinical evidence suggests that IGF2 is likely to be safe and tolerable at therapeutic doses. In the preventative treatment context, the intranasal route of administration is likely to be the preferred method for achieving the therapeutic effect without risking adverse side effects. For patients already experiencing AD dementia, routes of administration that deliver IGF2 directly access the CNS may be necessary. Finally, we discuss several strategies for improving the translational validity of animal models used to study the therapeutic potential of IGF2.

RevDate: 2023-03-27

Perovic M, Ciric J, Matovic V, et al (2023)

The presymptomatic treatment with 3HFWC nanosubstance decreased plaque load in 5XFAD mouse model of Alzheimer's disease.

CNS neuroscience & therapeutics [Epub ahead of print].

INTRODUCTION: In the present study, we assessed the effects of the hyper-harmonized-hydroxylated fullerene-water complex (3HFWC) on Alzheimer's disease (AD) neuropathological hallmarks in 5XFAD mice, an AD animal model.

METHODS: The 3-week-old 5XFAD mice were exposed to 3HFWC water solution ad libitum for 3 months in the presymptomatic phase of pathology. The functional effects of the treatment were confirmed through near-infrared spectroscopy (NIRS) analysis through machine learning (ML) using artificial neural networks (ANNs) to classify the control and 3HFWC-treated brain tissue samples. The effects of 3HFWC treatment on amyloid-β (Aβ) accumulation, plaque formation, gliosis, and synaptic plasticity in cortical and hippocampal tissue were assessed.

RESULTS: The 3HFWC treatment significantly decreased the amyloid-β plaque load in specific parts of the cerebral cortex. At the same time, 3HFWC treatment did not induce the activation of glia (astrocytes and microglia) nor did it negatively affect synaptic protein markers (GAP-43, synaptophysin, and PSD-95).

CONCLUSION: The obtained results point to the potential of 3HFWC, when applied in the presymptomatic phase of AD, to interfere with amyloid plaque formation without inducing AD-related pathological processes such as neuroinflammation, gliosis, and synaptic vulnerability.

RevDate: 2023-03-28

Hu YY, Yang G, Liang XS, et al (2023)

Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application.

Frontiers in neurology, 14:1117188.

Transcranial ultrasound stimulation is a neurostimulation technique that has gradually attracted the attention of researchers, especially as a potential therapy for neurological disorders, because of its high spatial resolution, its good penetration depth, and its non-invasiveness. Ultrasound can be categorized as high-intensity and low-intensity based on the intensity of its acoustic wave. High-intensity ultrasound can be used for thermal ablation by taking advantage of its high-energy characteristics. Low-intensity ultrasound, which produces low energy, can be used as a means to regulate the nervous system. The present review describes the current status of research on low-intensity transcranial ultrasound stimulation (LITUS) in the treatment of neurological disorders, such as epilepsy, essential tremor, depression, Parkinson's disease (PD), and Alzheimer's disease (AD). This review summarizes preclinical and clinical studies using LITUS to treat the aforementioned neurological disorders and discusses their underlying mechanisms.

RevDate: 2023-03-28

Kandeel M, Morsy MA, Abd El-Lateef HM, et al (2023)

Cognitive- and memory-enhancing effects of Augmentin in Alzheimer's rats through regulation of gene expression and neuronal cell apoptosis.

Frontiers in pharmacology, 14:1154607.

Introduction: Alzheimer's disease (AD) is the most common type of dementia among older persons. This study looked at how Augmentin affected behavior, gene expression, and apoptosis in rats in which AD had been induced by scopolamine. Methods: The rats were divided into five groups: control, sham, memantine, Augmentin, and pre-Augmentin (the last group received Augmentin before scopolamine administration and was treated with memantine). A Morris water maze was utilized to measure spatial memory in the animals, and real-time quantitative reverse transcription PCR (qRT-PCR) and flow cytometry were employed to analyze gene expression and neuronal cell apoptosis, respectively. Results: Memantine and Augmentin increased spatial memory in healthy rats. The use of scopolamine impaired spatial memory. Both Augmentin and memantine improved spatial memory in AD rats, particularly in the group that received memantine; however, the outcomes were more substantial when Augmentin was administered before scopolamine was given to induce AD. Furthermore, the expression of presenilin-2 (PSEN2) and inositol-trisphosphate 3-kinase B (ITPKB) increased, whereas the expression of DEAD-box helicase 5 (DDX5) fell in the AD-treated groups; however, the results were more substantial after combination therapy. According to flow cytometry studies, Augmentin pre-treatment reduced apoptosis in AD rats. Discussion: The results showed that administering Augmentin to AD rats before memantine improved their spatial memory, reduced neuronal cell death, upregulated protective genes, and suppressed genes involved in AD pathogenesis.

RevDate: 2023-03-28

McKee CG, Hoffos M, Vecchiarelli HA, et al (2023)

Microglia: A pharmacological target for the treatment of age-related cognitive decline and Alzheimer's disease.

Frontiers in pharmacology, 14:1125982.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS. Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress. Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

RevDate: 2023-03-28

Khalid A, Khan W, Zia K, et al (2023)

Natural coumarins from Murraya paniculata as mixed-type inhibitors of cholinesterases: In vitro and in silico investigations.

Frontiers in pharmacology, 14:1133809.

Currently, acetylcholinesterase (AChE) inhibiting drugs in clinical use, such as tacrine, donepezil, rivastigmine, and galanthamine, are associated with serious side effects and short half-lives. In recent years, numerous phytochemicals have been identified as inhibitors of cholinesterases with potential applications in the management of Alzheimer's disease (AD). In this study three natural coumarins, 2'-O-ethylmurrangatin (1), murranganone (2), and paniculatin (3) isolated previously by our group from the leaves of Murraya paniculata, were tested against the two cholinesterases (ChE) enzymes, AChE and butyrylcholinesterase (BChE) using in vitro assay. Molecular docking was performed to highlight the structural properties that contribute to the molecular recognition pattern in the inhibition of ChE and the structural differences resulting in the selectivity of these compounds toward AChE. Classical enzyme inhibition kinetics data suggested that compounds 2 and 3 were potent inhibitors of AChE and BChE, while 1 was found inactive against both enzymes. The findings from molecular docking studies revealed the competitive and non-competitive inhibition mechanisms of compounds 2 and 3 against both enzymes. Molecular docking and simulations have revealed that hydrogen bonding, mediated by ketone and hydroxyl functionalities in various positions, significantly contributes to the binding of the inhibitor to the receptor. According to MD simulation studies, the stability of the ligand-AChE complex for the most active compound (3) is found to be comparable to that of the widely used drug Tacrine. In addition, to evaluate the drug-likeness of compounds, in silico ADME evaluation was performed, and the compounds presented good ADME profiles. Data suggested that the coumarin nucleus having diverse side chains at the C-8 position can serve as a potential inhibitor of cholinesterases and can act as a lead to develop a new semisynthetic drug for the treatment of AD.

RevDate: 2023-03-28

Muhammad N, Brooks Iii N, Chatham L, et al (2023)

Efficacy of Electroconvulsive Therapy for the Treatment of Movement Disorders: A Literature Review.

Cureus, 15(3):e36634.

Electroconvulsive therapy (ECT) is a safe and effective treatment modality for various psychiatric disorders. However, evidence suggests a putative role of ECT in treating movement disorders that are refractory to less invasive modalities. ECT is primarily used in treatment-resistant psychiatric disorders. However, growing evidence exists for its use in movement disorders with and without psychiatric comorbidity. The primary objective of this systematic review was to examine the efficacy of ECT as a primary treatment modality for movement disorders. Relevant, peer-reviewed publications were retrieved from PubMed, SCOPUS, CINAHL, and PsycINFO. Keywords related to ECT and movement disorders were used as search phrases to identify relevant articles. A total of 90 articles that met the inclusion criteria were included in this review. Core findings were subsequently appraised on the role of ECT in treating movement disorders. Inclusion and exclusion criteria were developed to guide the search and selection process. Sources that met the inclusion criteria were those published between 2001 and January 2023. Additionally, peer-reviewed journals published in the English language covering the role of ECT in movement disorders were deemed appropriate for inclusion. Sources published before 2001, written in a non-English language, and not from peer-reviewed journals were excluded from this systematic review. The exclusion criteria also entailed eliminating duplicates from the review list. Most reviewed sources revealed that ECT improved outcomes in symptoms associated with various movement symptoms. However, ECT does not have a long-lasting impact on neuroacanthocytosis symptoms. Additionally, ECT is negatively associated with aggression and agitation, two of the most critical movement symptoms of Alzheimer's disease. Evidence affirms the efficacy of ECT in providing symptomatic relief for movement disorders aside from psychiatric comorbidities. This positive association highlights the need for randomized controlled studies to identify movement disorder sub-populations that may respond to ECT.

RevDate: 2023-03-27

Son SH, Lee NR, Gee MS, et al (2023)

Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer's Disease.

ACS central science, 9(3):417-426.

Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer's disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aβ) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.

RevDate: 2023-03-27

Butterworth RF (2023)

Adamantanes for the treatment of neurodegenerative diseases in the presence of SARS-CoV-2.

Frontiers in neuroscience, 17:1128157.

Advent of the acute respiratory coronavirus SARS-CoV-2 has resulted in the search for novel antiviral agents and in the repurposing of existing agents with demonstrated efficacy against other known coronaviruses in the search for an agent with antiviral activity for use during the COVID-19 pandemic. Adamantanes including amantadine, rimantadine, and memantine have well-established benefit in the treatment of neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD) and fatigue related to Multiple sclerosis (MS) all of which are known comorbidities related to COVID-19 Moreover, results of basic pharmacological studies both in vitro and in vivo reveal that amantadine has the potential to inhibit SARS-CoV-2 via down-regulation of host-cell proteases resulting in impaired viral genome release into the host cell and via amantadine's property as an NMDA receptor antagonist resulting in the prevention of the acute lung injury and respiratory distress that is characteristic of COVID-19. Cases suggestive of COVID-19 prophylaxis have been reported in patients with PD or MS or severe cognitive impairment treated in all cases for several months with an adamantane [amantadine or memantine] who were subsequently infected with SARS-CoV-2 confirmed by RT-PCR, and, in all cases, no signs of infectious disease were encountered. Amantadine is effective for the treatment of fatigue in MS and for the neurological complications of Traumatic Brain Injury (TBI).

RevDate: 2023-03-27

Kumar S, Manoharan A, J J, et al (2023)

Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation.

RSC advances, 13(14):9513-9529.

Alzheimer's disease (AD), a neurodegenerative condition associated with ageing, can occur. AD gradually impairs memory and cognitive function, which leads to abnormal behavior, incapacity, and reliance. By 2050, there will likely be 100 million cases of AD in the world's population. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition are significant components of AD treatment. This work developed models using the genetic method multiple linear regression, atom-based, field-based, and 3-D pharmacophore modelling. Due to internal and external validation, all of the models have solid statistical (R [2] > 0.81 and Q [2] > 0.77) underpinnings. From a pre-plated CNS library (6055), we discovered a hit compound using virtual screening on a QSAR model. Through molecular docking, additional hit compounds were investigated (XP mode). Finally, a molecular dynamics simulation revealed that the Molecule5093-4BDS complex was stable (100 ns). Finally, the expected ADME properties for the hit compounds (Molecule5093, Molecule1076, Molecule4412, Molecule1053, and Molecule3344) were found. According to the results of our investigation and the prospective hit compounds, BuChE inhibitors may be used as a treatment for AD.

RevDate: 2023-03-27

Wang H, Zong Y, Zhu L, et al (2023)

Chemokines in patients with Alzheimer's disease: A meta-analysis.

Frontiers in aging neuroscience, 15:1047810.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly people. Many researches have reported that neuroinflammation is related to AD. Chemokines are a class of small cytokines that play important roles in cell migration and cell communication, which involved in neuroinflammation. Up to now there is no meta-analysis to explore the difference of chemokines between AD patients and healthy elderly individuals.

METHOD: We searched PubMed, Web of science, Cochrane library, EMBASE and Scopus databases from inception to January 2022. Data were extracted by two independent reviewers, and the Review Manager 5.3 was used for the meta-analysis.

RESULT: Thirty-two articles were included and analyzed. The total number of participants in the included study was 3,331. We found that the levels of CCL5 (SMD = 2.56, 95% CI: 1.91-3.21), CCL15 (SMD = 3.30, 95% CI: 1.48-5.13) and IP-10 (SMD = 3.88, 95% CI: 1.84-5.91) in the plasma of AD patients were higher than healthy people. MCP-1 protein (SMD = 0.67, 95% CI: 0.29-1.05) in the AD patients' CSF was higher than healthy controls.

CONCLUSION: These results suggested that chemokines may play an important role in AD. These findings could provide evidences for the diagnosis and treatment of AD.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021278736, identifier: CRD42021278736.

RevDate: 2023-03-26

Chen C (2023)

Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.

Pharmacology & therapeutics pii:S0163-7258(23)00058-X [Epub ahead of print].

Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ[9]-tetrahydrocannabinol (Δ[9]-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurodegenerative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in the brain.

RevDate: 2023-03-26

Liu X, Huang R, J Wan (2023)

Puerarin: a potential natural neuroprotective agent for neurological disorders.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 162:114581 pii:S0753-3322(23)00369-4 [Epub ahead of print].

Puerarin is an isoflavone compound derived from Pueraria lobata in traditional Chinese medicine. Accumulating evidence has indicated that puerarin demonstrates multiple pharmacological effects and exhibits treatment potential for various neurological disorders. Based on the latest research progress on puerarin as a neuroprotective agent, its pharmacological activity, molecular mechanism, and therapeutic application were systematically reviewed with emphasis on pre-clinical studies. The related information was extracted and compiled from major scientific databases, including PubMed, ScienceDirect, SpringerLink, and Chinese National Knowledge Infrastructure, using 'Puerarin', 'Neuroprotection', 'Apoptosis', 'Autophagy', 'Antioxidant', 'Mitochondria', 'Anti-inflammation' as keywords. This review complied with The Preferred Reporting Items for Systematic Reviews criteria. Forty-three articles met established inclusion and exclusion criteria. Puerarin has shown neuroprotective effects against a variety of neurological disorders, including ischemic cerebrovascular disease, subarachnoid hemorrhage, epilepsy, cognitive disorders, traumatic brain injury, Parkinson's disease, Alzheimer's disease, anxiety, depression, diabetic neuropathy, and neuroblastoma/glioblastoma. Puerarin demonstrates anti-apoptosis, proinflammatory mediator inhibitory, autophagy regulatory, anti-oxidative stress, mitochondria protection, Ca[2+] influx inhibitory, and anti-neurodegenerative activities. Puerarin exerts noticeable neuroprotective effects on various models of neurological disorders in vivo (animal). This review will contribute to the development of puerarin as a novel clinical drug candidate for the treatment of neurological disorders. However, well-designed, high-quality, large-scale, multicenter randomized clinical studies are needed to determine the safety and clinical utility of puerarin in patients with neurological disorders.

RevDate: 2023-03-25

Yang S, Wang L, Zeng Y, et al (2023)

Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 114:154762 pii:S0944-7113(23)00123-X [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a neurogenerative disease and remains no effective method for stopping its progress. Ferroptosis and adaptive immunity have been proven to contribute to AD pathogenesis. Salidroside exhibits neuroprotective and immunomodulatory effects. However, the underlying mechanisms linking salidroside, ferroptosis, and adaptive immunity in AD remain uncertain.

PURPOSE: The objective of this study is to explore the neuroprotective effects and the potential molecular mechanisms of salidroside against neuronal ferroptosis and CD8[+] T cell infiltration in senescence-accelerated mouse prone 8 (SAMP8) mice.

STUDY DESIGN AND METHODS: SAMP8 mice were employed as an AD model and were treated with salidroside for 12 weeks. Behavioral tests, immunohistochemistry, HE and Nissl staining, immunofluorescence, transmission electron microscopy, quantitative proteomics, bioinformatic analysis, flow cytometry, iron staining, western blotting, and molecular docking were performed.

RESULTS: Treatment with salidroside dose-dependently attenuated cognitive impairment, reduced the accumulation of Aβ plaques and restored neuronal damage. Salidroside also suppressed the infiltration of CD8[+]T cells, oxidative stress, and inflammatory cytokines, and improved mitochondrial metabolism, iron metabolism, lipid metabolism, and redox in the SAMP8 mice brain. The administration of salidroside decreased iron deposition, reduced TFR1, and ACSL4 protein expression, upregulated SLC7A11, and GPX4 protein expression, and promoted the Nrf2/GPX4 axis activation.

CONCLUSION: In conclusion, neuronal ferroptosis and CD8[+]T cells are involved in the process of cognitive impairment in SAMP8 mice. Salidroside alleviates cognitive impairment and inhibits neuronal ferroptosis. The underlying mechanisms may involve the Nrf2/GPX4 axis activation and reduction in CD8[+]T cells infiltration. This study provides some evidence for the roles of salidroside in adaptive immunity and neuronal ferroptosis in SAMP8 mice.

RevDate: 2023-03-25

Xiao C, Chen T, Yuan M, et al (2023)

A Novel Polysaccharide DSPP-1 from Durian Seed: Structure Characterization and Its Protective Effects Against Alzheimer's Disease in a Transgenic Caenorhabditis elegans Model.

Plant foods for human nutrition (Dordrecht, Netherlands) [Epub ahead of print].

Durian seeds are normally considered as agricultural waste in durian fruit processing, resulting in a huge waste of resources. The structure characterization of polysaccharide from durian seed and its neuroprotective effects against Alzheimer's disease (AD) in a transgenic Caenorhabditis elegans model were conducted in this study. A water-soluble polysaccharide was obtained using atmospheric pressure plasma treatment, and named DSPP-1. DSPP-1 was composed of rhamnose, galactose and galacturonic acid and its molecular weight was 3.765 × 10[5] Da. PDSP and DSPP-1 showed considerable antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging compared to the positive control (vitamin C). Besides, compared with the positive group (epigallocatechin gallate), PDSP and DSPP-1 exhibited the certain Abeta1 - 42 aggregation inhibitory effectiveness (p < 0.05). In contrast, DSPP-2 exerted a poor antioxidant and anti-aggregation effect (p < 0.05). In vivo results showed that DSPP-1 could decrease abnormal Aβ1-42 aggregation to delay the paralysis process of AD-nematodes. Moreover, DSPP-1 significantly improved the antioxidant enzyme activities and reduced lipid peroxidation in AD-nematodes. Taken together, these results indicated that DSPP-1 could be used as a potential natural source for the prevention and treatment of AD.

RevDate: 2023-03-27

Dranitsaris G, Zhang Q, Mu L, et al (2023)

Therapeutic preference for Alzheimer's disease treatments: a discrete choice experiment with caregivers and neurologists.

Alzheimer's research & therapy, 15(1):60.

BACKGROUND: Alzheimer's disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists.

METHODS: An initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference.

RESULTS: Both caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS =  - 0.26 and - 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS =  - 0.02 and - 0.13) were the least important characteristics of any new treatment. Neurologists' also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression.

CONCLUSIONS: Caregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.

RevDate: 2023-03-27

Das S, Goossens J, Jacobs D, et al (2023)

Synaptic biomarkers in the cerebrospinal fluid associate differentially with classical neuronal biomarkers in patients with Alzheimer's disease and frontotemporal dementia.

Alzheimer's research & therapy, 15(1):62.

BACKGROUND: Loss of synaptic functionality has been recently identified as an early-stage indicator of neurological diseases. Consequently, monitoring changes in synaptic protein levels may be relevant for observing disease evolution or treatment responses in patients. Here, we have studied the relationship between fluid biomarkers of neurodegeneration and synaptic dysfunction in patients with Alzheimer's disease (AD), frontotemporal dementia (FTD), and subjective cognitive decline (SCD).

METHODS: The exploratory cohort consisted of cerebrospinal fluid (CSF) samples (n = 60) from patients diagnosed with AD (n = 20), FTD (n = 20), and SCD (n = 20) from the Amsterdam Dementia Cohort. We developed two novel immunoassays for the synaptic proteins synaptosomal-associated protein-25 (SNAP25) and vesicle-associated membrane protein-2 (VAMP2). We measured the levels of these biomarkers in CSF, in addition to neuronal pentraxin-2 (NPTX2), glutamate ionotropic receptor-4 (GluR4), and neurogranin (Ng) for this cohort. All in-house immunoassays were validated and analytically qualified prior to clinical application. CSF neurogranin (Ng) was measured using a commercially available ELISA.

RESULTS: This pilot study indicated that SNAP25, VAMP2, and Ng may not be specific biomarkers for AD as their levels were significantly elevated in patients with both AD and FTD compared to SCD. Moreover, the strength of the correlations between synaptic proteins was lower in the AD and FTD clinical groups compared to SCD. SNAP25, VAMP2, and Ng correlated strongly with each other as well as with total Tau (Tau) and phosphorylated Tau (PTau) in all three clinical groups. However, this correlation was weakened or absent with NPTX2 and GluR4. None of the synaptic proteins correlated to neurofilament light (NfL) in any clinical group.

CONCLUSION: The correlation of the synaptic biomarkers with CSF Tau and PTau but the lack thereof with NfL implies that distinct pathological pathways may be involved in synaptic versus axonal degeneration. Our results reflect the diversity of synaptic pathology in neurodegenerative dementias.

RevDate: 2023-03-25

Ostertag C, Visani M, Urruty T, et al (2023)

Long-term cognitive decline prediction based on multi-modal data using Multimodal3DSiameseNet: transfer learning from Alzheimer's disease to Parkinson's disease.

International journal of computer assisted radiology and surgery [Epub ahead of print].

PURPOSE: Monitoring and predicting the cognitive state of subjects with neurodegenerative disorders is crucial to provide appropriate treatment as soon as possible. In this work, we present a machine learning approach using multimodal data (brain MRI and clinical) from two early medical visits, to predict the longer-term cognitive decline of patients. Using transfer learning, our model can be successfully transferred from one neurodegenerative disease (Alzheimer's) to another (Parkinson's).

METHODS: Our model is a Deep Neural Network with siamese sub-modules dedicated to extracting features from each modality. We pre-train it with data from ADNI (Alzheimer's disease), then transfer it on the smaller PPMI dataset (Parkinson's disease). We show that, even when we do not fine-tune the filters learnt from the ADNI MRIs, the transferred model's results are satisfying on PPMI.

RESULTS: The first main result is that our model provides satisfying long-term predictions of cognitive decline from any pair of early visits, with no fixed time delay between these visits (provided the potential decline has started at the second visit). The second main result is that the prediction performance on Parkinson's dataset (PPMI) reaches an AUC of 0.81 on PPMI after transfer learning from Alzheimer's dataset (ADNI), without even having to re-train the image filters, versus an AUC of 0.72 for the model trained from scratch on PPMI.

CONCLUSIONS: First, our model is effective for predicting long-term cognitive decline from only two visits, even with irregular intervals of time. When dealing with neurodegenerative diseases, where patients often miss some control visits, this is an important finding. Second, our model is able to transfer the knowledge learnt from one neurodegenerative disease (Alzheimer's) to another (Parkinson's), when using the same imaging modalities (brain MRI) and different clinical variables. This makes it usable even for diseases that are rare or under-studied.

RevDate: 2023-03-24

Das A, V Menon (2023)

Concurrent- and after-effects of medial temporal lobe stimulation on directed information flow to and from prefrontal and parietal cortices during memory formation.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.1728-22.2023 [Epub ahead of print].

Electrical stimulation of the medial temporal lobe (MTL) has the potential to uncover causal circuit mechanisms underlying memory function. However, little is known about how MTL stimulation alters information flow with frontoparietal cortical regions implicated in episodic memory. We used intracranial electroencephalography recordings from humans (14 participants, 10 females) to investigate how MTL stimulation alters directed information flow between MTL and prefrontal cortex (PFC) and between MTL and posterior parietal cortex (PPC). Participants performed a verbal episodic memory task during which they were presented with words and asked to recall them after a delay of ∼20 seconds. 50 Hz stimulation was applied to MTL electrodes on selected trials during memory encoding. Directed information flow was examined using phase transfer entropy. Behaviorally, we observed that MTL stimulation reduced memory recall. MTL stimulation decreased top-down PFC→MTL directed information flow during both memory encoding and subsequent memory recall, revealing aftereffects more than 20 seconds after end of stimulation. Stimulation suppressed top-down PFC→MTL influences to a greater extent than PPC→MTL. Finally, MTL→PFC information flow on stimulation trials was significantly lower for successful, compared to unsuccessful, memory recall; in contrast, MTL→ventral PPC information flow was higher for successful, compared to unsuccessful, memory recall. Together these results demonstrate that the effects of MTL stimulation are behaviorally, regionally, and directionally specific, that MTL stimulation selectively impairs directional signaling with PFC, and that causal MTL-ventral PPC circuits support successful memory recall. Findings provide new insights into dynamic casual circuits underling episodic memory and their modulation by MTL stimulation.SIGNIFICANCE STATEMENT:The medial temporal lobe (MTL) and its interactions with prefrontal cortex (PFC) play a critical role in human memory. Dysfunctional MTL-PFC circuits are prominent in psychiatric and neurological disorders including Alzheimer's disease and schizophrenia. Brain stimulation has emerged as a potential mechanism for enhancing memory and cognitive functions, but the underlying neurophysiological mechanisms and dynamic causal circuitry underlying bottom-up and top-down signaling involving the MTL are unknown. Here, we use intracranial electroencephalography recordings to investigate the effects of MTL stimulation on causal signaling in key episodic memory circuits linking the MTL with PFC. Our findings have implications for translational applications aimed at realizing the promise of brain stimulation-based treatment of memory disorders.

RevDate: 2023-03-24

Jiang R, Chi XD, Jing Y, et al (2023)

Reduction of NgR in perforant path protects neuronal morphology and function in APP/PS1 transgenic mice.

Aging, 15: pii:204605 [Epub ahead of print].

Neuronal loss is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD causes the death of neurons point towards protection of neuronal morphology and function as important therapeutic strategies. The perforant path projections from the entorhinal cortex to the dentate gyrus is the most vulnerable circuit with respect to AD. It's known that the perforant path is a very important structure for synaptic plasticity and cognitive functions. NgR (Nogo receptor) is not only involved in limiting injury-induced axonal growth but also in pathological features of AD. So, the mechanism of how NgR affects the perforant path needs further investigation. In this study, the effect of NgR in the perforant path on the neuronal morphology and function in APP/PS1 transgenic mice was studied. The results showed that downregulation of NgR in perforant path ameliorate the damaged morphology and decreased number of neurons in APP/PS1 mice. Concurrently, NgR knockdown enhanced dendritic complexity and increased postsynaptic protein density in APP/PS1 mice. Furthermore, the RT-PCR results indicated that there is downregulation of M1 phenotypes of microglial gene expression in the hippocampus of TG-shNgR mice. Our study suggests that NgR plays a critical role in microglial phenotype polarization, which might account for the NgR knockdown in the perforant path initiated a decrease in neuronal death and improved synaptic function. Our study provided a better understanding of the perforant path and the role of NgR in AD pathogenesis, thus offering the potential application of hippocampal neurons in treatment of AD.

RevDate: 2023-03-26

Murawski A, Ramirez-Zohfeld V, Schierer A, et al (2023)

Transforming a Negotiation Framework to Resolve Conflicts among Older Adults and Family Caregivers.

Geriatrics (Basel, Switzerland), 8(2):.

BACKGROUND: Family caregivers of older people with Alzheimer's dementia (PWD) often need to advocate and resolve health-related conflicts (e.g., determining treatment necessity, billing errors, and home health extensions). As they deal with these health system conflicts, family caregivers experience unnecessary frustration, anxiety, and stress. The goal of this research was to apply a negotiation framework to resolve real-world family caregiver-older adult conflicts.

METHODS: We convened an interdisciplinary team of national community-based family caregivers, social workers, geriatricians, and negotiation experts (n = 9; Illinois, Florida, New York, and California) to examine the applicability of negotiation and conflict management frameworks to three older adult-caregiver conflicts (i.e., caregiver-older adult, caregiver-provider, and caregiver-caregiver). The panel of caregivers provided scenarios and dialogue describing conflicts they experienced in these three settings. A qualitative analysis was then performed grouping the responses into a framework matrix.

RESULTS: Upon presenting the three conflicts to the caregivers, 96 responses (caregiver-senior), 75 responses (caregiver-caregiver), and 80 responses (caregiver-provider) were generated. A thematic analysis showed that the statements and responses fit the interest-rights-power (IRP) negotiation framework.

DISCUSSION: The interests-rights-power (IRP) framework, used in business negotiations, provided insight into how caregivers experienced conflict with older adults, providers, and other caregivers. Future research is needed to examine applying the IRP framework in the training of caregivers of older people with Alzheimer's dementia.

RevDate: 2023-03-25

Li D, Ma J, Wei B, et al (2023)

Effectiveness and safety of ginkgo biloba preparations in the treatment of Alzheimer's disease: A systematic review and meta-analysis.

Frontiers in aging neuroscience, 15:1124710.

OBJECTIVE: To conduct a meta-analysis of the effectiveness and safety of ginkgo biloba preparations combined with donepezil hydrochloride vs. donepezil for the treatment of Alzheimer's disease (AD).

METHODS: Three English databases (Cochrane Library, PubMed, EMBASE), and four Chinese databases [the China National Knowledge Infrastructure (CKNI), the Chinese Biomedical Literature database (CBM), the Chongqing VIP database, and WANFANG DATA)] were manually searched for literature published from the respective dates of inception of the databases to December 2022. The randomized controlled trials (RCTs) of ginkgo biloba preparations with donepezil hydrochloride vs. donepezil for the treatment of AD were included. Relevant literature was screened, and the data in the included studies were extracted for quality assessment according to the Risk of bias tool. The RevMan 5.3 software was used for meta-analysis.

RESULTS: A total of 1,642 participants were enrolled in the 18 RCTs. Of these, 842 were in the experimental group (ginkgo biloba preparations combined with donepezil hydrochloride) and 800 were in the control group (donepezil). The overall methodological quality of the included RCTs is poor due to the high risks of blindness and allocation concealment. The meta-analysis results showed statistically significant differences in several outcomes including Risk Ratio (RR) in change for clinical effectiveness rate (1.23, 95% CI 1.13, 1.34, P < 0.00001), mean difference (MD) in change for Mini-Mental State Examination score (3.02, 95% CI 2.14, 3.89, P < 0.00001), Activity of Daily Living Scale score (-4.56, 95% CI -5.09, -4.03, P < 0.00001), Hasegawa Dementia Scale score (2.04, 95% CI 1.74, 2.34, P < 0.00001), Montreal Cognitive Assessment score (2.38, 95% CI 0.72, 4.06, P = 0.005), between the experimental and control groups. But there is no statistically significant difference in change for adverse reaction (0.91, 95% CI 0.58, 1.42, P = 0.69).

CONCLUSION: Ginkgo biloba preparations plus donepezil can improve clinical effectiveness rate and vocabulary memory outcomes. However, more relevant high-quality RCTs are needed in the future to validate these results.

Identifier CRD42022378970.

RevDate: 2023-03-25

Li Z, Cao Y, Pei H, et al (2023)

The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer's disease and the potential countermeasure.

Frontiers in neuroscience, 17:1158204.

Alzheimer's disease (AD) is the most common neurodegenerative disease. There are many studies targeting extracellular deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles (NFTs), however, there are no effective treatments to halt the progression. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have long been found to be associated with various pathogenesis hypotheses of AD, such as Aβ deposition, mitochondrial dysfunction, and calcium homeostasis. However, there is a lack of literature summarizing recent advances in the mechanism and treatment studies. Accordingly, this article reviews the latest research involving the roles of MAM structure and tethering proteins in the pathogenesis of AD and summarizes potential strategies targeting MAMs to dissect treatment perspectives for AD.

RevDate: 2023-03-24

Bansal K, Singh V, Singh S, et al (2023)

Neuroprotective Potential of Hesperidin as Therapeutic Agent in the Treatment of Brain Disorders: Preclinical Evidence-based Review.

Current molecular medicine pii:CMM-EPUB-130257 [Epub ahead of print].

Neurodegenerative disorders (NDs) are progressive morbidities that represent a serious health issue in the aging world population. There is a contemporary upsurge in worldwide interest in the area of traditional remedies and phytomedicines are widely accepted by researchers due to their health-promoted effects and fewer side effects. Hesperidin, a flavanone glycoside present in the peels of citrus fruits, possesses various biological activities including anti-inflammatory and antioxidant actions. In various preclinical studies, hesperidin has provided significant protective actions in a variety of brain disorders such as Alzheimer's disease, epilepsy, Parkinson's disease, multiple sclerosis, depression, neuropathic pain, etc. as well as their underlying mechanisms. The findings indicate that the neuroprotective effects of hesperidin are mediated by modulating antioxidant defence activities and neural growth factors, diminishing apoptotic and neuro-inflammatory pathways. This review focuses on the potential role of hesperidin in managing and treating diverse brain disorders.

RevDate: 2023-03-23

Lee D, Clark ED, Antonsdottir IM, et al (2023)

A 2023 update on the advancements in the treatment of agitation in Alzheimer's disease.

Expert opinion on pharmacotherapy [Epub ahead of print].

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is one of the most common and distressing NPS, yet we lack safe and effective treatment options. While nonpharmacologic interventions are considered first line treatment, these may not be effective or appropriate for every patient. Our current approaches to the pharmacologic treatment of agitation in AD consist of the off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite their prevalent use, they have questionable efficacy and significant safety concerns.

AREAS COVERED: Advances in the understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. A comprehensive search of ClinicalTrials.gov was completed from January 2017 to June 2022 using the search terms "Alzheimer's Disease" and "Agitation". A subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified for promise in treating agitation, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin.

EXPERT OPINION: Clinical trials remain underway utilizing both novel and repurposed agents to address symptoms of agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel the development of agitation in AD, the use of enhanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we are advancing closer to having safe and efficacious treatment options for agitation in AD.

RevDate: 2023-03-23

Duan R, Hong CG, Chen ML, et al (2023)

Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease.

Chemico-biological interactions pii:S0009-2797(23)00129-1 [Epub ahead of print].

Alzheimer's disease (AD) is a common degenerative disease among the elderly population. In addition to cognitive impairment, AD is often accompanied by behavioral manifestations. However, little attention has been paid to changes in bone metabolism and related mechanisms in patients with AD. We found that AD mice (APPswe/PS1dE9) had reduced bone density, weakened bone strength, and amyloid beta (Aβ) deposition in the bone tissue. It was further found that targeting autophagy receptors Optineurin (OPTN) and Sequestosome 1 (SQSTM1) increased bone density and bone strength in AD mice, promoted the clearance of Aβ in the bone tissue, and maintained bone homeostasis. Our study suggests that abnormal Aβ deposition may be the co-pathogenesis of AD and osteoporosis (OP). Targeting OPTN and SQSTM1 has a dual-functional effect of alleviating both AD and OP through selective autophagy that specifically targets Aβ for clearance. Therapeutic strategies targeting autophagy may help guide the treatment of patients with AD complicated with OP.

RevDate: 2023-03-23

Park J, Gong JH, Chen Y, et al (2023)

Activation of ROS-PERK-TFEB by Filbertone Ameliorates Neurodegenerative Diseases via Enhancing the Autophagy-Lysosomal Pathway.

The Journal of nutritional biochemistry pii:S0955-2863(23)00058-X [Epub ahead of print].

The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B (NF-κB). Here, we report that filbertone activates PERK through mitochondrial ROS (mtROS) production, resulting in the increased nuclear translocation of transcription factor-EB (TFEB) in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway (ALP), which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet (HFD). Filbertone treatment also reduced HFD-induced α-synuclein accumulation through upregulation of the ALP pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the MPTP-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease.

RevDate: 2023-03-25

Pishbin E, Sadri F, Dehghan A, et al (2023)

Recent advances in isolation and detection of exosomal microRNAs related to Alzheimer's disease.

Environmental research, 227:115705 pii:S0013-9351(23)00497-8 [Epub ahead of print].

Alzheimer's disease, a progressive neurological condition, is associated with various internal and external risk factors in the disease's early stages. Early diagnosis of Alzheimer's disease is essential for treatment management. Circulating exosomal microRNAs could be a new class of valuable biomarkers for early Alzheimer's disease diagnosis. Different kinds of biosensors have been introduced in recent years for the detection of these valuable biomarkers. Isolation of the exosomes is a crucial step in the detection process which is traditionally carried out by multi-step ultrafiltration. Microfluidics has improved the efficiency and costs of exosome isolation by implementing various effects and forces on the nano and microparticles in the microchannels. This paper reviews recent advancements in detecting Alzheimer's disease related exosomal microRNAs based on methods such as electrochemical, fluorescent, and SPR. The presented devices' pros and cons and their efficiencies compared with the gold standard methods are reported. Moreover, the application of microfluidic devices to detect Alzheimer's disease related biomarkers is summarized and presented. Finally, some challenges with the performance of novel technologies for isolating and detecting exosomal microRNAs are addressed.

RevDate: 2023-03-23

Saposnik G, Sánchez-Benavidez G, García-Arcelay E, et al (2023)

Design of a Non-Interventional Study to Assess Neurologists' Perspectives and Pharmacological Treatment Decisions in Early Alzheimer's Disease.

Neurology and therapy [Epub ahead of print].

INTRODUCTION: The current therapeutic landscape of Alzheimer's disease (AD) is evolving rapidly. Our treatment options include new anti-amyloid-β protein disease-modifying therapies (DMTs) that decrease cognitive decline in patients with early AD (prodromal and mild AD dementia). Despite these advances, we have limited information on how neurologists would apply the results of recent DMT trials to make treatment decisions. Our goal is to identify factors associated with the use of new AD DMTs among neurologists applying concepts from behavioral economics.

METHODS: This non-interventional, cross-sectional, web-based study will assess 400 neurologists with expertise in AD from across Spain. Participants will start by completing demographic information, practice settings, and a behavioral battery to address their tolerance to uncertainty and risk preferences. Participants will then be presented with 10 simulated case scenarios or vignettes of common encounters in patients with early AD to evaluate treatment initiation with anti-amyloid-β DMTs (e.g., aducanumab, lecanemab, etc.). The primary outcomes will be therapeutic inertia and suboptimal decisions. Discrete choice experiments will be used to determine the weight of factors influencing treatment choices.

RESULTS: The results of this study will provide new insights into a better understanding of the most relevant factors associated with therapeutic decisions on the use of DMTs, assessing how neurologists handle uncertainty when making treatment choices, and identifying the prevalence of therapeutic inertia in the management of early AD.

RevDate: 2023-03-24
CmpDate: 2023-03-24

Yang H, Jia H, Deng M, et al (2023)

Design, synthesis and evaluation of OA-tacrine hybrids as cholinesterase inhibitors with low neurotoxicity and hepatotoxicity against Alzheimer's disease.

Journal of enzyme inhibition and medicinal chemistry, 38(1):2192439.

A series of OA-tacrine hybrids with the alkylamine linker was designed, synthesized, and evaluated as effective cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some hybrids possessed significant inhibitory activities against acetylcholinesterase (AChE). Among them, compounds B4 (hAChE, IC50 = 14.37 ± 1.89 nM; SI > 695.89) and D4 (hAChE, IC50 = 0.18 ± 0.01 nM; SI = 3374.44) showed excellent inhibitory activities and selectivity for AChE as well as low nerve cell toxicity. Furthermore, compounds B4 and D4 exhibited lower hepatotoxicity than tacrine in cell viability, apoptosis, and intracellular ROS production for HepG2 cells. These properties of compounds B4 and D4 suggest that they deserve further investigation as promising agents for the prospective treatment of AD.

RevDate: 2023-03-24

Karvandi MS, Sheikhzadeh Hesari F, Aref AR, et al (2023)

The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation.

Frontiers in cellular neuroscience, 17:1105247.

Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.

RevDate: 2023-03-24

Zhou X, Huang K, Wang Y, et al (2023)

Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer's disease mouse model and proteomics analysis.

Frontiers in pharmacology, 14:1082602.

The pathophysiology of Alzheimer's disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non-amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.

RevDate: 2023-03-24
CmpDate: 2023-03-24

Wu H, Xi M, W Xie (2023)

Epidemiological and clinical characteristics of older adults with burns: a 15-year retrospective analysis of 2554 cases in Wuhan Institute of Burns.

BMC geriatrics, 23(1):162.

BACKGROUND: With the increase of geriatric burns, it's urgent to summarize its characteristics. The aim of this study was to analyze the epidemiological and clinical characteristics of older adults with burns in a large center, and to provide suggestions for the prevention and treatment of geriatric burns.

METHODS: This retrospective study was conducted at Wuhan Institute of Burns which is the largest burn center in central China between 2004 to 2018. Demographic and clinical data of the 60 years or above older burn inpatients were collected from medical records, analyzed and compared among groups.

RESULTS: This study analyzed 2554 elderly burns, which included 50.9% in young geriatric group (60-69 years old), 32.9% in middle geriatric group (70-79 years old) and 16.2% in the oldest geriatric group (80 years old or above). The most common causes of elderly burns were flames (1081, 42.3%) and scalding (1041, 40.8%). Elderly burns with total body surface area (TBSA) of 0-9% accounted for 60.6% and the larger TBSA, the fewer number of patients. The majority of patients (70.5%) injured at home.The median of time interval from injury to admission was 7 h and the oldest geriatric group (24 h) was highest. One hundred and twenty-one cases (8.5%) were treated by cooling treatment, and 72.7% of these patients were treated less than 10 min. The median number of pre-injury diseases was one. Ninety patients (6.3%) had inhalation injury.The median length of stay (LOS) was 14 days.The median hospital cost was 10,410 CNY or 2137 CNY per % TBSA, which was correlated with TBSA, LOS, surgery, inhalation injury, number of pre-injury diseases and etiology. The mortality rate was 3.0% and correlated with TBSA, inhalation injury, pulmonary disease and Alzheimer's disease. The lethal area 50% (LA50) for total admitted elderly burns was 78.3% TBSA (95% confidence interval [CI] = 69.8 ~ 89.9% TBSA).

CONCLUSION: Geriatric burns was still common and even increasing in central China, with flame burns and scalds the most common causes, majority of whom injured at home and often had problems such as few cooling treatment, improper emergency management and delayed admission. TBSA, etiology, pre-injury diseases and inhalation injury were the risk factors of length of stay, hospital cost and treatment outcomes.

RevDate: 2023-03-24
CmpDate: 2023-03-24

Matrisciano F, G Pinna (2023)

The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.

Advances in experimental medicine and biology, 1411:513-535.

Peroxisome proliferator-activated receptors (PPARs) are nonsteroid nuclear receptors and transcription factors that regulate several neuroinflammatory and metabolic processes, recently involved in several neuropsychiatric conditions, including Alzheimer's disease, Parkinson's disease, major depressive disorder, post-traumatic stress disorder (PTSD), schizophrenia spectrum disorders, and autism spectrum disorders. PPARs are ligand-activated receptors that, following stimulation, induce neuroprotective effects by decreasing neuroinflammatory processes through inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) expression and consequent suppression of pro-inflammatory cytokine production. PPARs heterodimerize with the retinoid X-receptor (RXR) and bind to PPAR-responsive regulatory elements (PPRE) in the promoter region of target genes involved in lipid metabolism, synthesis of cholesterol, catabolism of amino acids, and inflammation. Interestingly, PPARs are considered functionally part of the extended endocannabinoid (eCB) system that includes the classic eCB, anandamide, which act at cannabinoid receptor types 1 (CB1) and 2 (CB2) and are implicated in the pathophysiology of stress-related neuropsychiatric disorders. In preclinical studies, PPAR stimulation improves anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. The peculiar functional role of PPARs by exerting anti-inflammatory and neuroprotective effects and their expression localization in neurons and glial cells of corticolimbic circuits make them particularly interesting as novel therapeutic targets for several neuropsychiatric disorders characterized by underlying neuroinflammatory/neurodegenerative mechanisms. Herein, we discuss the pathological hallmarks of neuropsychiatric conditions associated with neuroinflammation, as well as the pivotal role of PPARs with a special emphasis on the subtype alpha (PPAR-α) as a suitable molecular target for therapeutic interventions.

RevDate: 2023-03-23

Pradhan SP, Sahu PK, A Behera (2023)

New insights toward molecular and nanotechnological approaches to antidiabetic agents for Alzheimer's disease.

Molecular and cellular biochemistry [Epub ahead of print].

Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting a major class of silver citizens. The disorder shares a mutual relationship on account of its cellular and molecular pathophysiology with type-II diabetes mellitus (DM). Chronic DM increases the risk for AD. Emerging evidence recommended that resistance in insulin production develops cognitive dysfunction, which generally leads to AD. Repurposing of antidiabetic drugs can be effective in preventing and treatment of the neurodegenerative disorder. Limitations of antidiabetic drugs restrict the repurposing of the drugs for other disorders. Therefore, nanotechnological intervention plays a significant role in the treatment of neurological disorders. In this review, we discuss the common cellular and molecular pathophysiologies between AD and type-II DM, the relevance of in vivo models of type II DM in the study of AD, and the repurposing of antidiabetic drugs and the nanodelivery systems of antidiabetic drugs against AD.

RevDate: 2023-03-22

Raschke S, Ebert F, Kipp AP, et al (2023)

Selenium homeostasis in human brain cells: Effects of copper (II) and Se species.

Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 78:127149 pii:S0946-672X(23)00025-1 [Epub ahead of print].

BACKGROUND: Both essential trace elements selenium (Se) and copper (Cu) play an important role in maintaining brain function. Homeostasis of Cu, which is tightly regulated under physiological conditions, seems to be disturbed in Alzheimer´s (AD) and Parkinson´s disease (PD) patients. Excess Cu promotes the formation of oxidative stress, which is thought to be a major cause for development and progression of neurological diseases (NDs). Most selenoproteins exhibit antioxidative properties and may counteract oxidative stress. However, expression of selenoproteins is altered under conditions of Se deficiency. Serum Se levels are decreased in AD and PD patients suggesting Se as an important factor in the development and progression of NDs. The aim of this study was to elucidate the interactions between Cu and Se in human brain cells particularly with respect to Se homeostasis.

METHODS: Firstly, modulation of Se status by selenite or SeMet were assessed in human astrocytes and human differentiated neurons. Therefore, cellular total Se content, intra- and extracellular selenoprotein P (SELENOP) content, and glutathione peroxidase (GPX) activity were quantified. Secondly, to investigate the impact of Cu on these markers, cells were exposed to copper(II)sulphate (CuSO4) for 48 h. In addition, putative protective effects of Se on Cu-induced toxicity, as measured by cell viability, DNA damage, and neurodegeneration were investigated.

RESULTS: Modulation of cellular Se status was strongly dependent on Se species. In detail, SeMet increased total cellular Se and SELENOP content, whereas selenite led to increased GPX activity and SELENOP excretion. Cu treatment resulted in 133-fold higher cellular Cu concentration with a concomitant decrease in Se content. Additionally, SELENOP excretion was suppressed in both cell lines, while GPX activity was diminished only in astrocytes. These effects of Cu could be partially prevented by the addition of Se depending on the cell line and Se species used. While Cu-induced oxidative DNA damage could not be prevented by addition of Se regardless of chemical species, SeMet protected against neurite network degeneration triggered by Cu.

CONCLUSION: Cu appears to negatively affect Se status in astrocytes and neurons. Especially with regard to an altered homeostasis of those trace elements during aging, this interaction is of high physiological relevance. Increasing Cu concentrations associated with decreased selenoprotein expression or functionality might be a promoting factor for the development of NDs.

RevDate: 2023-03-23

Burke AD, D Goldfarb (2023)

Diagnosing and Treating Alzheimer Disease During the Early Stage.

The Journal of clinical psychiatry, 84(2): pii:LI21019AH3C.

Recent advances in technology can lead to earlier detection of Alzheimer disease (AD) in patients and therefore opportunities for early diagnosis and treatment. In addition, novel agents can slow disease progression and improve symptoms. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Early detection and intervention are crucial to slow symptom progression, and these advances provide a window of opportunity to diagnose the disease early and even prevent it from becoming symptomatic. Clinicians need education on early recognition of AD and on sharing the diagnosis of AD with patients and families as well as guidance for providing patients and families with information on next steps and facilitating early treatment initiation for AD. Partnering with clinicians in the primary care setting and providing them with the necessary tools can change the trajectory of the disease for patients and caregivers.

RevDate: 2023-03-23

Lenze EJ, Reiersen AM, Zorumski CF, et al (2023)

Beyond "Psychotropic": Repurposing Psychiatric Drugs for COVID-19, Alzheimer's Disease, and Cancer.

The Journal of clinical psychiatry, 84(3): pii:22r14494.

Importance: "Psychotropic" drugs have widespread reach and impact throughout the brain and body. Thus, many of these drugs could be repurposed for non-psychiatric indications of high public health impact. Observations: The selective serotonin reuptake inhibitor (SSRI) fluvoxamine was shown efficacious as a COVID-19 treatment based on randomized controlled trials (RCTs), and a benefit of other antidepressants has been posited based on observational and preclinical studies. In this review, we illuminate features of SSRIs and other psychiatric drugs that make them candidates to repurpose for non-psychiatric indications. We summarize research that led to fluvoxamine's use in COVID-19 and provide guidance on how to use it safely. We summarize studies suggestive of benefit of other antidepressants versus COVID-19 and long COVID. We also describe putative mechanisms of psychiatric drugs in treating long COVID, Alzheimer's disease, cancer, and other conditions. Conclusion and Relevance: There is a potentially great clinical and public health impact of psychotropic drug repurposing. Challenges exist to such repurposing efforts, but solutions exist for researchers, regulators, and funders that overcome these challenges.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Pang Y, Kukull W, Sano M, et al (2023)

Predicting Progression from Normal to MCI and from MCI to AD Using Clinical Variables in the National Alzheimer's Coordinating Center Uniform Data Set Version 3: Application of Machine Learning Models and a Probability Calculator.

The journal of prevention of Alzheimer's disease, 10(2):301-313.

Clinical trials are increasingly focused on pre-manifest and early Alzheimer's disease (AD). Accurately predicting clinical progressions from normal to MCI or from MCI to dementia/AD versus non-progression is challenging. Accurate identification of symptomatic progressors is important to avoid unnecessary treatment and improve trial efficiency. Due to large inter-individual variability, biomarker positivity and comorbidity information are often insufficient to identify those destined to have symptomatic progressions. Using only clinical variables, we aimed to predict clinical progressions, estimating probabilities of progressions with a small set of variables selected by machine learning approaches. This work updates our previous work that was applied to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set Version 2 (V2), by using the most recent version (V3) with additional analyses. We generated a user-friendly conversion probability calculator which can be used for effectively pre-screening trial participants.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Salehipour A, Dolatshahi M, Haghshomar M, et al (2023)

The Role of Thyroid Dysfunction in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The journal of prevention of Alzheimer's disease, 10(2):276-286.

Imbalances in thyroid hormones have been linked with Alzheimer's dementia. Several studies have reported an association between thyroid disorders, such as hyper- or hypothyroidism, with Alzheimer's disease. However, there remains no consensus about the precise role of thyroid dysfunction in Alzheimer's disease. In this study we systematically searched PubMed, Embase and Scopus for clinical studies which reported the prevalence of hyper- or hypothyroidism in people with Alzheimer's disease compared to controls. Meta-analysis was performed to compare thyroid disorder prevalence in Alzheimer's disease and controls. Subgroup analysis was performed to assess the clinical and subclinical thyroid dysfunction, separately. Seven studies, including 1189 people with Alzheimer's disease and 72711 controls, were included in our sample. Hypothyroidism was significantly more prevalent in Alzheimer's disease compared with controls (6.4% vs 2.4%, p=0.01). Subgroup analysis showed that clinical hypothyroidism was not significantly different between Alzheimer's disease compared to controls (10.0% vs 5.3%, p=0.35). There was no difference in the crude overall prevalence of clinical and subclinical hyperthyroidism in Alzheimer's disease versus controls (2.4 vs 1.9%, p=0.73). Our analyses revealed a higher prevalence of hypothyroidism in Alzheimer's disease. Whether this finding is explained by hypothyroidism being a risk factor for, or consequence of, Alzheimer's disease requires longitudinal analysis. Our review supports further work into a potential role for treatment of hypothyroidism in the prevention or delay of Alzheimer's disease.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Mallinckrodt C, Tian Y, Aisen PS, et al (2023)

Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab.

The journal of prevention of Alzheimer's disease, 10(2):171-177.

OBJECTIVES: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies.

DESIGN: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies.

SETTING: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries.

PARTICIPANTS: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE.

INTERVENTION: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks.

MEASUREMENTS: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab.

RESULTS: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms.

CONCLUSIONS: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Pruzin JJ, Brunton S, Alford S, et al (2023)

Medical Journey of Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease Dementia: A Cross-sectional Survey of Patients, Care Partners, and Neurologists.

The journal of prevention of Alzheimer's disease, 10(2):162-170.

BACKGROUND: Alzheimer's disease (AD) is a progressive, neurodegenerative disease presenting along a continuum ranging from asymptomatic disease to mild cognitive impairment (MCI), followed by dementia characterized as mild, moderate, or severe.

OBJECTIVES: To better understand the medical journey of patients with all-cause MCI or mild AD dementia from the perspective of patients, care partners, and physicians.

DESIGN: Cross-sectional study.

SETTING: Online surveys in the United States between February 4, 2021, and March 1, 2021.

PARTICIPANTS: 103 patients with all-cause MCI or mild AD dementia and 150 care partners participated in this survey. 301 physicians (75 of whom were neurologists) completed a survey.

MEASUREMENTS: The surveys included questions regarding attitudes, experiences, and behaviors related to diagnosis and management of MCI and mild AD dementia. For the patient and care partner surveys, questions regarding healthcare received for MCI and mild AD dementia were only asked of care partners.

RESULTS: Most patients (73%) had a similar medical journey. The majority (64%) initially consulted a primary care physician on average 15 months after symptom onset, with symptoms primarily consisting of forgetfulness and short-term memory loss. About half (51%) of patients in the typical medical journey were diagnosed by a neurologist. Upon diagnosis, most neurologists reported having discussions with patients and care partners about the potential causes of MCI or mild AD dementia (83%); of these physicians, 83% explained the effect other conditions have on the risk of the diagnoses and symptom progression. Neurologists (52%) consider themselves the coordinator of care for patients with MCI or mild AD dementia. Amongst patients and care partners, about one-third (35%) perceive the neurologists to be the coordinating physician.

CONCLUSIONS: Neurologists commonly diagnose MCI and mild AD dementia but are typically not the first point of contact in the medical journey, and patients do not consult with a physician for over a year after symptom onset. Neurologists play a key role in the medical journey for patients and care partners, and could help ensure earlier diagnosis and treatment, and improve clinical outcomes by coordinating MCI and mild AD dementia care and collaborating with primary care physicians.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Bogolepova AN (2023)

[Cerebrolysin in the treatment of cognitive impairment].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 123(3):20-25.

Cognitive impairment is one of the most important problems of modern health care. Currently, according to WHO, more than 55 million people worldwide are living with dementia. Dementia is one of the leading causes of disability and addiction among older people worldwide. Even more significant is the number of patients with mild cognitive impairment who have an increased risk of progression to dementia compared to people of the same age without cognitive impairment. The number of patients with cognitive impairment has also increased due to the consequences of COVID-19. It is necessary to use drugs that not only improve cognitive functions, but also slow down their progression. One of these drugs is cerebrolysin, the effectiveness of which has been confirmed in various types of cognitive impairment. Cerebrolysin, being a preparation from the brain of a pig, belongs to the group of biological drugs. In the production of Cerebrolysin very strict measures are taken to comply with the technology, which ensures the quality and identity of the product from batch to batch. The experience of many years of clinical use of Cerebrolysin testifies not only to its high efficiency, but also to its safety. It should be taken into account that similar substances can be developed in relation to biological products - biosimilars or biosimilars, which can be considered comparable only in case of equivalent pharmacokinetic parameters, efficacy and safety.

RevDate: 2023-03-22

Preußner M, Smith HL, Hughes D, et al (2023)

ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo.

EMBO molecular medicine [Epub ahead of print].

Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold-induced expression. Genetic removal or antisense oligonucleotide (ASO)-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increased RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease-associated prion protein. Our promising results in mice support the possibility that RBM3-inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease.

RevDate: 2023-03-22

Uzunhisarcıklı E, Çelik İ, MB Yerer (2023)

Detection of natural compounds by virtual screening, molecular docking and dynamics studies and evaluation of their effects on tau level in vitro Alzheimer's model.

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

In Alzheimer's disease (AD), neurofibrillary tangles are composed of hyperphosphorylated tau protein, and tau hyperphosphorylation reduces microtubule binding. Many protein kinases are thought to be involved in tau hyperphosphorylation. Based on the fact that tau hyperphosphorylation can be prevented by inhibition of glycogen synthase kinase-3β (GSK-3β), which is one of the tau kinases, the effectiveness of potential GSK-3β inhibitors determined by virtual screening, molecular docking, and dynamics simulations studies on Alzheimer's pathology has been examined and its role in neurodegeneration has been investigated by studies. Neomangiferin was determined as the most effective molecule according to the results of studies with potential compounds determined by virtual screening and molecular docking to be GSK-3β inhibitors in the in vitro Alzheimer's model created by neuronal differentiation studies. Neomangiferin has been shown to have a protective role in induced neurodegeneration by the MTT method and Real Time Cell Analysis. It has been determined that Neomangiferin inhibits GSK-3β and reduces the level of phosphorylated tau. In summary, our findings suggested Neomangiferin can be a therapeutic candidate for AD treatment.Communicated by Ramaswamy H. Sarma.

RevDate: 2023-03-22

Qiu W, Liu H, Liu Y, et al (2023)

Regulation of beta-amyloid for the treatment of Alzheimer's disease: Research progress of therapeutic strategies and bioactive compounds.

Medicinal research reviews [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is difficult to treat. Extracellular amyloid is the principal pathological criterion for the diagnosis of AD. Amyloid β (Aβ) interacts with various receptor molecules on the plasma membrane and mediates a series of signaling pathways that play a vital role in the occurrence and development of AD. Research on receptors that interact with Aβ is currently ongoing. Overall, there are no effective medications to treat AD. In this review, we first discuss the importance of Aβ in the pathogenesis of AD, then summarize the latest progress of Aβ-related targets and compounds. Finally, we put forward the challenges and opportunities in the development of effective AD therapies.

RevDate: 2023-03-22

Ahlawat J, Wilson DL, Carreon A, et al (2023)

Resolving the soluble-to-toxic transformation of amyloidogenic proteins: A method to assess intervention by small-molecules.

Research square pii:rs.3.rs-2631727.

The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aβ), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others is associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. Conversely, the dissolution of mature fibrils and toxic amyloidogenic intermediates including oligomers remains the holy grail in the treatment of neurodegenerative disorders. Yet, methods to effectively, and quantitatively, report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. For the first time, we describe the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique permits rapid, inexpensive and quantitative assessment of the fraction of amyloid monomers that form intermediates and mature fibrils. In addition, the method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers or retain amyloid proteins in their monomeric forms. Importantly, our methodological advance diminishes major existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.

RevDate: 2023-03-22

Perez FP, Rahmani M, Morisaki J, et al (2023)

Numerical Modeling and Computer Simulation of a Meander Line Antenna for Alzheimer's Disease Treatment, a Feasibility Study.

Journal of biosciences and medicines, 11(2):177-185.

Alzheimer's disease (AD) is a brain disorder that eventually causes memory loss and the ability to perform simple cognitive functions; research efforts within pharmaceuticals and other medical treatments have minimal impact on the disease. Our preliminary biological studies showed that Repeated Electromagnetic Field Stimulation (REFMS) applying an EM frequency of 64 MHz and a specific absorption rate (SAR) of 0.4 - 0.9 W/kg decrease the level of amyloid-β peptides (Aβ), which is the most likely etiology of AD. This study emphasizes uniform E/H field and SAR distribution with adequate penetration depth penetration through multiple human head layers driven with low input power for safety treatments. In this work, we performed numerical modeling and computer simulations of a portable Meander Line antenna (MLA) to achieve the required EMF parameters to treat AD. The MLA device features a low cost, small size, wide bandwidth, and the ability to integrate into a portable system. This study utilized a High-Frequency Simulation System (HFSS) in the design of the MLA with the desired characteristics suited for AD treatment in humans. The team designed a 24-turn antenna with a 60 cm length and 25 cm width and achieved the required resonant frequency of 64 MHz. Here we used two numerical human head phantoms to test the antenna, the MIDA and spherical head phantom with six and seven tissue layers, respectively. The antenna was fed from a 50-Watt input source to obtain the SAR of 0.6 W/kg requirement in the center of the simulated brain tissue layer. We found that the E/H field and SAR distribution produced was not homogeneous; there were areas of high SAR values close to the antenna transmitter, also areas of low SAR value far away from the antenna. This paper details the antenna parameters, the scattering parameters response, the efficiency response, and the E and H field distribution; we presented the computer simulation results and discussed future work for a practical model.

RevDate: 2023-03-21

Pramanik SK, Sanphui P, Das AK, et al (2023)

Small-Molecule Cdc25A Inhibitors Protect Neuronal Cells from Death Evoked by NGF Deprivation and 6-Hydroxydopamine.

ACS chemical neuroscience [Epub ahead of print].

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that are presently incurable. There have been reports of aberrant activation of cell cycle pathways in neurodegenerative diseases. Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have synthesized a small library of molecules targeting Cdc25A and tested their neuroprotective potential in cellular models of neurodegeneration. The Buchwald reaction and amide coupling were crucial steps in synthesizing the Cdc25A-targeting molecules. Several of these small-molecule inhibitors significantly prevented neuronal cell death induced by nerve growth factor (NGF) deprivation as well as 6-hydroxydopamine (6-OHDA) treatment. Lack of NGF signaling leads to neuron death during development and has been associated with AD pathogenesis. The NGF receptor TrkA has been reported to be downregulated at the early stages of AD, and its reduction is linked to cognitive failure. 6-OHDA, a PD mimic, is a highly oxidizable dopamine analogue that can be taken up by the dopamine transporters in catecholaminergic neurons and can induce cell death by reactive oxygen species (ROS) generation. Some of our newly synthesized molecules inhibit Cdc25A phosphatase activity, block loss of mitochondrial activity, and inhibit caspase-3 activation caused by NGF deprivation and 6-OHDA. Hence, it may be proposed that Cdc25A inhibition could be a therapeutic possibility for neurodegenerative diseases and these Cdc25A inhibitors could be effective treatments for AD and PD.

RevDate: 2023-03-21

Balaji N, Balachandar R, Algodayan S, et al (2023)

New impetus for amyloid-PET imaging following the Food and Drug administration approval of a new Alzheimer's disease treatment.

Nuclear medicine communications pii:00006231-990000000-00136 [Epub ahead of print].

RevDate: 2023-03-21

Chen HF, Sheng XN, Yang ZY, et al (2023)

Multi-networks connectivity at baseline predicts the clinical efficacy of left angular gyrus-navigated rTMS in the spectrum of Alzheimer's disease: A sham-controlled study.

CNS neuroscience & therapeutics [Epub ahead of print].

INTRODUCTION: Neuro-navigated repetitive transcranial magnetic stimulation (rTMS) is effective in alleviating cognitive deficits in Alzheimer's disease (AD). However, the strategy for target determination and the mechanisms for cognitive improvement remain unclear.

METHODS: One hundred and thirteen elderly subjects were recruited in this study, including both cross-sectional (n = 79) and longitudinal experiments (the rTMS group: n = 24; the sham group: n = 10). The cross-sectional experiment explored the precise intervention target based on the cortical-hippocampal network. The longitudinal experiment investigated the clinical efficacy of neuro-navigated rTMS treatment over a four-week period and explored its underlying neural mechanism using seed-based and network-based analysis. Finally, we applied connectome-based predictive modeling to predict the rTMS response using these functional features at baseline.

RESULTS: RTMS at a targeted site of the left angular gyrus (MNI: -45, -67, 38) significantly induced cognitive improvement in memory and language function (p < 0.001). The improved cognition correlated with the default mode network (DMN) subsystems. Furthermore, the connectivity patterns of DMN subsystems (r = 0.52, p = 0.01) or large-scale networks (r = 0.85, p = 0.001) at baseline significantly predicted the Δ language cognition after the rTMS treatment. The connectivity patterns of DMN subsystems (r = 0.47, p = 0.019) or large-scale networks (r = 0.80, p = 0.001) at baseline could predict the Δ memory cognition after the rTMS treatment.

CONCLUSION: These findings suggest that neuro-navigated rTMS targeting the left angular gyrus could improve cognitive function in AD patients. Importantly, dynamic regulation of the intra- and inter-DMN at baseline may represent a potential predictor for favorable rTMS treatment response in patients with cognitive impairment.

RevDate: 2023-03-22
CmpDate: 2023-03-22

Cho MH, Han K, Lee S, et al (2023)

Blood pressure and dementia risk by physical frailty in the elderly: a nationwide cohort study.

Alzheimer's research & therapy, 15(1):56.

BACKGROUND: Midlife hypertension has been recognized as a modifiable risk factor for dementia, but association between blood pressure (BP) in late life and dementia has been inconclusive. In addition, few studies have investigated effects of BP control on dementia incidence in the frail elderly. Thus, this study aimed to investigate the association of BP and dementia incidence with concomitant consideration of physical frailty in the young elderly population.

METHODS: Using the Korean National Health Information Database, we identified 804,024 subjects without history of dementia at age 66. Dementia diagnosis was defined with prescription records of anti-dementia drugs and dementia-related diagnostic codes. Physical frailty was measured using the Timed Up and Go test. Association of BP and dementia incidence with concomitant consideration of physical frailty was investigated using Cox hazards analyses.

RESULTS: The risks of Alzheimer's and vascular dementia increased from systolic BP ≥ 160 and 130-139 mmHg, respectively; a significant association of dementia incidence with low BP was not observed. In the analyses stratified by the physical frailty status, low BP was not associated with increased risks of dementia within the groups both with and without physical frailty.

CONCLUSIONS: High BP was associated with increased risks of dementia, especially for vascular dementia, while low BP was not associated with increased risks of any type of dementia in young elderly people, even in those with physical frailty. This study suggests the need for tight BP control in young elderly people, irrespective of frailty status, to prevent dementia and supports the current clinical guidelines of hypertension treatment.

RevDate: 2023-03-22
CmpDate: 2023-03-22

Oroszi T, Geerts E, Rajadhyaksha R, et al (2023)

Whole-body vibration ameliorates glial pathological changes in the hippocampus of hAPP transgenic mice, but does not affect plaque load.

Behavioral and brain functions : BBF, 19(1):5.

BACKGROUND: Alzheimer's disease (AD) is the core cause of dementia in elderly populations. One of the main hallmarks of AD is extracellular amyloid beta (Aβ) accumulation (APP-pathology) associated with glial-mediated neuroinflammation. Whole-Body Vibration (WBV) is a passive form of exercise, but its effects on AD pathology are still unknown.

METHODS: Five months old male J20 mice (n = 26) and their wild type (WT) littermates (n = 24) were used to investigate the effect of WBV on amyloid pathology and the healthy brain. Both J20 and WT mice underwent WBV on a vibration platform or pseudo vibration treatment. The vibration intervention consisted of 2 WBV sessions of 10 min per day, five days per week for five consecutive weeks. After five weeks of WBV, the balance beam test was used to assess motor performance. Brain tissue was collected to quantify Aβ deposition and immunomarkers of astrocytes and microglia.

RESULTS: J20 mice have a limited number of plaques at this relatively young age. Amyloid plaque load was not affected by WBV. Microglia activation based on IBA1-immunostaining was significantly increased in the J20 animals compared to the WT littermates, whereas CD68 expression was not significantly altered. WBV treatment was effective to ameliorate microglia activation based on morphology in both J20 and WT animals in the Dentate Gyrus, but not so in the other subregions. Furthermore, GFAP expression based on coverage was reduced in J20 pseudo-treated mice compared to the WT littermates and it was significantly reserved in the J20 WBV vs. pseudo-treated animals. Further, only for the WT animals a tendency of improved motor performance was observed in the WBV group compared to the pseudo vibration group.

CONCLUSION: In accordance with the literature, we detected an early plaque load, reduced GFAP expression and increased microglia activity in J20 mice at the age of ~ 6 months. Our findings indicate that WBV has beneficial effects on the early progression of brain pathology. WBV restored, above all, the morphology of GFAP positive astrocytes to the WT level that could be considered the non-pathological and hence "healthy" level. Next experiments need to be performed to determine whether WBV is also affective in J20 mice of older age or other AD mouse models.

RevDate: 2023-03-20

Wang P, Yi T, Mao S, et al (2023)

Neuroprotective mechanism of human umbilical cord mesenchymal stem cell-derived extracellular vesicles improving the phenotype polarization of microglia via the PI3K/AKT/Nrf2 pathway in vascular dementia.

Synapse (New York, N.Y.) [Epub ahead of print].

OBJECTIVE: Vascular dementia (VaD) is a prevalent cause of dementia after Alzheimer's disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-Evs) are critical for VaD treatment. We explored the mechanism of hUCMSC-Evs in VaD.

METHODS: VaD rat model was established by bilateral common carotid artery ligation and hUCMSC-Evs were extracted. VaD rats were injected with Evs through the tail vein. Rat neurological scores, neural behaviors, memory and learning abilities, brain tissue pathological changes, and neurological impairment were evaluated by Zea-Longa method, Morris water maze tests, HE staining, and ELISA [through acetylcholine (ACH) and dopamine (DA) assessment]. Microglia M1/M2 polarization was detected by immunofluorescence staining. Pro-/anti-inflammatory factor levels in brain tissue homogenate, oxidative stress-related indicators, and p-PI3K, PI3K, p-AKT, AKT, and Nrf2 protein levels were determined by ELISA, kits, and Western blot. VaD rats were jointly treated with PI3K phosphorylation inhibitor Ly294002 and hUCMSC-Evs.

RESULTS: VaD rats manifested increased neurological function injury scores, decreased cognitive function and learning ability, abnormal brain structure, obvious inflammatory infiltration, diminished ACH and DA levels, increased microglial cells and M1-polarized cells, M1/M2 polarization ratio, inflammation, and oxidative stress. hUCMSC-Evs alleviated the neurological damage of VaD rats, inhibited M1 polarization, inflammation, and oxidative stress of microglial cells in brain tissues of VaD rats, and activated the PI3K/AKT/Nrf2 pathway. Ly294002 partially averted the effects of hUCMSC-Evs on microglial polarization, inflammation, and oxidative stress.

CONCLUSION: HUCMSC-Evs activated the PI3K/AKT/Nrf2 pathway and inhibited microglial M1 polarization, inflammation, and oxidative stress, thus protecting VaD rat nerve functions. This article is protected by copyright. All rights reserved.

RevDate: 2023-03-20

Chappelle SD, Gigliotti C, Léger GC, et al (2023)

Comparison of the telephone-Montreal Cognitive Assessment (T-MoCA) and Telephone Interview for Cognitive Status (TICS) as screening tests for early Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options.

METHODS: The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) were administered to participants independently classified through in-person clinical evaluation as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25), or dementia (n = 23). Cerebrospinal fluid AD biomarkers were measured (n = 79).

RESULTS: TICS and T-MoCA were highly correlated (r = 0.787; P < 0.001): groups differed on both (CN
DISCUSSION: TICS and T-MoCA are effective for remotely detecting cognitive impairment associated with AD in older adults. Strong correlation between tests provides construct validity for the newer T-MoCA.

HIGHLIGHTS: Construct validity for the telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) was newly established against the Telephone Interview for Cognitive Status (TICS). TICS and T-MoCA effectively detected cognitive impairment with remote administration. Both tests negatively correlated with a composite cerebrospinal fluid Alzheimer's disease (AD) biomarker (tau/amyloid beta 1-42).

RevDate: 2023-03-21

Cai Z, Liu M, Zeng L, et al (2023)

Role of traditional Chinese medicine in ameliorating mitochondrial dysfunction via non-coding RNA signaling: Implication in the treatment of neurodegenerative diseases.

Frontiers in pharmacology, 14:1123188.

Neurodegenerative diseases (NDs) are common chronic disorders associated with progressive nervous system damage, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Mitochondria are abundant in various nervous system cells and provide a bulk supply of the adenosine triphosphate necessary for brain function, considered the center of the free-radical theory of aging. One common feature of NDs is mitochondrial dysfunction, which is involved in many physiopathological processes, including apoptosis, inflammation, oxidative stress, and calcium homeostasis. Recently, genetic studies revealed extensive links between mitochondrion impairment and dysregulation of non-coding RNAs (ncRNAs) in the pathology of NDs. Traditional Chinese medicines (TCMs) have been used for thousands of years in treating NDs. Numerous modern pharmacological studies have demonstrated the therapeutic effects of prescription, herbal medicine, bioactive ingredients, and monomer compounds of TCMs, which are important for managing the symptoms of NDs. Some highly effective TCMs exert protective effects on various key pathological features regulated by mitochondria and play a pivotal role in recovering disrupted signaling pathways. These disrupted signaling pathways are induced by abnormally-expressed ncRNAs associated with mitochondrial dysfunction, including microRNAs, long ncRNAs, and circular RNAs. In this review, we first explored the underlying ncRNA mechanisms linking mitochondrial dysfunction and neurodegeneration, demonstrating the implication of ncRNA-induced mitochondrial dysfunction in the pathogenesis of NDs. The ncRNA-induced mitochondrial dysfunctions affect mitochondrial biogenesis, dynamics, autophagy, Ca[2+] homeostasis, oxidative stress, and downstream apoptosis. The review also discussed the targeting of the disease-related mitochondrial proteins in NDs and the protective effects of TCM formulas with definite composition, standardized extracts from individual TCMs, and monomeric compounds isolated from TCM. Additionally, we explored the ncRNA regulation of mitochondrial dysfunction in NDs and the effects and potential mechanisms of representative TCMs in alleviating mitochondrial pathogenesis and conferring anti-inflammatory, antioxidant, and anti-apoptotic pathways against NDs. Therefore, this review presents an overview of the role of mitochondrion-related ncRNAs and the target genes for TCM-based therapeutic interventions in NDs, providing insight into understanding the "multi-level compound-target-pathway regulatory" treatment mechanism of TCMs.

RevDate: 2023-03-21

Azevedo CV, Hashiguchi D, Campos HC, et al (2023)

The effects of resistance exercise on cognitive function, amyloidogenesis, and neuroinflammation in Alzheimer's disease.

Frontiers in neuroscience, 17:1131214.

With the increasing prevalence of Alzheimer's disease (AD) and difficulties in finding effective treatments, it is essential to discover alternative therapies through new approaches. In this regard, non-pharmacological therapies, such as physical exercise, have been proposed and explored for the treatment of AD. Recent studies have suggested that resistance exercise (RE) is an effective strategy for promoting benefits in memory and cognitive function, producing neuroprotective and anti-inflammatory effects, and reducing amyloid load and plaques, thereby reducing the risk, and alleviating the neurodegeneration process of AD and other types of dementia in the elderly. In addition, RE is the exercise recommended by the World Health Organization for the elderly due to its benefits in improving muscle strength and balance, and increasing autonomy and functional capacity, favoring improvements in the quality of life of the elderly population, who is more likely to develop AD and other types of dementia. In this mini-review, we discuss the impact of RE on humans affected by MCI and AD, and animal models of AD, and summarize the main findings regarding the effects of RE program on memory and cognitive functions, neurotrophic factors, Aβ deposition and plaque formation, as well as on neuroinflammation. Overall, the present review provides clinical and preclinical evidence that RE plays a role in alleviating AD symptoms and may help to understand the therapeutic potential of RE, thereby continuing the advances in AD therapies.

RevDate: 2023-03-21

Žnidaršič N, Štrbenc M, Grgurevič N, et al (2023)

Potential revival of cholinesterase inhibitors as drugs in veterinary medicine.

Frontiers in veterinary science, 10:1125618.

The cholinergic system is involved in the regulation of all organ systems and has acetylcholine (ACh) as almost its only neurotransmitter. Any substance is called cholinergic if it can alter the action of acetylcholine. Cholinesterases (ChEs) are enzymes that enable the hydrolysis of acetylcholine and in this way ensure homeostasis in cholinergic synapses. Cholinesterase inhibitors (ChEi) are a group of indirect-acting cholinergic agonists that influence the activity of the cholinergic system. Several compounds that can inhibit cholinesterases are of importance to veterinary medicine from pharmacological and toxicological perspective. The frequency of their use in veterinary medicine has fluctuated over the years and is now reduced to a minimum. They are mainly used in agriculture as pesticides, and some are rarely used as parasiticides for companion animals and livestock. In recent years, interest in the use of new cholinesterase inhibitors has increased since canine cognitive dysfunction (CCD) became a recognized and extensively studied disease. Similar to Alzheimer's disease (AD) in humans, CCD can be treated with cholinesterase inhibitors that cross the blood-brain barrier. In this review, the mammalian cholinergic system and the drugs that interact with cholinesterases are introduced. Cholinesterase inhibitors that can be used for the treatment of CCD are described in detail.

RevDate: 2023-03-21

Wu Q, Su S, Cai C, et al (2023)

Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer's disease.

Computational and structural biotechnology journal, 21:1907-1920.

Despite the massive investment in Alzheimer's disease (AD), there are still no disease-modifying treatments (DMTs) for AD. One major reason is attributed to the limitation of clinical "one-size-fits-all" approach, since the same AD treatment solely based on clinical diagnosis was unlikely to achieve good clinical efficacy. In recent years, computational approaches based on multiomics data have provided an unprecedented opportunity for drug discovery since they can substantially lower the costs and boost the efficiency. In this study, we intended to identify potential drug candidates for different pathological stages of AD by computationally repurposing Food and Drug Administration (FDA) approved drugs. First, we assembled gene expression data from three different AD pathological stages, which include mild cognitive impairment (MCI) and early and late stages of AD (EAD, LAD). We next quantified the network distances between drug target networks and AD modules by utilizing a network proximity approach, and identified 193 candidates that possessed significant associations with AD. After searching for previous literature evidence, 63 out of 193 (32.6%) predicted drugs were demonstrated to exert therapeutic effects on AD. We further explored the novel mechanism of action (MOA) for these drug candidates by determining the specific brain cells they might function on based on AD patient single cell transcriptomic data. Additionally, we selected several promising candidates that could cross the blood brain barrier together with confirmed neuroprotective effects, and subsequently determined the antioxidative activity of these compounds. Experimental results showed that azathioprine decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD) activity in APP-SH-SY5Y cells. Finally, we deciphered the potential MOA of azathioprine against AD via network analysis and validated several apoptosis-related proteins (Caspase 3, Cleaved Caspase 3, Bax, Bcl2) through western blotting. In summary, this study presented an effective computational strategy utilizing omics data for AD drug repurposing, which provides a new perspective for drug discovery and development.

RevDate: 2023-03-21

Chen K, Li H, Yang L, et al (2023)

Comparative efficacy and safety of antidepressant therapy for the agitation of dementia: A systematic review and network meta-analysis.

Frontiers in aging neuroscience, 15:1103039.

BACKGROUND: Dementia is a clinical syndrome commonly seen in the elderly individuals. With the prevalence of dementia, the incidence of neuropsychiatric symptoms in dementia patients is increasing annually. Agitation, as one of the neuropsychiatric symptoms, has a serious impact on the quality of life of patients with dementia. Several antidepressant drugs have been shown to be effective for treating agitated behavior symptoms in patients with dementia, but there are no direct comparisons among those drugs. Therefore, we carried out a network meta-analysis (NMA) to examine the efficacy and safety of those antidepressant drugs.

METHODS: We searched eight databases (PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, China National Knowledge Infrastructure, VIP Database and China biomedical literature service) from their inception to 6 November 2022. Randomized controlled trials (RCTs) reporting the efficacy and safety of antidepressant drugs in treating agitated behavior symptoms in patients with dementia were included in our analysis. The quality assessment was carried out by two researchers individually and the analysis was based on the frequency method.

RESULTS: Twelve articles with 1,146 participants were included in our analysis. Based on the outcome of the agitation score, treatment with citalopram (standardized mean difference, SMD = -0.44, 95% confidence interval, 95% CI = -0.72 to -0.16) showed significant benefits over the placebo group. Treatment with trazodone (odds ratio, OR = 4.58, 95% CI = 1.12-18.69) was associated with a higher risk of total adverse events compared with a placebo treatment.

CONCLUSION: Among the antidepressant drugs included in this study, treatment with citalopram was probably the only optimal intervention, when considering the improvement from baseline to the end of the intervention, and there was not a statistically significant difference in safety when compared with a placebo treatment.

https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: PROSPERO, CRD42022320932.

RevDate: 2023-03-21

Zhuang J, Tian J, Xiong X, et al (2023)

Associating brain imaging phenotypes and genetic risk factors via a hypergraph based netNMF method.

Frontiers in aging neuroscience, 15:1052783.

ABSTRACT: Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective treatment. Mild cognitive impairment (MCI) is an early disease that may progress to AD. The effective diagnosis of AD and MCI in the early stage has important clinical significance.

METHODS: To this end, this paper proposed a hypergraph-based netNMF (HG-netNMF) algorithm for integrating structural magnetic resonance imaging (sMRI) of AD and MCI with corresponding gene expression profiles.

RESULTS: Hypergraph regularization assumes that regions of interest (ROIs) and genes were located on a non-linear low-dimensional manifold and can capture the inherent prevalence of two modalities of data and mined high-order correlation features of the two data. Further, this paper used the HG-netNMF algorithm to construct a brain structure connection network and a protein interaction network (PPI) with potential role relationships, mine the risk (ROI) and key genes of both, and conduct a series of bioinformatics analyses.

CONCLUSION: Finally, this paper used the risk ROI and key genes of the AD and MCI groups to construct diagnostic models. The AUC of the AD group and MCI group were 0.8 and 0.797, respectively.

RevDate: 2023-03-21

Wu L, Dong Y, Zhu C, et al (2023)

Effect and mechanism of acupuncture on Alzheimer's disease: A review.

Frontiers in aging neuroscience, 15:1035376.

With the development trend of an aging society, Alzheimer's disease (AD) has become an urgent problem in the field of medicine worldwide. Cognitive impairment in AD patients leads to a decline in the ability to perform daily living and abnormalities in behavior and personality, causing abnormal psychiatric symptoms, which seriously affect the daily life of patients. Currently, mainly drug therapy is used for AD patients in the clinic, but a large proportion of patients will experience drug efficacy not working, and even some drugs bring severe sleep disorders. Acupuncture, with its unique concept and treatment method, has been validated through a large number of experiments and proved its reliability of acupuncture in the treatment of AD. Many advances have been made in the study of the neurobiological mechanisms of acupuncture in the treatment of AD, further demonstrating the good efficacy and unique advantages of acupuncture in the treatment of AD. This review first summarizes the pathogenesis of AD and then illustrates the research progress of acupuncture in the treatment of AD, which includes the effect of acupuncture on the changes of biochemical indicators in AD in vivo and the specific mechanism of action to exert the therapeutic effect. Changes in relevant indicators of AD similarly further validate the effectiveness of acupuncture treatment. The clinical and mechanistic studies of acupuncture in the treatment of AD are intensified to fit the need for social development. It is believed that acupuncture will achieve new achievements in the treatment of AD as research progresses.

RevDate: 2023-03-19

Rogers CL, Lageman SK, Fontanesi J, et al (2023)

Low-dose whole brain radiation therapy for Alzheimer's dementia: Results from a pilot trial in human subjects.

International journal of radiation oncology, biology, physics pii:S0360-3016(23)00286-9 [Epub ahead of print].

PURPOSE: To report neurocognitive, imaging, ophthalmologic, and safety outcomes following low-dose whole brain radiation therapy (LD-WBRT) for patients with early Alzheimer's dementia (eAD) treated on a pilot trial.

METHODS AND MATERIALS: Trial enrolled patients were at least 55 years of age and had eAD meeting NINCDS-ADRDA criteria, with confirmatory FDG and Florbetapir PET findings, and had the capacity to complete neurocognitive function (NCF), psychological function (PF), and quality of life (QOL) assessments, with a Rosen Modified Hachinski Score <4, and estimated survival >12 months.

RESULTS: Five patients were treated with LD-WBRT (2Gy x 5 over 1 week; 3 female; mean age 73.2 years {range 69-77}). Four of 5 patients had improved (n=3) or stable (n=1) MMSE-2 T-scores at 1 year. The post-treatment scores of all 3 patients who improved increased to the average range. There were additional findings of stability of naming and other cognitive skills, as well as stability to possible improvement in imaging findings. No safety issues were encountered. The only side effect was temporary epilation with satisfactory hair regrowth.

CONCLUSIONS: Our results from five subjects with eAD treated with LD-WBRT (10 Gy in 5 fractions) demonstrate a positive safety profile, and provide preliminary, hypothesis-generating data to suggest that this treatment stabilizes/improves cognition. These findings will require further evaluation in larger, definitive, randomized trials.

RevDate: 2023-03-19

Yang T, Zhang Y, Chen L, et al (2023)

The potential roles of ATF family in the treatment of Alzheimer's disease.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 161:114544 pii:S0753-3322(23)00332-3 [Epub ahead of print].

Activating transcription factors, ATFs, is a family of transcription factors that activate gene expression and transcription by recognizing and combining the cAMP response element binding proteins (CREB). It is present in various viruses as a cellular gene promoter. ATFs is involved in regulating the mammalian gene expression that is associated with various cell physiological processes. Therefore, ATFs play an important role in maintaining the intracellular homeostasis. ATF2 and ATF3 is mostly involved in mediating stress responses. ATF4 regulates the oxidative metabolism, which is associated with the survival of cells. ATF5 is presumed to regulate apoptosis, and ATF6 is involved in the regulation of endoplasmic reticulum stress (ERS). ATFs is actively studied in oncology. At present, there has been an increasing amount of research on ATFs for the treatment of neurological diseases. Here, we have focused on the different types of ATFs and their association with Alzheimer's disease (AD). The level of expression of different ATFs have a significant difference in AD patients when compared to healthy control. Recent studies have suggested that ATFs are implicated in the pathogenesis of AD, such as neuronal repair, maintenance of synaptic activity, maintenance of cell survival, inhibition of apoptosis, and regulation of stress responses. In this review, the potential role of ATFs for the treatment of AD has been highlighted. In addition, we have systematically reviewed the progress of research on ATFs in AD. This review will provide a basic and innovative understanding on the pathogenesis and treatment of AD.

RevDate: 2023-03-20

Grymonprez M, Petrovic M, De Backer TL, et al (2023)

Comparing the risk of dementia in subjects with atrial fibrillation using non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists: a Belgian nationwide cohort study.

Age and ageing, 52(3):.

BACKGROUND: Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs.

METHODS: AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes.

RESULTS: Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban.

CONCLUSION: NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use.

RevDate: 2023-03-18

Visvanathan R, Utsuki T, Beck DE, et al (2023)

A novel fluorogenic reporter substrate for 1-Phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCγ2): Application to high-throughput screening for activators to treat Alzheimer's Disease.

SLAS discovery : advancing life sciences R & D pii:S2472-5552(23)00024-2 [Epub ahead of print].

A rare coding variant in PLCγ2 (P522R) expressed in microglia induces a mild activation of enzymatic activity when compared to wild-type. This mutation is reported to be protective against cognitive decline associated with late-onset Alzheimer's disease (LOAD) and therefore, activation of wild-type PLCγ2 has been suggested as a potential therapeutic target for the prevention and treatment of LOAD. Additionally, PLCγ2 has been associated with other diseases such as cancer and some autoimmune disorders where mutations with much greater increases in PLCγ2 activity have been identified. Here, pharmacological inhibition may provide a therapeutic effect. In order to facilitate our investigation of the activity of PLCγ2, we developed an optimized fluorogenic substrate to monitor enzymatic activity in aqueous solution. This was accomplished by first exploring the spectral properties of various "turn-on" fluorophores. The most promising turn-on fluorophore was incorporated into a water-soluble PLCγ2 reporter substrate, which we named C8CF3-coumarin. The ability of PLCγ2 to enzymatically process C8CF3-coumarin was confirmed, and the kinetics of the reaction were determined. Reaction conditions were optimized to identify small molecule activators, and a pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed with the goal of identifying small molecule activators of PLCγ2. The optimized screening conditions allowed identification of potential PLCγ2 activators and inhibitors, thus demonstrating the feasibility of this approach for high-throughput screening.

RevDate: 2023-03-20

Liu JF, Peng WJ, Wu Y, et al (2023)

Proteomic and phosphoproteomic characteristics of the cortex, hippocampus, thalamus, lung, and kidney in COVID-19-infected female K18-hACE2 mice.

EBioMedicine, 90:104518 [Epub ahead of print].

BACKGROUND: Neurological damage caused by coronavirus disease 2019 (COVID-19) has attracted increasing attention. Recently, through autopsies of patients with COVID-19, the direct identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their central nervous system (CNS) has been reported, indicating that SARS-CoV-2 might directly attack the CNS. The need to prevent COVID-19-induced severe injuries and potential sequelae is urgent, requiring the elucidation of large-scale molecular mechanisms in vivo.

METHODS: In this study, we performed liquid chromatography-mass spectrometry-based proteomic and phosphoproteomic analyses of the cortex, hippocampus, thalamus, lungs, and kidneys of SARS-CoV-2-infected K18-hACE2 female mice. We then performed comprehensive bioinformatic analyses, including differential analyses, functional enrichment, and kinase prediction, to identify key molecules involved in COVID-19.

FINDINGS: We found that the cortex had higher viral loads than did the lungs, and the kidneys did not have SARS-COV-2. After SARS-CoV-2 infection, RIG-I-associated virus recognition, antigen processing and presentation, and complement and coagulation cascades were activated to different degrees in all five organs, especially the lungs. The infected cortex exhibited disorders of multiple organelles and biological processes, including dysregulated spliceosome, ribosome, peroxisome, proteasome, endosome, and mitochondrial oxidative respiratory chain. The hippocampus and thalamus had fewer disorders than did the cortex; however, hyperphosphorylation of Mapt/Tau, which may contribute to neurodegenerative diseases, such as Alzheimer's disease, was found in all three brain regions. Moreover, SARS-CoV-2-induced elevation of human angiotensin-converting enzyme 2 (hACE2) was observed in the lungs and kidneys, but not in the three brain regions. Although the virus was not detected, the kidneys expressed high levels of hACE2 and exhibited obvious functional dysregulation after infection. This indicates that SARS-CoV-2 can cause tissue infections or damage via complicated routes. Thus, the treatment of COVID-19 requires a multipronged approach.

INTERPRETATION: This study provides observations and in vivo datasets for COVID-19-associated proteomic and phosphoproteomic alterations in multiple organs, especially cerebral tissues, of K18-hACE2 mice. In mature drug databases, the differentially expressed proteins and predicted kinases in this study can be used as baits to identify candidate therapeutic drugs for COVID-19. This study can serve as a solid resource for the scientific community. The data in this manuscript will serve as a starting point for future research on COVID-19-associated encephalopathy.

FUNDING: This study was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the Natural Science Foundation of Beijing.


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 )