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RSC Advances Apr 2024Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily... (Review)
Review
Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily life activities. There is no concrete evidence to identify the exact reason behind the disease, so several relevant hypotheses emerged, highlighting many possible therapeutic targets, such as acetylcholinesterase, cholinergic receptors, -methyl d-aspartate receptors, phosphodiesterase, amyloid β protein, protein phosphatase 2A, glycogen synthase kinase-3 beta, β-secretase, γ-secretase, α-secretase, serotonergic receptors, glutaminyl cyclase, tumor necrosis factor-α, γ-aminobutyric acid receptors, and mitochondria. All of these targets have been involved in the design of new potential drugs. An extensive number of these drugs have been studied in clinical trials. However, only galantamine, donepezil, and rivastigmine (ChEIs), memantine (NMDA antagonist), and aducanumab and lecanemab (selective anti-Aβ monoclonal antibodies) have been approved for AD treatment. Many drugs failed in the clinical trials to such an extent that questions have been posed about the significance of some of the aforementioned targets. On the contrary, the data of other drugs were promising and shed light on the significance of their targets for the development of new potent anti-alzheimer drugs.
PubMed: 38586442
DOI: 10.1039/d3ra08333k -
Research Square Mar 2024The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We...
The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations () compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in and ) and extracellular matrix (particularly in ) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.
PubMed: 38585969
DOI: 10.21203/rs.3.rs-4103685/v1 -
Memantine suppresses the excitotoxicity but fails to rescue the ataxic phenotype in SCA1 model mice.Biomedicine & Pharmacotherapy =... May 2024Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment...
Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.
Topics: Animals; Memantine; Disease Models, Animal; Spinocerebellar Ataxias; Phenotype; Mice; Ataxin-1; Motor Activity; Cerebellum; Purkinje Cells; Receptors, N-Methyl-D-Aspartate; Mice, Transgenic; Mice, Inbred C57BL; Neuroglia; Male; Neuronal Plasticity
PubMed: 38574621
DOI: 10.1016/j.biopha.2024.116526 -
Neuropsychopharmacology Reports Jun 2024Behavioral psychological symptoms of dementia (BPSD) are sometimes difficult to treat due to severe psychiatric symptoms such as delusions of poisoning and violent...
AIM
Behavioral psychological symptoms of dementia (BPSD) are sometimes difficult to treat due to severe psychiatric symptoms such as delusions of poisoning and violent behavior. Moreover, in cases of parental neglect, the management of these psychiatric symptoms becomes more difficult. Therefore, home-visiting doctors sometimes have to manage patients with BPSD and severe psychiatric symptoms, and a new approach is needed. In this case report, the effect of blonanserin transdermal patch on these patients is to be highlighted.
METHODS
The patient is a 91-year-old woman diagnosed with Alzheimer's disease. She had severe BPSD such as delusion of robbery and violent behavior, and refused oral medications including memantine and yokukansan. Then she was treated with blonanserin transdermal patch (20 mg/day). The severity of psychiatric symptoms of BPSD was assessed over time using the Neuropsychiatric Inventory (NPI) score. Moreover, the patient's cognitive function was also assessed over time by Mini-Mental State Examination (MMSE).
RESULTS
After the introduction of blonanserin patch, the patient's psychiatric symptoms were stabilized markedly, and both NPI and MMSE scores improved. The patient was able to stay at home calmly and was mentally well stabilized to the extent that she did not require hospitalization. No apparent side effects were admitted.
CONCLUSIONS
The blonanserin transdermal patch may be able to manage BPSD at home and is effective in patients who refuse oral medications. Home-visiting doctors may consider the use of blonanserin patches at home for patients with severe BPSD, manifesting as delusions of poisoning and refusing oral drugs.
Topics: Humans; Female; Piperidines; Aged, 80 and over; Transdermal Patch; Piperazines; Alzheimer Disease; Dementia; Treatment Outcome; Antipsychotic Agents
PubMed: 38558544
DOI: 10.1002/npr2.12434 -
Biomedicine & Pharmacotherapy =... Apr 2024The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the...
The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.
Topics: Humans; Cholinesterase Inhibitors; Alzheimer Disease; Butyrylcholinesterase; Aminoquinolines; Acetylcholinesterase; Ligands
PubMed: 38492439
DOI: 10.1016/j.biopha.2024.116399 -
Magyar Onkologia Mar 2024In patients with poor performance status (KPS<50), ineligibility for effective systemic treatment and multiple brain metastases (BM) best supportive care is the...
In patients with poor performance status (KPS<50), ineligibility for effective systemic treatment and multiple brain metastases (BM) best supportive care is the preferred treatment over whole brain radiotherapy (WBRT). WBRT should be considered for the treatment of non-limited number (>4) brain metastases, depending on the patient's life expectancy, neurological symptoms, size, number and location of brain metastases, indication, type and availability of systemic therapy. In these patients if life expectancy is >4 months without small cell histology and without hippocampal lesions, hippocampal sparing WBRT with or without memantine is recommended. Simultaneous integrated boost for the BM is a logical and supportable concept. Prophylactic cranial irradiation (PCI) is still recommended in small cell lung cancer patients with complete remission. Hippocampal sparing WBRT needs further validation in this indication.
Topics: Humans; Brain Neoplasms; Brain; Treatment Outcome; Cranial Irradiation; Radiosurgery; Lung Neoplasms
PubMed: 38484376
DOI: No ID Found -
Neuropsychiatric Disease and Treatment 2024Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between...
PURPOSE
Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients.
PATIENTS AND METHODS
A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment.
RESULTS
A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60-0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents.
CONCLUSION
Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.
PubMed: 38405423
DOI: 10.2147/NDT.S432556 -
Advances in Radiation Oncology Feb 2024Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery, hippocampal avoidance whole brain...
Advancing Beyond the Hippocampus to Preserve Cognition for Patients With Brain Metastases: Dosimetric Results From a Phase 2 Trial of Memory-Avoidance Whole Brain Radiation Therapy.
PURPOSE
Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery, hippocampal avoidance whole brain radiation therapy (WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a "memory-avoidance" WBRT (MA-WBRT) approach that spares these substructures for patients with >15 brain metastases.
METHODS AND MATERIALS
Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory-avoidance region was created using a 5-mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9 Gy and D0.03 cm ≤ 16 Gy (variation acceptable to 20 Gy). LINAC-based volumetric modulated arc therapy plans were generated for a prescription dose of 30 Gy in 10 fractions.
RESULTS
On average, the memory avoidance structure volume was 37.1 cm (range, 25.2-44.6 cm), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8 of 10 plans met the D0.03 cm constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% > 25 Gy) and homogeneity (D2% ≤ 37.5 Gy) were achieved for all plans.
CONCLUSIONS
Modern volumetric modulated arc therapy techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.
PubMed: 38405310
DOI: 10.1016/j.adro.2023.101337 -
International Journal of Alzheimer's... 2024Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United...
Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United States Food and Drug Administration (FDA). Three (donepezil, rivastigmine, and galantamine) out of these four drugs are anticholinesterase inhibitors, while the fourth one memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Currently, two immunotherapy drugs that target amyloid protein (donanemab and lecanemab) are being considered for the treatment of Alzheimer's disease at an early stage. All these drug molecules are still not the complete answer to the treatment of Alzheimer's disease. A recent report from the Office of National Statistics showed that AD is the leading cause of death in 2022. Therefore, there is an urgency to develop more drugs that can treat AD. Based on this urgency, we aim to investigate how bioactive and already approved drugs could be repurposed for inhibiting the anticholinesterase enzyme using computational studies. To achieve this, the data science tool-Python coding was compiled on Jupyter Notebook to mine bioactive compounds from the ChEMBL database. The most bioactive compounds obtained were further investigated using Molecular Operating Environment (MOE) software to carry out molecular docking and ligand analysis, and this was followed by molecular dynamics simulation production at 35 ns using GROMACS 2022.4 on Archer 2 machine. The molecular dynamic analysis was carried out using HeroMDanalysis software. Data mining of the ChEMBL database was carried out for lipase inhibitors, and this gave CHEMBL-ID 1240685, a peptide molecule, the most active compound at the time of data mining. Further literature studies gave Zoladex an FDA-approved drug for the treatment of breast cancer as another compound of interest. The studies were carried out against the anticholinesterase enzyme using two FDA-approved drugs donepezil and galantamine as a template for comparing the activities of the repurposed drugs. A very useful receptor for this study was PDB-1DX6, a cocrystallized galantamine inhibitor of acetylcholinesterase enzyme. The molecular docking analysis (using ligand interactions) and molecular dynamic analysis (root mean square deviation (RMSD) and root mean square fluctuation (RMSF)) showed that the two peptide molecules CHEMBL-1240685 and Zoladex gave the best binding energy and stability when compared to the FDA-approved drugs (donepezil and galantamine). Finally, further literature studies revealed that Zoladex affects memory reduction; therefore, it was dropped as a possible repurposed drug. Our research showed that CHEMBL-1240685 is a potential compound that could be investigated for the inhibition of anticholinesterase enzyme and might be another drug molecule that could be used to treat Alzheimer's disease.
PubMed: 38371416
DOI: 10.1155/2024/2988685 -
EClinicalMedicine Mar 2024Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network...
BACKGROUND
Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network meta-analysis was to determine the efficacy of augmentation drugs for the treatment of schizophrenia.
METHODS
In accordance with the PRISMA statement, the PubMed, Web of Science, Google Scholar, CENTRAL, clinical trial and EUDRACT databases were searched from inception to May 15th, 2023. To ensure the robustness of the results, only double-blind randomised controlled trials with a low risk of bias (measured by the Risk Of Bias v2 (ROB2) tool) were included. The studies were categorised according to the background regimen: participants were treated with risperidone, mixed antipsychotics or clozapine. A Bayesian network meta-analysis was conducted using a random effects model. PROSPERO register: CRD42023420964.
FINDINGS
A total of 44 trials (comprising 45 augmentation drugs and 3358 participants) were included in the analysis. One-third of the drugs (16 drugs) demonstrated significant efficacy vs. placebo for at least one outcome. The most notable effect sizes (ESs) were observed for the use of tropisetron (standard mean difference: -0.83 [95% interval confidence -1.12 to -0.55]), memantine (-0.50 [-0.66 to -0.32]) and minocycline (-0.56 [-0.72 to -0.39]) to treat negative symptoms among patients treated with risperidone (moderate-to-high ESs). Studies involving mixed antipsychotics yielded lower ESs (small-to-moderate). Sodium benzoate (-0.41 [-0.60 to -0.21]) and memantine (-0.23 [-0.36 to -0.11]) were found have significant effects on positive symptoms, while memantine demonstrated efficacy for negative symptoms (-0.32 [-0.45 to -0.19]) and general psychopathology (-0.32 [-0.44 to -0.20]). Studies focusing exclusively on patients treated with clozapine revealed that duloxetine produced the best results (negative symptoms: -1.12 [-1.35 to -0.91]). Sodium benzoate was the only augmentation drug that demonstrated efficacy in relieving persistent positive symptoms (-0.32 [-0.59 to -0.08]) among patients treated with clozapine. Treatment with clozapine in combination with antipsychotics yielded small-to-moderate ESs.
INTERPRETATION
The GRADE framework indicated that the quality of the evidence among the included studies was moderate, primarily due to the limited number of randomised controlled trials with a low risk of bias. Important drugs did not appear in these results due to insufficient low-risk-of-bias data for these medications. These results highlight new pathways for treating schizophrenia that should be incorporated into future guidelines after further validation.
FUNDING
No funding.
PubMed: 38356727
DOI: 10.1016/j.eclinm.2024.102473