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BMC Cancer Jan 2024Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory...
A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol.
BACKGROUND
Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma.
METHODS/DESIGN
GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O-methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland.
TRIAL REGISTRATION
NCT05664464. Registered 23 December 2022.
Topics: Adult; Humans; Brain Neoplasms; Chemoradiotherapy; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Repositioning; Glioblastoma; Glutamates; Multicenter Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Steroids
PubMed: 38225589
DOI: 10.1186/s12885-023-11797-z -
Cureus Dec 2023Dementia is a debilitating neurological condition that is characterized by persistent cognitive decline. It is a global health challenge, with a rapidly increasing... (Review)
Review
Dementia is a debilitating neurological condition that is characterized by persistent cognitive decline. It is a global health challenge, with a rapidly increasing prevalence due to an increasing aging population. Although definitive diagnosis of various conditions of dementia is only possible by autopsy, clinical diagnosis can be performed by a specialist. The diagnostic process has evolved with recent breakthroughs in diagnostic tools, such as advanced imaging techniques and biomarkers. These tools facilitate early and accurate identification of the condition. Early diagnosis is vital, as it enables timely interventions to improve the quality of life for affected individuals. Treatment strategies for dementia encompass both pharmacological and non-pharmacological approaches. Non-pharmacological treatments include cognitive training and lifestyle modifications. Among pharmacological treatments, acetyl-cholinesterase inhibitors including donepezil, rivastigmine, and galantamine can be used in various doses based on the severity of the disease. Apart from these, N-methyl-D-aspartate receptor antagonists such as memantine can also be used. Furthermore, personalized treatments have also gained significant attention in dementia treatment. Interdisciplinary care, involving healthcare professionals, social workers, and support networks, is crucial for comprehensive and holistic dementia management.
PubMed: 38222245
DOI: 10.7759/cureus.50522 -
BMC Public Health Jan 2024The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014,... (Observational Study)
Observational Study
Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer's disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study.
BACKGROUND
The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer's disease (AD) between July 2011 and June 2017 which spanned the 2014 revision.
METHODS
This multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017).
RESULTS
Subjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001).
CONCLUSIONS
Comparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.
Topics: Humans; Female; Aged, 80 and over; Male; Alzheimer Disease; Retrospective Studies; Acetylcholinesterase; Donepezil; Cholinesterase Inhibitors
PubMed: 38216922
DOI: 10.1186/s12889-024-17671-2 -
Molecules (Basel, Switzerland) Dec 2023In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated...
Glutamate's Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer's Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel.
In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated the effect of glutamate on the Alzheimer's disease (AD) brain. Human post-mortem AD brain slices of the frontal cortex and anterior cingulate were incubated with [H]MK-801 and adjacent sections were tested for Aβ and Tau. The binding of [H]MK-801 was measured in the absence and presence of glutamate and glycine. Increased [H]MK-801 binding in AD brains was observed at baseline and in the presence of glutamate, indicating a significant increase (>100%) in glutamate-induced NMDA ion channel activity in AD brains compared to cognitively normal brains. The glycine effect was lower, suggesting a decrease of the co-agonist effect of glutamate and glycine in the AD brain. Our preliminary findings suggest that the targeting of the NMDA ion channel as well as the glutamate site may be appropriate in the diagnosis and treatment of AD. However, the low baseline levels of [H]MK-801 binding in the frontal cortex and anterior cingulate in the absence of glutamate and glycine indicate significant hurdles for in vivo imaging probe development and validation.
Topics: Humans; N-Methylaspartate; Alzheimer Disease; Dizocilpine Maleate; Brain; Ion Channels; Glutamic Acid; Fabaceae; Glycine; Receptors, N-Methyl-D-Aspartate; Positron-Emission Tomography
PubMed: 38202606
DOI: 10.3390/molecules29010020 -
Frontiers in Neurology 2023Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability... (Review)
Review
Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability of daily life as the cardinal symptoms, influencing the life quality of patients severely. There are currently approximately 46 million people living with Alzheimer's disease worldwide, and the number is expected to triple by 2050, which will pose a huge challenge for healthcare. At present, the Food and Drug Administration of the United States has approved five main drugs for the clinical treatment of Alzheimer's disease, which are cholinesterase inhibitors tacrine, galantamine, capalatine and donepezil, and N-methyl-d-aspartate receptor antagonist memantine, although these drugs have shown good efficacy in clinical trials, the actual clinical effect is less effective due to the existence of blood brain barrier. With the continuous development of ultrasound technology in recent years, focused ultrasound, as a non-invasive treatment technique, may target ultrasound energy to the deep brain for treatment without damaging the surrounding tissue. For the past few years, some studies could use focused ultrasound combined with microvesicles to induce blood brain barrier opening and targeted drug delivery to treat Alzheimer's disease, providing new opportunities for the treatment of Alzheimer's disease. This article reviews the application research and progress of focused ultrasound in the treatment of Alzheimer's disease, in order to provide new directions and ideas for the treatment of Alzheimer's disease.
PubMed: 38187144
DOI: 10.3389/fneur.2023.1323386 -
SSM - Population Health Mar 2024•Compared to Swedish-born people, foreign-born people were less likely to receive dementia diagnostic tests.•Being born in Africa or Europe was associated with lower...
•Compared to Swedish-born people, foreign-born people were less likely to receive dementia diagnostic tests.•Being born in Africa or Europe was associated with lower chance of receiving cholinesterase inhibitors.•Asian-born people had higher chance of receiving cholinesterase inhibitors, but were less likely to receive memantine.•Disparities existed in dementia diagnostics and treatment between Swedish-born and foreign-born people, but were not consistent after adjusting for MMSE scores.
PubMed: 38162224
DOI: 10.1016/j.ssmph.2023.101573 -
Frontiers in Neurology 2023Dementia is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and functional deterioration. Pharmacological interventions...
BACKGROUND
Dementia is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and functional deterioration. Pharmacological interventions play a crucial role in managing dementia symptoms and potentially slowing down disease progression.
OBJECTIVES
This study aimed to investigate the impact of pharmacological interventions, including acetylcholinesterase inhibitors (AChEIs), memantine, and extract, on the progression of dementia, with a specific focus on mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-Alzheimer dementias.
METHODS
A total of 547 participants out of 3,547 cases in a specific dataset followed by the same author, including healthy controls, individuals with MCI, AD, and non-Alzheimer dementias, were included in this study. The follow-up duration was up to 211 months, allowing for a minimum 3 visits comprehensive assessment of disease progression. The treatment approaches included AChEIs, memantine, and combination therapy, with variations in the starting time for these treatments based on the dementia type.
RESULTS
The use of AChEIs and memantine showed efficacy in improving cognitive function and overall function in individuals with MCI, AD, and non-AD dementias. Combination therapy EGb761 like extract with AChEIs and/or Memantine demonstrated a slower progression compared to AChEIs alone in individuals with prodromal dementia (MCI) and AD. The starting time for memantine and combination therapy was earlier in non-AD dementia cases compared to AD dementia cases and prodromal dementia.
CONCLUSION
Pharmacological interventions, particularly the use of AChEIs and memantine, can have a positive impact on cognitive function and overall function in individuals with dementia. The combination of AChEIs with EGb761 like extract may provide additional benefits in slowing down disease progression in AD cases. Early recognition and accurate classification of MCI subtypes are crucial, and the use of EGb761 like extract is recommended for symptomatic treatment. Future personalized risk predictions based on biomarker constellations may further enhance the multi-target treatment approaches of MCI and different dementia types.
PubMed: 38156089
DOI: 10.3389/fneur.2023.1240655 -
Frontiers in Neuroscience 2023Alzheimer's disease (AD) is a devastating neurodegenerative condition with no effective treatments. Recent research highlights the role of NMDA receptors in AD...
Alzheimer's disease (AD) is a devastating neurodegenerative condition with no effective treatments. Recent research highlights the role of NMDA receptors in AD development, as excessive activation of these receptors triggers excitotoxicity. Memantine, an NMDA receptor antagonist, shows promise in curbing excitotoxicity. What sets our study apart is our novel exploration of memantine's potential to protect hippocampal neurons from neurotoxicity induced by NMDA and amyloid β1-42, a hallmark of AD. To achieve this, we conducted a series of experiments using rat hippocampal cell cultures. We employed Hoechst and propidium iodide double staining to assess neuronal viability. Analyzing the viability of neurons in normal conditions compared to their status after 24 h of exposure to the respective agents revealed compelling results. The incubation of hippocampal neurons with NMDA or amyloid β1-42 led to a more than twofold increase in the number of apoptotic and necrotic neurons. However, when memantine was co-administered with NMDA or amyloid β1-42, we witnessed a notable augmentation in the number of viable cells. This unique approach not only suggests that memantine may act as a neuroprotective agent but also emphasizes the relevance of hippocampal neuron cultures as valuable models for investigating excitotoxicity and potential AD treatments.
PubMed: 38144212
DOI: 10.3389/fnins.2023.1269664 -
Biomolecules Dec 2023N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the...
N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (Aβ) is linked to the pathogenesis of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases might be the risk factors for developing AD. The present study examines the acute effects of soluble Aβ on the function of NMDA receptors in rats RVLM. We used the magnitude of increases in the blood pressure (pressor responses) induced by microinjection of NMDA into the RVLM as an index of NMDA receptor function in the RVLM. Soluble Aβ was applied by intracerebroventricular (ICV) injection. Aβ1-40 at a lower dose (0.2 nmol) caused a slight reduction, and a higher dose (2 nmol) showed a significant decrease in NMDA-induced pressor responses 10 min after administration. ICV injection of Aβ1-42 (2 nmol) did not affect NMDA-induced pressor responses in the RVLM. Co-administration of Aβ1-40 with ifenprodil or memantine blocked the inhibitory effects of Aβ1-40. Immunohistochemistry analysis showed a significant increase in the immunoreactivity of phosphoserine 1480 of GluN2B subunits (pGluN2B-serine1480) in the neuron of the RVLM without significant changes in phosphoserine 896 of GluN1 subunits (pGluN1-serine896), GluN1 and GluN2B, 10 min following Aβ1-40 administration compared with saline. Interestingly, we found a much higher level of Aβ1-40 compared to that of Aβ1-42 in the cerebrospinal fluid (CSF) measured using enzyme-linked immunosorbent assay 10 min following ICV administration of the same dose (2 nmol) of the peptides. In conclusion, the results suggest that ICV Aβ1-40, but not Aβ1-42, produced an inhibitory effect on NMDA receptor function in the RVLM, which might result from changes in pGluN2B-serine1480 (regulated by casein kinase II). The different elimination of the peptides in the CSF might contribute to the differential effects of Aβ1-40 and Aβ1-42 on NMDA receptor function.
Topics: Rats; Animals; Receptors, N-Methyl-D-Aspartate; N-Methylaspartate; Amyloid beta-Peptides; Phosphoserine; Blood Pressure
PubMed: 38136607
DOI: 10.3390/biom13121736 -
Science Advances Dec 2023Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor...
Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals ( = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.
Topics: Rats; Animals; Memantine; Brain Injuries, Traumatic; Brain; Electrocorticography; Receptors, N-Methyl-D-Aspartate
PubMed: 38091390
DOI: 10.1126/sciadv.adj2417