-
Medical Care May 2024Several antidementia medications have been approved for symptomatic treatment of cognitive and functional impairment due to Alzheimer disease. Antipsychotics are often...
BACKGROUND
Several antidementia medications have been approved for symptomatic treatment of cognitive and functional impairment due to Alzheimer disease. Antipsychotics are often prescribed off-label for behavioral symptoms.
OBJECTIVE
The aim of this study was to describe the basis for regional variation in antidementia and antipsychotic medication use.
SETTING
US nursing homes (n=9735), hospital referral regions (HRR; n=289).
SUBJECTS
Long-stay residents with dementia (n=273,004).
METHODS
Using 2018 Minimum Data Set 3.0 linked to Medicare data, facility information, and Dartmouth Atlas files, we calculated prevalence of use and separate multilevel logistic models [outcomes: memantine, cholinesterase inhibitor (ChEI), antipsychotic use] estimated adjusted odds ratios (aOR) and 95% CIs for resident, facility, and HRR characteristics. We then fit a series of cross-classified multilevel logistic models to estimate the proportional change in cluster variance (PCV).
RESULTS
Overall, 20.9% used antipsychotics, 16.1% used memantine, and 23.3% used ChEIs. For antipsychotics, facility factors [eg, use of physical restraints (aOR: 1.08; 95% CI: 1.05-1.11) or poor staffing ratings (aOR: 1.10; 95% CI: 1.06-1.14)] were associated with more antipsychotic use. Nursing homes in HRRs with the highest health care utilization had greater antidementia drug use (aOR memantine: 1.68; 95% CI: 1.44-1.96). Resident/facility factors accounted for much regional variation in antipsychotics (PCVSTATE: 27.80%; PCVHRR: 39.54%). For antidementia medications, HRR-level factors accounted for most regional variation (memantine PCVSTATE: 37.44%; ChEI PCVSTATE: 39.02%).
CONCLUSION
Regional variations exist in antipsychotic and antidementia medication use among nursing home residents with dementia suggesting the need for evidence-based protocols to guide the use of these medications.
PubMed: 38833712
DOI: 10.1097/MLR.0000000000002016 -
Ageing Research Reviews Jun 2024Based on "reducing amyloid plaques in the brain", the U.S. Food and Drug Administration has granted accelerated and full approval for two monoclonal anti-Alzheimer's... (Review)
Review
Based on "reducing amyloid plaques in the brain", the U.S. Food and Drug Administration has granted accelerated and full approval for two monoclonal anti-Alzheimer's antibodies, aducanumab and lecanemab, respectively. Approval of a third antibody, donanemab, is pending. Moreover, lecanemab and donanemab are claimed to cause delay in the cognitive decline that characterizes the disease. We believe that these findings are subject to misinterpretation and statistical bias. Donanemab is claimed to cause removal of up to 86% of cerebral amyloid and 36% delay in cognitive decline compared to placebo. In reality, these are very small changes on an absolute scale and arguably less than what can be achieved with cholinesterase inhibitor/memantine therapy. Moreover, the "removal" of amyloid, based on the reduced accumulation of amyloid-PET tracer, most likely also reflects therapy-related tissue damage. This would also correlate with the minimal clinical effect, the increased frequency of amyloid-related imaging abnormalities, and the accelerated loss of brain volume in treated compared to placebo patients observed with these antibodies. We recommend halting approvals of anti-AD antibodies until these issues are fully understood to ensure that antibody treatment does not cause more harm than benefit to patients.
PubMed: 38830549
DOI: 10.1016/j.arr.2024.102348 -
Analytical Science Advances Feb 2024In the development of bioanalytical methods, stabilizing drug molecules in biological matrices is crucial for ensuring reliable exposure data in pharmacokinetic and...
In the development of bioanalytical methods, stabilizing drug molecules in biological matrices is crucial for ensuring reliable exposure data in pharmacokinetic and toxicokinetic sample analyses. This study focuses on the evaluation of stabilizing effects on the synthetic triterpenoid TX101, a cyanoenone triterpenoid Nrf2 activator with known instability in plasma samples. The molecule's unsaturated double bond is susceptible to oxidation, either nonenzymatically via oxygen or enzymatically through cytochrome P450 enzyme-catalyzed epoxidation. The research explores the impact of antioxidants (L-ascorbic acid, sodium metabisulfite, sodium sulfite) and P450 enzyme inhibitors (sodium diethyldithiocarbamate, memantine hydrochloride, 1-aminobenzotriazole) on TX101 stability in rat plasma samples. Results reveal that adding 2.5 mg/mL sodium sulfite or sodium metabisulfite effectively inhibits the nonenzymatic oxidation of TX101 to TX101-epoxide, while L-ascorbic acid shows minimal stabilizing effect. Among P450 enzyme inhibitors, sodium diethyldithiocarbamate and memantine hydrochloride exhibit modest stabilizing effects, likely attributed to their antioxidant activity. The developed High-formance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method, incorporating Supported Liquid Extraction for sample cleanup, allows simultaneous monitoring of TX101 and TX101-epoxide. Application of this method in a rat dose-range finding study confirms successful inhibition of TX101-epoxide formation in samples treated with sodium sulfite or sodium metabisulfite. Overall, the study emphasizes the importance of stabilizers in preventing nonenzymatic oxidation reactions during sample storage, providing valuable insights for bioanalytical method development and validation.
PubMed: 38828082
DOI: 10.1002/ansa.202300058 -
Research Square May 2024Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI)...
Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. A potential functional parameter to be monitored is long-term potentiation (LTP), which is a correlate of learning and memory, that would be one of the first functions effected by AD onset. Mature human iPSC-derived cortical neurons and primary astrocytes were co-cultured on microelectrode arrays (MEA) where surface chemistry was utilized to create circuit patterns connecting two adjacent electrodes to model LTP function. LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42 induced LTP impairment. The results presented here illustrate the significance of the system as a validated platform that can be utilized to model and study MCI AD pathology, and potentially for the pre-MCI phase before the occurrence of significant cell death. It also has the potential to become an ideal platform for high content therapeutic screening for other neurodegenerative diseases.
PubMed: 38826367
DOI: 10.21203/rs.3.rs-4313679/v1 -
Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.Cell Death & Disease May 2024Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in...
Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.
Topics: Niemann-Pick Disease, Type C; Humans; Autophagy; NAD; Induced Pluripotent Stem Cells; Fibroblasts; Mitochondria; Memantine; Neurons; Cell Death; Cell Survival; Mitophagy; Apoptosis
PubMed: 38821960
DOI: 10.1038/s41419-024-06770-y -
Epilepsy & Behavior : E&B May 2024Neurological conditions such as Alzheimer's disease (AD) and epilepsy share a significant clinical overlap, particularly in the elderly, with each disorder potentiating... (Review)
Review
Neurological conditions such as Alzheimer's disease (AD) and epilepsy share a significant clinical overlap, particularly in the elderly, with each disorder potentiating the risk of the other. This interplay is significant amidst an aging global demographic. The review explores the classical pathologies of AD, including amyloid-beta plaques and hyperphosphorylated tau, and their potential role in the genesis of epilepsy. It also delves into the imbalance of glutamate and gamma-amino butyric acid activities, a key mechanism in epilepsy that may be influenced by AD pathology. The impact of age of onset on comorbidity is examined, with early-onset AD and Down syndrome presenting higher risks of epilepsy. The review suggests that epilepsy might precede cognitive symptoms in AD, indicating a complex interaction. Sleep modulation is highlighted as a factor, with sleep disturbances potentially contributing to AD progression. The necessity for cautious medication management is emphasized due to the cognitive effects of certain antiepileptic drugs. Animal models are recognized for their importance in understanding the relationship between AD and epilepsy, though creating fully representative models presents a challenge. The review concludes by noting the efficacy of medications such as lamotrigine, levetiracetam, and memantine in managing both conditions and suggests the ketogenic diet and cannabidiol as emerging treatment options, warranting further investigation for comprehensive patient care strategies.
PubMed: 38820684
DOI: 10.1016/j.yebeh.2024.109849 -
Alzheimer's Research & Therapy May 2024A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to... (Observational Study)
Observational Study
BACKGROUND
A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents.
METHODS
This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method.
RESULTS
We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts.
CONCLUSION
The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.
Topics: Humans; Memantine; Nursing Homes; Female; Male; Dementia; Longitudinal Studies; Aged, 80 and over; Cholinesterase Inhibitors; Retrospective Studies; Aged; Homes for the Aged; France
PubMed: 38812028
DOI: 10.1186/s13195-024-01481-0 -
Medicinal Chemistry (Shariqah (United... May 2024Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
INTRODUCTION
Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
METHOD
This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.
RESULT
This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.
CONCLUSION
Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.
PubMed: 38803179
DOI: 10.2174/0115734064304100240511112619 -
BMC Oral Health May 2024This study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME)...
PURPOSE
This study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME) features such as immune infiltration. It aims to provide potential diagnostic markers of ferroptosis for clinical management of periodontitis.
METHODS
Utilizing the periodontitis-related microarray dataset GSE16134 from the Gene Expression Omnibus (GEO) and a set of 528 ferroptosis-related genes identified in prior studies, this research unveils differentially expressed ferroptosis-related genes in periodontitis. Subsequently, a protein-protein interaction network was constructed. Subtyping of periodontitis was explored, followed by validation through immune cell infiltration and gene set enrichment analyses. Two algorithms, randomForest and SVM(Support Vector Machine), were employed to reveal potential ferroptosis diagnostic markers for periodontitis. The diagnostic efficacy, immune correlation, and potential transcriptional regulatory networks of these markers were further assessed. Finally, potential targeted drugs for differentially expressed ferroptosis markers in periodontitis were predicted.
RESULTS
A total of 36 ferroptosis-related genes (30 upregulated, 6 downregulated) were identified from 829 differentially expressed genes between 9 periodontitis samples and the control group. Subsequent machine learning algorithm screening highlighted 4 key genes: SLC1A5(Solute Carrier Family 1 Member 5), SLC2A14(Solute Carrier Family 1 Member 14), LURAP1L(Leucine Rich Adaptor Protein 1 Like), and HERPUD1(Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1). Exploration of these 4 key genes, supported by time-correlated ROC analysis, demonstrated reliability, while immune infiltration results indicated a strong correlation between key genes and immune factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted for the four key genes, revealing enrichment in GO/KEGG pathways that have a significant impact on periodontitis. Finally, the study predicted potential transcriptional regulatory networks and targeted drugs associated with these key genes in periodontitis.
CONCLUSIONS
The ferroptosis-related genes identified in this study, including SLC1A5, SLC2A14, LURAP1L, and HERPUD1, may serve as novel diagnostic and therapeutic targets for periodontitis. They are likely involved in the occurrence and development of periodontitis through mechanisms such as immune infiltration, cellular metabolism, and inflammatory chemotaxis, potentially linking the ferroptosis pathway to the progression of periodontitis. Targeted drugs such as flurofamide, L-733060, memantine, tetrabenazine, and WAY-213613 hold promise for potential therapeutic interventions in periodontitis associated with these ferroptosis-related genes.
Topics: Ferroptosis; Humans; Periodontitis; Protein Interaction Maps; Gene Regulatory Networks; Biomarkers
PubMed: 38802844
DOI: 10.1186/s12903-024-04342-2 -
Clinical & Translational Oncology :... May 2024Whole-brain radiotherapy (WBRT) is a standard and effective approach for brain metastases, but it is linked to neurocognitive complications, specifically issues related... (Review)
Review
BACKGROUND
Whole-brain radiotherapy (WBRT) is a standard and effective approach for brain metastases, but it is linked to neurocognitive complications, specifically issues related to the hippocampus. Innovative strategies are being explored to enhance outcomes. However, a consensus is yet to be reached in this field. Our aim is to investigate the efficacy and safety of WBRT combined with simultaneous integrated boost (SIB), memantine, and hippocampal avoidance (HA) techniques in treatment of brain metastases.
METHODS
In this systematic review and meta-analysis, we comprehensively searched PubMed, MEDLINE, Embase, and Cochrane for studies reporting the efficacy and toxicity of WBRT-based combination therapies from inception to September 19, 2023. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I statistic.
RESULTS
Among 2175 articles, 29 studies involving 3460 patients were included. The meta-analysis revealed that compared to WBRT alone, combination therapies significantly mitigated neurocognitive function decline (RD = -0.09, 95% CI [-0.18-0.01]; P = 0.03) and intracranial control failure (RR = 0.86, 95% CI [0.52-1.44]; P = 0.02), without increasing the risk of hippocampal recurrence or high-grade toxicities. Notably, HA-WBRT + SIB/memantine demonstrated improved neurocognitive outcomes and survival benefits.
CONCLUSION
WBRT-based combination therapies demonstrate improved efficacy and comparable safety to WBRT alone, with specific emphasis on the effectiveness of HA-WBRT + Memantine and HA-WBRT + SIB in optimizing therapeutic outcomes for brain metastases.
PubMed: 38789890
DOI: 10.1007/s12094-024-03525-1