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The International Journal of... Jun 2024The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior.
METHODS
We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes.
RESULTS
We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction.
CONCLUSION
The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.
Topics: Humans; Ketamine; Locus Coeruleus; Male; Adult; Magnetic Resonance Imaging; Cross-Over Studies; Young Adult; Attention; Excitatory Amino Acid Antagonists; Double-Blind Method; Antidepressive Agents
PubMed: 38833581
DOI: 10.1093/ijnp/pyae022 -
Targeted Oncology Jun 2024The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib,...
BACKGROUND
The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI.
OBJECTIVE
We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment.
METHODS
Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis.
RESULTS
Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9).
CONCLUSIONS
Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.
PubMed: 38825654
DOI: 10.1007/s11523-024-01072-x -
Alzheimer's Research & Therapy May 2024Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and...
BACKGROUND
Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology.
METHODS
142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates.
RESULTS
At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity.
CONCLUSIONS
Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.
Topics: Humans; Female; Male; Alzheimer Disease; Aged; Locus Coeruleus; Magnetic Resonance Imaging; Parietal Lobe; Aged, 80 and over; Attention; Frontal Lobe; Positron-Emission Tomography; Cross-Sectional Studies; Neural Pathways; Cognitive Dysfunction; Neuropsychological Tests
PubMed: 38822365
DOI: 10.1186/s13195-024-01485-w -
Epilepsy & Behavior : E&B May 2024Hippocampal sclerosis (HS) is a prevalent cause of temporal lobe epilepsy (TLE). However, up to 30% of individuals with TLE present negative magnetic resonance imaging...
BACKGROUND
Hippocampal sclerosis (HS) is a prevalent cause of temporal lobe epilepsy (TLE). However, up to 30% of individuals with TLE present negative magnetic resonance imaging (MRI) findings. A comprehensive grasp of the similarities and differences in brain activity among distinct TLE subtypes holds significant clinical and scientific importance.
OBJECTIVE
To comprehensively examine the similarities and differences between TLE with HS (TLE-HS) and MRI-negative TLE (TLE-N) regarding static and dynamic abnormalities in spontaneous brain activity (SBA). Furthermore, we aimed to determine whether these alterations correlate with epilepsy duration and cognition, and to determine a potential differential diagnostic index for clinical utility.
METHODS
We measured 12 SBA metrics in 38 patients with TLE-HS, 51 with TLE-N, and 53 healthy volunteers. Voxel-wise analysis of variance (ANOVA) and post-hoc comparisons were employed to compare these metrics. The six static metrics included amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC), degree centrality (DC), and global signal correlation (GSCorr). Additionally, six corresponding dynamic metrics were assessed: dynamic ALFF (dALFF), dynamic fALFF (dfALFF), dynamic ReHo (dReHo), dynamic DC (dDC), dynamic VMHC (dVMHC), and dynamic GSCorr (dGSCorr). Receiver operating characteristic (ROC) curve analysis of abnormal indices was employed. Spearman correlation analyses were also conducted to examine the relationship between the abnormal indices, epilepsy duration and cognition scores.
RESULTS
Both TLE-HS and TLE-N presented as extensive neural network disorders, sharing similar patterns of SBA alterations. The regions with increased fALFF, dALFF, and dfALFF levels were predominantly observed in the mesial temporal lobe, thalamus, basal ganglia, pons, and cerebellum, forming a previously proposed mesial temporal epilepsy network. Conversely, decreased SBA metrics (fALFF, ReHo, dReHo, DC, GSCorr, and VMHC) consistently appeared in the lateral temporal lobe ipsilateral to the epileptic foci. Notably, SBA alterations were more obvious in patients with TLE-HS than in those with TLE-N. Additionally, patients with TLE-HS exhibited reduced VMHC in both mesial and lateral temporal lobes compared with patients with TLE-N, with the hippocampus displaying moderate discriminatory power (AUC = 0.759). Correlation analysis suggested that alterations in SBA indicators may be associated with epilepsy duration and cognitive scores.
CONCLUSIONS
The simultaneous use of static and dynamic SBA metrics provides evidence supporting the characterisation of both TLE-HS and TLE-N as complex network diseases, facilitating the exploration of mechanisms underlying epileptic activity and cognitive impairment. Overall, SBA abnormality patterns were generally similar between the TLE-HS and TLE-N groups, encompassing networks related to TLE and auditory and occipital visual functions. These changes were more pronounced in the TLE-HS group, particularly within the mesial and lateral temporal lobes.
PubMed: 38820678
DOI: 10.1016/j.yebeh.2024.109751 -
The International Journal of... May 2024Surface decontamination in the reconstructive therapy of peri-implantitis is of paramount importance to achieve favorable outcomes. The objective of this single-center...
Surface decontamination in the reconstructive therapy of peri-implantitis is of paramount importance to achieve favorable outcomes. The objective of this single-center study derived from a large multicenter clinical trial was to compare the electrolytic method (EM) used as an adjunct to mechanical decontamination, to hydrogen peroxide (HP) also used as an adjunct to mechanical decontamination, in the reconstructive therapy of peri-implantitis. At 12-month (T2) follow-up, 19 patients (Nimplants= 23) completed the study. None of the tested modalities demonstrated superiority in terms of the assessed clinical parameters. Only mucosal recession showed higher stability in the EM group. Alike, radiographic marginal bone level gain and defect angle changes at T2 did not differ between the evaluated strategies. Notably, disease resolution was ∼16% higher in the EM; however, differences did not reach statistical significance. Additionally, it was demonstrated that pocket depth and intra-bony component depth at baseline were predictors of disease resolution. In conclusion, the EM combined with mechanical instrumentation results in a safe and effective surface decontamination modality in the reconstructive therapy of peri-implantitis. This strategy resulted in ∼91% disease resolution rate.
PubMed: 38820275
DOI: 10.11607/prd.7151 -
Journal of Parkinson's Disease May 2024Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD),...
BACKGROUND
Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be.
OBJECTIVE
Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains.
METHODS
Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD.
RESULTS
Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum.
CONCLUSIONS
Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.
PubMed: 38820022
DOI: 10.3233/JPD-240075 -
Neurological Sciences : Official... May 2024Pediatric-Onset Multiple Sclerosis (POMS) is considered a complex disease entity and several genetic, hormonal, and environmental factors have been associated with...
BACKGROUND
Pediatric-Onset Multiple Sclerosis (POMS) is considered a complex disease entity and several genetic, hormonal, and environmental factors have been associated with disease pathogenesis. Linkage studies in Caucasians have consistently suggested the human leukocyte antigen (HLA) polymorphisms, as the genetic locus most strongly linked to MS, with the HLA-DRB1*15:01 allele, being associated with both adult and pediatric MS patients. Here we aim to investigate the prevalence of the HLA-DRB1 alleles among a Hellenic POMS cohort and any possible associations with clinical and imaging disease features.
MATERIALS AND METHODS
100 POMS patients fulfilling the IPMSSG criteria, 168 Adult-Onset MS (AOMS) patients, and 246 Healthy Controls (HCs) have been enrolled. HLA genotyping was performed with a standard low-resolution sequence-specific oligonucleotide (SSO) technique.
RESULTS
POMS patients display a significantly increased HLA-DRB1*03 frequency compared to both HCs [24% vs. 12.6%, OR [95%CI]: 2.19 (1.21-3.97), p=0.016) and AOMS (24% vs. 13.1%, OR [95%CI]: 2.1 (1.1-3.98), p=0.034] respectively. HLA-DRB1*03-carriers display reduced risk for brainstem lesion development (OR [CI 95%]:0.19 (0.06-0.65), p=0.011). A significantly lower frequency of HLA-DRB1*07 (4% vs 13.4%, OR (95% CI): 0.27 (0.09-0.78), p= 0.017) and HLA-DRB1*11 (37% vs 52%, OR [95% CI]: 0.54 (0.34-0.87), p= 0.016) was observed in POMS compared to HCs.
CONCLUSION
The HLA-DRB1*03 allele was associated with a higher risk for POMS, replicating our previous findings, and with a lower risk for brainstem lesion development, a common clinical and neuroimaging feature in POMS, while HLA-DRB1*07 and HLA-DRB1*11 display a protective role. These findings expand the existing knowledge of HLA associations and POMS.
PubMed: 38819529
DOI: 10.1007/s10072-024-07619-0 -
Cell Death Discovery May 2024Deceased donor liver transplantation (LT) is a crucial lifesaving option for patients with end-stage liver diseases. Although donation after brain death (DBD) remains...
Deceased donor liver transplantation (LT) is a crucial lifesaving option for patients with end-stage liver diseases. Although donation after brain death (DBD) remains the main source of donated organs, exploration of donation after circulatory death (DCD) addresses donor scarcity but introduces challenges due to warm ischemia. While technical advances have improved outcomes, challenges persist, with a 13% mortality rate within the first year. Delving into liver transplantation complexities reveals the profound impact of molecular signaling on organ fate. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation play a pivotal role, influencing inflammatory responses. The NLRP3 inflammasome, found in hepatocytes, contributes to inflammation, fibrosis, and liver cell death. This study explores these dynamics, shedding light on potential biomarkers and therapeutic targets. Samples from 36 liver transplant patients were analyzed for ASC specks detection and inflammasome-related gene expression. Liver biopsies, obtained before and after cold ischemia storage, were processed for immunofluorescence, qRT-PCR, and Western blot. One year post-LT clinical follow-up included diagnostic procedures for complications, and global survival was assessed. Immunofluorescence detected activated inflammasome complexes in fixed liver tissues. ASC specks were identified in hepatocytes, showing a trend toward more specks in DCD livers. Likewise, inflammasome-related gene expression analysis indicated higher expression in DCD livers, decreasing after cold ischemia. Similar results were found at protein level. Patients with increased ASC specks staining exhibited lower overall survival rates, correlating with IL1B expression after cold ischemia. Although preliminary, these findings offer novel insights into utilizing direct detection of inflammasome activation in liver tissue as a biomarker. They suggest its potential impact on post-transplant outcomes, potentially paving the way for improved diagnostic approaches and personalized treatment strategies in LT.
PubMed: 38816358
DOI: 10.1038/s41420-024-02042-y -
AJNR. American Journal of Neuroradiology May 2024The abnormalities of long arm of chromosome 18 (18q) constitute a complex spectrum. We aimed to systematically analyze their MRI features. We hypothesized that there...
BACKGROUND AND PURPOSE
The abnormalities of long arm of chromosome 18 (18q) constitute a complex spectrum. We aimed to systematically analyze their MRI features. We hypothesized that there would be variable but recognizable white matter and structural patterns in this cohort.
MATERIALS AND METHODS
In this retrospective cohort study, we included pediatric patients with a proven abnormality of 18q between 2000-2022. An age and sex matched control cohort was also constructed.
RESULTS
Thirty-six cases, median MRI age 19.6 months (4.3 - 59.3), satisfied our inclusion criteria. Majority were females (25, 69%, F:M ratio 2.2:1). Fifty MR imaging studies were analyzed and 35 (70%) had delayed myelination. Two independent readers scored brain myelination with excellent interrater reliability. Three recognizable evolving MRI patterns with distinct age distributions and improving myelination scores were identified - PMD-like (9.9 months, 37), intermediate (22 months, 48) and washed-out pattern (113.6 months, 53). Etiologically, MRIs were analyzed across three subgroups - 18q- (34, 69%), trisomy 18 (10, 21%) and ring chromosome 18 (5, 10%). Ring chromosome 18 had the highest myelination lag (27, P value = 0.005) and multifocal white matter changes (P value = 0.001). Trisomy 18 had smaller pons and cerebellar dimensions (APD pons P value = 0.002, CC vermis P value <0.001 and TCD P value = 0.04).
CONCLUSIONS
In this cohort of 18q chromosomal abnormalities, MRI revealed recognizable patterns correlating with improving brain myelination. Imaging findings appear to be on a continuum with more severe white matter abnormalities in ring chromosome 18 and greater prevalence of structural abnormalities of pons and cerebellum in trisomy 18.
ABBREVIATIONS
18q-: 18q deletion; CC: corpus callosum; CC-APD: CC anteroposterior diameter; FOD: fronto-occipital diameter; TCD: transverse cerebellar diameter; APD: anteroposterior diameter; CCD: craniocaudal diameter; MBP: myelin basic protein; PMD: Pelizaeus-Merzbacher Disease; GWMD: gray-white matter differentiation.
PubMed: 38816019
DOI: 10.3174/ajnr.A8361 -
Brain Research Sep 2024Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus...
Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury.
Topics: Animals; Male; Norepinephrine; Female; Rats, Sprague-Dawley; Prefrontal Cortex; Central Nervous System Stimulants; Methylphenidate; Brain Concussion; Rats; Brain Injuries, Traumatic; Locus Coeruleus; Arousal; Microdialysis
PubMed: 38815643
DOI: 10.1016/j.brainres.2024.149040