Distinct Volume Alterations of Thalamic Nuclei Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. STUDY DESIGN: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. STUDY RESULTS: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. CONCLUSIONS: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia.

Exploring neonicotinoid effects on Drosophila: insights into olfactory memory, neurotransmission, and synaptic connectivity.

Neonicotinoid insecticides, the fastest-growing class in recent decades, interfere with cholinergic neurotransmission by binding to the nicotinic acetylcholine receptor. This disruption affects both targeted and non-targeted insects, impairing cognitive functions such as olfaction and related behaviors, with a particular emphasis on olfactory memory due to its ecological impact. Despite the persistent presence of these chemicals in the environment, significant research gaps remain in understanding the intricate interplay between cognitive function, development, neuronal activity, and neonicotinoid-induced toxicity. This study focuses on the fruit fly Drosophila melanogaster, chosen for its genetic tractability, well-characterized neural circuitry, and remarkable parallels with bees in neurotransmitter systems and brain structures. Our aim is to establish the fruit fly as a valuable model organism for studying the effects of neonicotinoids on behavior and neuronal circuitry, with particular attention to olfactory memory and associated brain circuitries. To achieve this aim, we conducted experiments to investigate the effects of short-term exposure to sublethal doses of the neonicotinoid imidacloprid, mimicking realistic environmental insecticide exposure, on the formation of odor memories. Additionally, we evaluated synaptic contacts and cholinergic neurotransmission within the mushroom body, the primary memory network of insects. Our results showed significant impairments in odor memory formation in flies exposed to imidacloprid, with exposure during the adult stage showing more pronounced effects than exposure during the larval stage. Additionally, functional studies revealed a decrease in synaptic contacts within the intrinsic olfactory projection neurons and the mushroom body. Furthermore, another experiment showed an odor-dependent reduction in cholinergic neurotransmission within this network. In summary, employing Drosophila as a model organism provides a robust framework for investigating neonicotinoid effects and understanding their diverse impacts on insect physiology and behavior. Our study initiates the establishment of the fruit fly as a pivotal model for exploring neonicotinoid influences, shedding light on their effects on olfactory memory, neuronal integrity, and synaptic transmission.

Lower cortical thickness and increased brain aging in adults with cocaine use disorder.

Background: Cocaine use disorder (CUD) is a global health issue with severe behavioral and cognitive sequelae. While previous evidence suggests a variety of structural and age-related brain changes in CUD, the impact on both, cortical thickness and brain age measures remains unclear. Methods: Derived from a publicly available data set (SUDMEX_CONN), 74 CUD patients and 62 matched healthy controls underwent brain MRI and behavioral-clinical assessment. We determined cortical thickness by surface-based morphometry using CAT12 and Brain Age Gap Estimate (BrainAGE) via relevance vector regression. Associations between structural brain changes and behavioral-clinical variables of patients with CUD were investigated by correlation analyses. Results: We found significantly lower cortical thickness in bilateral prefrontal cortices, posterior cingulate cortices, and the temporoparietal junction and significantly increased BrainAGE in patients with CUD [mean (SD) = 1.97 (±3.53)] compared to healthy controls (p < 0.001, Cohen's d = 0.58). Increased BrainAGE was associated with longer cocaine abuse duration. Conclusion: Results demonstrate structural brain abnormalities in CUD, particularly lower cortical thickness in association cortices and dose-dependent, increased brain age.

Basal-Forebrain Cholinergic Nuclei Alterations are Associated With Medication and Cognitive Deficits Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: The cholinergic system is altered in schizophrenia. Particularly, patients' volumes of basal-forebrain cholinergic nuclei (BFCN) are lower and correlated with attentional deficits. It is unclear, however, if and how BFCN changes and their link to cognitive symptoms extend across the schizophrenia spectrum, including individuals with at-risk mental state for psychosis (ARMS) or during first psychotic episode (FEP). STUDY DESIGN: To address this question, we assessed voxel-based morphometry (VBM) of structural magnetic resonance imaging data of anterior and posterior BFCN subclusters as well as symptom ratings, including cognitive, positive, and negative symptoms, in a large multi-site dataset (n = 4) comprising 68 ARMS subjects, 98 FEP patients (27 unmedicated and 71 medicated), 140 patients with established schizophrenia (SCZ; medicated), and 169 healthy controls. RESULTS: In SCZ, we found lower VBM measures for the anterior BFCN, which were associated with the anticholinergic burden of medication and correlated with patients' cognitive deficits. In contrast, we found larger VBM measures for the posterior BFCN in FEP, which were driven by unmedicated patients and correlated at-trend with cognitive deficits. We found no BFCN changes in ARMS. Altered VBM measures were not correlated with positive or negative symptoms. CONCLUSIONS: Results demonstrate complex (posterior vs. anterior BFCN) and non-linear (larger vs. lower VBM) differences in BFCN across the schizophrenia spectrum, which are specifically associated both with medication, including its anticholinergic burden, and cognitive symptoms. Data suggest an altered trajectory of BFCN integrity in schizophrenia, influenced by medication and relevant for cognitive symptoms.

ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery.

The drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regulation mechanisms that control these transporters, is critical to solving this clinical problem.In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier research and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood-brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their potential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS disease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be targeted for therapeutic purposes in the clinic. SIGNIFICANCE STATEMENT: The ABCB1/ABCG2 drug efflux system at the blood-brain barrier poses a significant problem to successful drug delivery to the brain. The article reviews signaling pathways that regulate blood-brain barrier ABCB1/ABCG2 and could potentially be targeted for therapeutic purposes.

Plasma protein-mediated uptake and contradictions to the free drug hypothesis: a critical review.

According to the free drug hypothesis (FDH), only free, unbound drug is available to interact with biological targets. This hypothesis is the fundamental principle that continues to explain the vast majority of all pharmacokinetic and pharmacodynamic processes. Under the FDH, the free drug concentration at the target site is considered the driver of pharmacodynamic activity and pharmacokinetic processes. However, deviations from the FDH are observed in hepatic uptake and clearance predictions, where observed unbound intrinsic hepatic clearance (CLint,u) is larger than expected. Such deviations are commonly observed when plasma proteins are present and form the basis of the so-called plasma protein-mediated uptake effect (PMUE). This review will discuss the basis of plasma protein binding as it pertains to hepatic clearance based on the FDH, as well as several hypotheses that may explain the underlying mechanisms of PMUE. Notably, some, but not all, potential mechanisms remained aligned with the FDH. Finally, we will outline possible experimental strategies to elucidate PMUE mechanisms. Understanding the mechanisms of PMUE and its potential contribution to clearance underprediction is vital to improving the drug development process.

Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice.

Background: A metabolic shift from fatty acid (FAO) to glucose oxidation (GO) occurs during cardiac hypertrophy (LVH) and heart failure with reduced ejection fraction (HFrEF), which is mediated by PGC-1α and PPARα. While the transcription factor EB (TFEB) regulates the expression of both PPARGC1A/PGC-1α and PPARA/PPARα, its contribution to metabolic remodeling is uncertain. Methods: Luciferase assays were performed to verify that TFEB regulates PPARGC1A expression. Cardiomyocyte-specific Tfeb knockout (cKO) and wildtype (WT) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry, qRT-PCR, and citrate synthase and complex II activity measurements. Results: Luciferase assays revealed that TFEB increases PPARGC1A/PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice exhibited a reduced cardiac function, elevated stress markers and a decrease in FAO and GO gene expression compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a comparable decrease in FAO- and increase in GO-related proteins in both genotypes. A significant reduction in mitochondrial quality control genes and a decreased citrate synthase and complex II activities was observed in hearts of WT but not cKO HFrEF mice. Conclusions: TFEB affects the baseline expression of metabolic and mitochondrial quality control genes in the heart, but has only minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH. Further studies are needed to elucidate if TFEB affects the metabolic flux in stressed cardiomyocytes.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review.

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson's disease. Finally, we discuss overarching issues and outline future research questions.

Characterization and comparison of human glioblastoma models.

Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.

Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model.

BACKGROUND: Deposition of amyloid beta (Aß) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aß pathology and glial cell-mediated neuroinflammation. RESULTS: Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aß and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aß and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome. CONCLUSIONS: Our data highlight that the autophagy activator spermidine holds the potential to enhance Aß degradation and to counteract glia-mediated neuroinflammation in AD pathology.

Impact of MRD status in patients with AML undergoing allogeneic stem cell transplantation in the first vs the second remission.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for relapse-free survival to most patients with acute myeloid leukemia (AML). It may be performed during complete remission or delayed until after the first relapse because of relevant treatment-related morbidity and mortality. The measurable residual disease (MRD) status at HSCT adds refined prognostic information to the assigned European LeukemiaNet (ELN) 2017 genetic risk at diagnosis. We analyzed 580 patients with AML who underwent allogeneic HSCT during either the first (79%) or second (21%) remission. Although, because of common treatment strategies, some adverse risk characteristics, such as monosomal or complex karyotypes, were less frequent in patients who underwent transplant in the second remission, those patients had worse outcomes compared with patients who had transplant in the first remission. The MRD status at HSCT was an independent prognostic factor, irrespective of the number of remissions at HSCT. Notably, patients who were MRD+ who underwent HSCT in the first remission and those who were MRD- and underwent transplant in the second remission had similar outcomes. In the clinically highly relevant group of individuals who had ELN2017 intermediate risk, the MRD status provided the highest prognostic value with very dismal outcomes for patients who were MRD+ and underwent second-remission transplants. The adverse outcomes of patients who are MRD+ and of those who undergo transplant in the second remission should be considered when planning consolidation treatment, to avert an allogeneic HSCT in MRD+ second remission when possible.

THESEUS1 modulates cell wall stiffness and abscisic acid production in Arabidopsis thaliana.

Plant cells can be distinguished from animal cells by their cell walls and high-turgor pressure. Although changes in turgor and the stiffness of cell walls seem coordinated, we know little about the mechanism responsible for coordination. Evidence has accumulated that plants, like yeast, have a dedicated cell wall integrity maintenance mechanism. It monitors the functional integrity of the wall and maintains integrity through adaptive responses induced by cell wall damage arising during growth, development, and interactions with the environment. These adaptive responses include osmosensitive induction of phytohormone production, defense responses, as well as changes in cell wall composition and structure. Here, we investigate how the cell wall integrity maintenance mechanism coordinates changes in cell wall stiffness and turgor in Arabidopsis thaliana We show that the production of abscisic acid (ABA), the phytohormone-modulating turgor pressure, and responses to drought depend on the presence of a functional cell wall. We find that the cell wall integrity sensor THESEUS1 modulates mechanical properties of walls, turgor loss point, ABA biosynthesis, and ABA-controlled processes. We identify RECEPTOR-LIKE PROTEIN 12 as a component of cell wall integrity maintenance-controlling, cell wall damage-induced jasmonic acid (JA) production. We propose that THE1 is responsible for coordinating changes in turgor pressure and cell wall stiffness.

Risk Stratification, Measurable Residual Disease, and Outcomes of AML Patients with a Trisomy 8 Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not been performed so far. METHODS: We retrospectively analyzed clinical features, outcomes, and measurable residual disease (MRD) of 659 AML (12%, n = 81, with a trisomy 8) patients subjected to allogeneic HSCT as a consolidation therapy. RESULTS: The presence of a trisomy 8 associated with a trend for higher age at diagnosis, AML of secondary origin, lower white blood cell counts at diagnosis, worse ELN2017 genetic risk, wild-type NPM1, and mutated IDH1/2 and JAK2. Outcomes after allogeneic HSCT in the entire cohort did not differ between patients with a sole trisomy 8, trisomy 8 with additional cytogenetic aberrations or without a trisomy 8. A trisomy 8 did not affect outcomes within the three ELN2017 risk groups. In accordance with findings in unselected patient cohorts, persistent MRD at allogeneic HSCT in patients with a trisomy 8 identified individuals with a higher risk of relapse following allogeneic HSCT. CONCLUSIONS: Outcomes of trisomy 8 patients after allogeneic HSCT did not compare unfavorably to that of other AML patients following allogeneic HSCT. Rather than the presence or absence of a trisomy 8, additional genetic aberrations and MRD at HSCT define outcome differences and aid in informed treatment decisions.

Clinical implications of SRSF2 mutations in AML patients undergoing allogeneic stem cell transplantation.

The SRSF2 mutations are frequently found in acute myeloid leukemia (AML) and mostly affect the P95 residue. Mutations in this splicing factor mediate abnormal splicing associated with exon skipping events, including EZH2 as a crucial target. While SRSF2 mutations are enriched in secondary AML and associated with worse outcomes following chemotherapy consolidation, very little is known about the associated biological and clinical implications in AML patients consolidated with allogeneic hematopoietic stemcell transplantation (HSCT). Here we retrospectively analyzed 263 adult AML patients who received an allogeneic HSCT regarding the biological and clinical implications of the SRSF2 mutation status at diagnosis and in morphologic remission at HSCT. We found 12.5% of the patients to be SRSF2 mutated at diagnosis. Mutated patients had increased EZH2 missplicing events with P95H likely driving this pathobiology most effectively. However, the amount of EZH2 missplicing events, as a functional surrogate marker did not associate with relevant biological or clinical characteristics. We observed a persistence of mutations in remission before HSCT in the majority (93%) of SRSF2 mutated AML patients. Importantly, the variant allele frequency (VAF) levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as a marker for residual AML disease. Following allogeneic HSCT SRSF2 mutated AML patients experienced a 2-year overall survival of 77%, indicating that SRSF2 mutated AML patients may benefit from HSCT consolidation.

ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation.

Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.