Disease Of Central Nervous System Research Articles

PEARL: A multicenter phase 2 study of lorlatinib in patients with ALK-rearranged NSCLC and central nervous system disease

PEARL: A multicenter phase 2 study of lorlatinib in patients with ALK-rearranged NSCLC and central nervous system disease

Targeting GPR52 for potential agonists for schizophrenia therapy: A computational drug discovery study.

Targeting GPR52 for potential agonists for schizophrenia therapy: A computational drug discovery study.

Duration of systemic antifungal therapy for patients with invasive fungal diseases: A reassessment.

Duration of systemic antifungal therapy for patients with invasive fungal diseases: A reassessment.

Astrocyte heterogeneity in ischemic stroke: Molecular mechanisms and therapeutic targets.

Astrocyte heterogeneity in ischemic stroke: Molecular mechanisms and therapeutic targets.

Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) measured by Guardant Reveal in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with long-term disease control on first-line trastuzumab-pertuzumab.

1052 Background: The CLEOPATRA and PERUSE trials established the combination of a taxane with the antiHER2 monoclonal antibodies trastuzumab and pertuzumab (HP) as the gold standard first-line treatment for HER2+ mBC. In both studies, the progression events reached a plateau after 4 years and up to 30% of pts remained long-term progression-free, hypothesizing HP maintenance can be safely discontinued. We therefore evaluated whether epigenomic-based ctDNA MRD analysis can potentially identify pts with a higher chance of permanent remission. PRE-PHENIX is a multi-center observational study that explores the prevalence of MRD measured by Guardant Reveal in HER2+ mBC pts on long-term first-line HP maintenance. Methods: A total of 40 pts with HER2+ mBC on first-line treatment with HP maintenance for a minimum of 4 years were included. Confirmation of no progressive disease by CT or PET-scan in the last 3 months previous to study entry was mandatory. Plasma samples were analysed using Guardant Reveal powered by the Guardant Infinity platform, a tissue-free epigenomic assay interrogating differentially methylated regions of DNA optimized to detect breast cancer DNA from normal cell-free DNA. Two ctDNA tests were performed on each patient within a 6 – 12-week interval. Additionally, 11 pts with confirmed disease progression on antiHER2 therapy for mBC were included as case controls. The primary objective was to establish the prevalence of positive MRD in both populations and the agreement between the two tests for the Long-Term responders. Results: Median age was 63.2 years (range 30.8 – 84.4). The median duration of first-line HP treatment was 6.9 years (range 4.2 - 11.1). At diagnosis, 26 pts (65%) presented with “de novo” mBC and 20 (50%) had visceral disease. The last radiological evaluation categorized 6 pts (15%) as having stable disease (SD), 2 pts (5%) with partial response (PR), and 32 pts (80%) with complete response (CR). Among the 11 pts with confirmed progression, 2 presented exclusive Central Nervous System (CNS) disease. Guardant Reveal identified MRD in 4 long-term responders (10%), 3 out of 6 pts (50%) with SD, 1 of 2 pts (50%) with PR, and no MRD among the 32 pts with CR. A perfect agreement was observed between the two tests (Kappa-index of 1). Ten out of the 11 pts (91%) with disease progression had MRD, including the two with exclusive CNS involvement. Conclusions: Our study demonstrates clinically significant performance of a tissue-free MRD test, Guardant Reveal, as a potential non-invasive monitoring tool to guide de-escalation strategies in pts HER2+ mBC pts with long-term remissions on HP treatment. A prospective study (PHENIX) to guide HP interruption by ctDNA monitoring is planned. This study was funded by a Fundación Contigo full grant (Spain) and Guardant Health.

TAPS chemistry: A novel, ultrasensitive pan-CNS cancer liquid biopsy assay.

e14034 Background: The gold standard of diagnosis for central nervous system (CNS) malignancy is biopsy of the tumor, an invasive procedure that, at times, comes with considerable risk or is not feasible. Treatment of CNS malignancies is now heavily based on the molecular profiling of tumor tissue. Without molecular profiling of the tumor, effective treatment decisions cannot be made. We report our development of a pan-CNS cancer liquid biopsy assay, which interrogates cell-free, tumor-derived DNA (cfDNA) found in cerebrospinal fluid (CSF). Our assay uses a novel chemistry, known as TAPS, which enables ultrasensitive and concurrent base sequencing and DNA methylation profiling. This enables detection of the tumor molecular profile from CSF based on sparse tumor-derived cfDNA with minimally invasive collection methods for CSF. Methods: DNA extraction and library preparation from a CSF sample begins with manual isolation of cfDNA from 1-5mL of CSF/sample, processed no more than 48 hours after sample collection. CfDNA is bound to magnetic nanoparticles, washed, and eluted, and cfDNA content is then quantified. Library preparation is performed using TET-assisted pyridine borane sequencing (TAPS chemistry), effectively converting all methylated cytosine (Cs) to thymine (Ts). Samples are then deep sequenced on the NOVASeq 2000.Our bioinformatics workflow leverages a multimodal approach to process and interpret sequencing data derived from TAPS. We align paired-end reads to the hg38 reference genome using BWA-MEM, followed by quality control, to achieve ~10x coverage. Post-processing steps include fragCounter and Dryclean, which implement GC and mappability bias correction and denoising through rPCA, respectively. Methylation signals are extracted using Rastair, a TAPS-specific module enabling genome-wide DNA methylation profiling. Results: TAPS demonstrates robust performance with high sensitivity for detecting CNS tumor biomarkers, enabling concurrent identification of mutations (IDH1/2, TP53, TERT), copy number aberrations (1p19q loss, EGFR amplification, CDKN2A loss), gene fusions (EGFRvIII, MN1:CXXC5), and targeted methylation analysis (including that of the MGMT promoter) within a single assay. Further, principal component analysis of 32 CSF samples showed clear methylation-based classification of CNS tumors, including glioblastomas, meningiomas, and metastatic carcinomas. Conclusions: Using our novel, ultrasensitive pan-CNS cancer CSF liquid biopsy assay, we are able to identify major drivers of CNS disease, both genomic and epigenetic, enabling minimally invasive diagnosis and longitudinal monitoring of CNS cancers. The approach's low DNA input requirements and minimal destructive effects highlight its potential for clinical implementation, particularly for pediatric and metastatic CNS tumors.

Bispecific antibody therapy in central nervous system (CNS) multiple myeloma (MM): Multicenter retrospective study.

e19505 Background: CNS involvement in MM is a rare, aggressive extramedullary manifestation with a poor prognosis (~4 months). The blood-brain barrier limits the effectiveness of cytotoxic drugs and novel therapies. Patients (pts) with CNS-MM are often excluded from clinical trials, leading to limited data on its incidence, prognosis, and optimal treatment. While bispecific antibodies (BsAbs) have revolutionized treatment for relapsed/refractory (R/R) MM, their effectiveness in CNS-MM remains uncertain due to the exclusion of these patients from key trials. Methods: This multicenter, retrospective study included 8 patients with CNS-MM who were treated with BsAbs across 3 academic medical centers in the U.S. All patients received at least one full dose after step-up dosing (SUD). Clinical characteristics and outcomes were collected and analyzed. Results: Of the 8 patients, 7 received talquetamab and 1 received teclistamab. The median age at diagnosis was 66 years (range 48-73), and 6 patients (75%) were male. Cytogenetic findings included 1q21 amplification in 6 patients (75%) and 17p deletion in 3 patients (37.5%). No patients had t(11;14), t(4;14), t(14;16), or t(14;20). CNS involvement included intraparenchymal plasmacytoma (37.5%), leptomeningeal disease (25%), or both (37.5%). Fifty percent had extramedullary disease outside of CNS-MM, with 2 patients (25%) having plasma cell leukemia and 1 patient having R-ISS Stage III disease. Most patients (87.5%) were penta-refractory at the time of BsAb initiation with 37.5% of patients having received prior CAR-T. Among the 6 evaluable patients, 100% achieved a CNS response, with a median time to best response of 10 weeks (median 6.5 doses). All patients with measurable systemic disease (n=6) had a systemic response of ≥ VGPR. CNS-directed therapies, such as radiation (RT) or intrathecal chemotherapy (IT), were used in 7 patients (87.5%). No cases of grade ≥ 3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Two patients were unable to have recorded CNS responses due to hospice enrollment or death. Conclusions: BsAbs show promise as a feasible and effective treatment for CNS-MM patients, offering good CNS disease control without an increased risk of CRS or ICANS. These findings underscore the potential of BsAbs in managing this high-risk population and support the need for further investigation.

Implantable systems for neurological chronotherapy.

Implantable systems for neurological chronotherapy.

Transcriptomic analysis of intracellular RNA granules and small extracellular vesicles: Unmasking their overlap in a cell model of Huntington's disease.

Transcriptomic analysis of intracellular RNA granules and small extracellular vesicles: Unmasking their overlap in a cell model of Huntington's disease.

Long‐term follow‐up of 35 dogs with meningoencephalitis of unknown origin treated with cytosine arabinoside and glucocorticosteroids

AbstractBackgroundMeningoencephalitis of unknown origin (MUO) is an idiopathic immune‐mediated central nervous system disease. Glucocorticosteroids are the main treatment, often combined with cytosine arabinoside (CA).MethodsThis retrospective, descriptive study evaluated the outcome of a 69‐week protocol using glucocorticosteroids and CA (two initial constant rate infusions followed by recurrent subcutaneous injections) in dogs diagnosed with MUO. Outcomes (e.g., treatment success, relapse or death) at 25, 69 and 93 weeks were descriptively analysed and compared to similar protocols reported in the literature. Relapse timing was documented at different treatment stages and glucocorticosteroid dosages.ResultsThirty‐five dogs met the inclusion criteria, of which six (17.1%) died within the first 7 days after diagnosis. Overall, 62.9% completed the 93‐week follow‐up, with 42.9% showing no relapse. Relapse occurred in 40% of dogs, with 20% of these relapsed dogs dying. The majority of dogs relapsed during the treatment protocol.LimitationsLimitations include the study's retrospective and descriptive nature, small sample size and lack of histopathological confirmation.ConclusionThe treatment protocol used in this study does not demonstrate superiority over protocols used in earlier studies. This study emphasises the need for long‐term follow‐up to detect relapses after treatment discontinuation.

Mitochondrial transfer as a novel therapeutic approach in ischemic stroke treatment: Current challenges and future perspectives

AbstractIschemic stroke, the second leading cause of human mortality, presents a formidable challenge to healthcare. Following ischemic insult, the brain undergoes intricate pathological transformations, prominently marked by mitochondrial damage, including swelling, fission, and mitophagy, collectively termed mitochondrial quality control disorder. Mitochondria, pivotal in energy regulation and oxidative stress modulation, play a critical role in neuronal apoptosis post‐stroke. To solve the problems caused by mitochondrial quality control disorders, mitochondrial transfer has become a new therapeutic strategy for central nervous system diseases. Mitochondrial transfer refers to the process by which certain cell types export their mitochondria and pass them on to other cell types, a process also known as intercellular mitochondrial transfer. Mechanistically, mitochondrial transfer occurs via tunneling nanotubes, extracellular vesicles, and free mitochondrial transfer, exerting multifaceted effects such as anti‐inflammatory, anti‐lipid peroxidation, ferroptosis modulation, and enhancement of mitochondrial metabolism. This review explores the therapeutic efficacy, current obstacles, and future prospects of mitochondrial transfer in ischemic stroke, offering insights to researchers and instilling hope in patients for conquering this debilitating condition.

Optimizing workflows for metastatic central nervous system disease: a systematic review and proposed guidelines.

Brain and spine metastases are a major cause of morbidity and mortality in patients with malignancy. Aside from advancements in medical, surgical, and radiation therapies, patient workflow optimization augments care. Here, we present the first systematic review to identify opportunities in workflow optimization and use these findings to present guidelines for operational excellence. PubMed/MEDLINE, Embase, and Web of Science databases were searched for peer-reviewed studies evaluating optimization points within treatment workflows for brain and spinal metastases. Inclusion criteria encompassed rapid diagnostic models, expedited care pathways, and quality improvement interventions for metastatic disease, whereas non-English and case reports were excluded. Eligible studies were screened, and data such as study design, outcomes, and bias were recorded using Cochrane's RoB-1 analysis. This protocol was prospectively registered in PROSPERO (CRD420251016218). 30 studies were included, with a total of 23,697 patient participants. These studies focused on patient education, referral to surgery, referral from surgery to radiation oncology, and referral from surgery to medical oncology. These studies highlighted the benefits of expediting triaging, referral speed, and treatment initiation in the context of valuable resources such as a comprehensive clinical team and artificial intelligence in radiology and cytopathology. Optimizing workflows around the current literature for metastatic brain and spine disease identifies critical areas of improvement to enhance outcomes. We draw from this literature to propose guidelines for delivering a comprehensive and standardized patient workflow. Future studies targeting these salient points will further improve quality and advance patient care.

Ultrasonic conductivity of the skull bones as a factor limiting the performance of operations using focused ultrasound in central nervous system diseases: Endocrinologist's view

Ultrasonic conductivity of the skull bones as a factor limiting the performance of operations using focused ultrasound in central nervous system diseases: Endocrinologist's view

Dual-Targeting Protein-Based Delivery System for Enhanced Drug Therapy of Neurodegenerative Disorders.

Conventional drugs for Alzheimer's disease (AD) treatment often suffer from low bioavailability due to the blood-brain barrier (BBB). In this investigation, we developed a dual-brain targeting protein-based drug delivery system for nose-to-brain drug delivery. The dual-brain targeting drug delivery system, Donepezil@Tf/cRGD-CS, was prepared using a simple self-assembly method. Donepezil was encapsulated in transferrin (Tf) nanoparticles, which were decorated with cRGD-conjugated chitosan (cRGD-CS), enabling dual-targeted drug delivery. Due to the specific interactions between Tf and the transferrin receptor (TfR) as well as cRGD and integrins, Donepezil@Tf/cRGD-CS exhibited enhanced BBB penetration as well as improved cellular uptake by brain neurons. An in vitro BBB model confirmed the enhanced permeability of the dual-targeted drug-loaded nanoparticles across the BBB. Compared to free donepezil, Donepezil@Tf/cRGD-CS nanoparticles significantly improved therapeutic outcomes, including reduced neurotoxicity induced by Aβ25-35 and downregulation of apoptosis-related proteins and Tau proteins. This study offers an effective strategy for improving the therapeutic outcomes of central nervous system diseases.

Incidence and Predictors of Postoperative Delirium in Patients Undergoing Elective Hip and Knee Arthroplasty: A Prospective Observational Study

Background/Objectives: Postoperative delirium has not been well explored in patients undergoing elective hip and knee arthroplasty. This study assessed the incidence of delirium in these patients in the postanesthetic care unit (PACU) and throughout their hospital admission. Predictors of postoperative delirium and impact of delirium on length of stay were also analyzed. Methods: This prospective observational study recruited patients (n = 978) with normal cognitive function presenting for elective primary hip or knee arthroplasty at a single tertiary academic center. Delirium was assessed using the Nursing Delirium Scoring Scale (NuDESC) in the PACU, and twice daily after that on postoperative days 1, 2 and 3, or until discharge, whichever came first. Results: In total, 26 (2.7%) patients developed delirium postoperatively. Unadjusted logistic regression analyses revealed that age; history of cardiovascular, central nervous system, hematologic, endocrinologic, psychiatric disease; postoperative opioid use; and ASA level were associated with an increased risk of delirium, with odds ratios (95% confidence interval) of 1.7 (1.35 to 2.11), 3.6 (1.09 to 12.25), 3.5 (1.53 to 8.03), 2.7 (1.09 to 6.45), 2.3 (1.04 to 4.97), 4.7 (2.10 to 10.70), 0.4 (0.17 to 0.89), and 2.37 (1.05 to 5.33), respectively. A Mann–Whitney U test showed no difference in PACU or hospital length of stay between patients who did and did not have delirium in the PACU (within the first hour). Conclusions: Age, ASA > 3, a history of cardiovascular disease, central nervous system disease, hematologic disease, endocrinologic disease, psychiatric disease and postoperative opioid use are individually associated with postoperative delirium. A future study with an even larger sample size is needed to further evaluate these factors in an adjusted analysis.

Balancing Microglial Density and Activation in Central Nervous System Development and Disease

Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.

Bilateral Internuclear Ophthalmoplegia: Multiple Sclerosis rather Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD)?

Increasing knowledge about neuro-inflammatory conditions as lead to new challenges in establishing a diagnosis. Clinical distinctive features might help. We present a 34-year-old patient with bilateral internuclear ophthalmoplegia (bINO). Investigation was compatible with demyelinating central nervous system (CNS) disease. Low-positive IgG myelin oligodendrocyte glycoprotein (MOG) antibodies were found. Rituximab was started and the patient has remained without further clinical or magnetic resonance imaging (MRI) activity. Acknowledging that bINO is a wellknown manifestation of multiple sclerosis (MS) but rarely reported among MOGAD patients its occurrence might help distinguish MS from MOGAD in an apparent overlap setting, favoring MS.

Unusual pineal gland lesion presenting with obstructive hydrocephalus: A multimodal imaging perspective

Metastatic melanoma to the pineal gland is exceedingly rare, with only a few cases documented in the literature. We report a 41-year-old male who presented with progressive headaches, nausea, vomiting, and altered mental status, ultimately found to have obstructive hydrocephalus secondary to a hypermetabolic pineal mass. Imaging revealed a well-circumscribed lesion on positron emission tomography/computed tomography (standardized uptake value [SUV] of 17.6) and magnetic resonance imaging findings consistent with cerebrospinal fluid obstruction. Further evaluation identified additional metastatic sites, including a left upper quadrant skin lesion. Histopathologic examination confirmed metastatic melanoma with a primary cutaneous origin. Despite undergoing whole-brain radiation therapy and systemic immunotherapy, the patient’s neurological condition deteriorated due to progressive central nervous system disease. This case underscores the critical role of advanced imaging techniques in identifying atypical metastatic sites and highlights the challenges in managing rare intracranial melanoma metastases.

The Mechanisms and Application Prospects of Astrocyte Reprogramming into Neurons in Central Nervous System Diseases.

Central nervous system (CNS) diseases, including ischemic stroke (IS), Alzheimer's disease (AD), and Parkinson's disease (PD), are leading causes of global disability and mortality, characterized by progressive neuronal loss and irreversible neural circuit damage. Despite advances in understanding their pathophysiology, therapeutic options remain limited due to the complexity of disease mechanisms and challenges in delivering treatments across the blood-brain barrier (BBB). In this context, astrocyte reprogramming has emerged as a groundbreaking strategy for neural repair. By leveraging the plasticity of astrocytes, researchers have demonstrated the potential to convert these glial cells into functional neurons, offering a novel approach to replenish lost neurons and restore neural function. This review explores the latest advancements in astrocyte reprogramming, focusing on transcription factor-mediated, miRNA-induced, and small molecule-based strategies, as well as the molecular mechanisms underlying this process. We also discuss the therapeutic potential of astrocyte reprogramming in CNS diseases, including IS, AD, PD, and other neurodegenerative disorders, while addressing the challenges and future directions for clinical translation. Through a systematic analysis of recent studies, this review highlights the promise of astrocyte reprogramming as a transformative therapeutic strategy for CNS repair, providing new hope for patients with debilitating neurological conditions.

Fluid and waste clearance in central nervous system health and diseases.

In respect to the circulatory system, the central nervous system (CNS) differs from other organs in the body by three main features. First, the CNS is surrounded by a compartment filled with cerebrospinal fluid (CSF). Second, the CNS is devoid of lymphatic vessels which are found in the dura mater of the meninges. Third, the CNS blood vasculature serves as a scaffold to perivascular spaces allowing CSF to circulate into the CNS parenchyma via the glymphatic system. This review highlights the contribution of the glymphatic system and meningeal lymphatic vasculature to CNS homeostasis, and also recapitulates the alterations of glymphatic-meningeal lymphatic system that have been associated to neurological disorders, especially neurodegenerative diseases. We discuss the controversies and limitations in current research, emphasizing the need for cautious interpretation while highlighting the potential of glymphatic and meningeal lymphatic pathways as therapeutic targets in neurological disorders.