Choroid Plexus Research Articles

"Dangling choroid" with contralateral glomus displacement and ischemic torsion in congenital hydrocephalus: illustrative case.

"Dangling choroid" is a prenatal sonographic marker of ventriculomegaly that measures the angle of choroid plexus (ChP) displacement in the lateral ventricle. To the authors' knowledge, postnatal sequelae related to this pathology, besides hydrocephalus, have never been reported. A female fetus was diagnosed with bilateral ventriculomegaly. Postnatally, the patient was diagnosed with hydrocephalus and macrocephaly secondary to aqueductal stenosis and underwent endoscopic third ventriculostomy with ChP cauterization. Intraoperatively, the septum pellucidum was incomplete, and the right-sided ChP glomus was contralaterally displaced and entangled with the left, with evidence of ischemic torsion and hemorrhage. In this case of an ischemic ChP secondary to transventricular displacement of the glomus, at least two biomechanical events are relevant. First, the choroid fissure and velum interpositum can be thinned in the setting of ventriculomegaly. Second, stretching and perforation of the septum pellucidum can occur. Both changes can increase the mobility of a dangling choroid, occasionally leading to entanglement of the vascular pedicles. Preoperative recognition of this complication can help optimize surgical planning, e.g., using flexible endoscopy to facilitate complete ChP cauterization and changing the surgical approach if the ChP has been displaced. https://thejns.org/doi/10.3171/CASE24505.

Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics

BackgroundOxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (Kp,uu) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H+/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague–Dawley rats.MethodsUsing brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.ResultsOur results indicated a reduced, sex-independent brain net uptake of oxycodone across the blood–brain barrier (BBB) measured in the striatum. Notably, the LPS challenge has significantly altered the systemic pharmacokinetics (PK) of oxycodone, in a sex-specific manner, leading to lower clearance and higher blood concentrations in females compared to LPS-treated males and healthy rats of both sexes. Proteomic analysis using Olink Target 96 Mouse Exploratory assay confirmed the induction of systemic inflammation and neuroinflammation. The inflammation led to an increased paracellular transport, measured using 4 kDa dextran, while preserving net active uptake of oxycodone across both BBB and the blood-cerebrospinal fluid barrier (BCSFB), with Kp,uu values of 2.7 and 2.5, respectively. The extent of uptake was 1.6-fold lower (p < 0.0001) at the BBB and unchanged at the BCSFB after the LPS challenge compared to that in healthy rats. However, the mean exposure of unbound oxycodone in the brain following LPS was similar to that in healthy rats, primarily due to the LPS-induced changes in systemic exposure.ConclusionsThese findings highlight the dissimilar responses at blood–brain interfaces during LPS-induced inflammation. Advancing the knowledge of neuropharmacokinetic mechanisms, specifically those involving the H+/OC antiporter system, will enable the development of more effective therapeutic strategies during inflammation conditions.Graphical

Sturge–Weber syndrome: updates in translational neurology

Sturge–Weber syndrome (SWS) is a rare congenital neurovascular disorder that initially presents with a facial port-wine birthmark (PWB) and most commonly associated with a R183Q somatic mosaic mutation in the gene GNAQ. This mutation is enriched in endothelial cells. Contrast-enhanced magnetic resonance imaging (MRI) diagnoses brain abnormalities including leptomeningeal vascular malformation, an enlarged choroid plexus, and abnormal cortical and subcortical blood vessels. Mouse SWS models identify dysregulated proteins important for abnormal vasculogenesis and blood brain barrier permeability. Recent clinical research has focused on early diagnosis, biomarker development, presymptomatic treatment, and development of novel treatment strategies. Prospective pilot clinical drug trials with cannabidiol (Epidiolex) or with sirolimus, an mTOR inhibitor, indicate possible reductions in seizure frequency and improved cognitive outcome. This review connects the most recent molecular research in SWS cell culture and animal models to developing new treatment methods and identifies future areas of research.

Transmembrane protein 106B amyloid is a potential off-target molecule of tau PET tracers in the choroid plexus

PurposeTau positron emission tomography (PET) has become an essential tool for the clinical diagnosis of neurodegenerative diseases and the study of tau pathology in the brain. However, some tau tracers exhibit off-target binding in the basal ganglia, choroid plexus, and meninges. Recently, transmembrane protein 106B (TMEM106B) was identified to form novel amyloid filaments in the brain during aging. In this study, we explored the possibility that TMEM106B aggregates might be responsible for off-target binding of tau PET tracers in the choroid plexus. MethodsThe binding properties of 18F-labeled tau and amyloid tracers against choroid plexus tissues from postmortem human brains were evaluated through in vitro autoradiography and in vitro binding assays and compared with histochemical staining. ResultsAutoradiography showed strong binding of [18F]PM-PBB3 followed by [18F]flortaucipir in the choroid plexus. Immunostaining of the same sections revealed a high level of transmembrane protein 106B aggregates, which are thioflavin-S-labeled Biondi ring structures, in the choroid plexus epithelium and co-localization with PM-PBB3-stained structures. In contrast, co-localization of flortaucipir with TMEM106B immunoreactivity was not confirmed because flortaucipir had a low fluorescence intensity. In vitro binding assays for [18F]PM-PBB3 and [18F]flortaucipir demonstrated high affinities for collagenase A-treated choroid plexus homogenate containing transmembrane protein 106B aggregates. ConclusionThis study demonstrated high affinity of [18F]PM-PBB3 for TMEM106B aggregates in the choroid plexus. In vivo off-target binding of [18F]PM-PBB3 to the choroid plexus might result from binding to TMEM106B aggregates.

Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis

AbstractAmong the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post‐mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in‐situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10‐13) and high frequency of innate immune cells expressing the markers MHC‐class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10‐4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10‐5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In‐situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to ‘type 2 immune response’, ‘defense to infections’, ‘antigen processing/presentation’. Analysis of 78 inflammatory molecules in paired post‐mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10‐6), PDGF‐bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to “surface‐in” gradient associated with concomitant prominent microglia activation. CP inflammation, predominantly characterized by innate immunity, represents another key determinant of intrathecal, compartmentalised inflammation persisting in progressive MS, which may be possibly activated by fibrinogen and influence periventricular pathology, even without substantial association with clinical features.

Decreased Water Diffusivity Along the Perivascular Space in Older Adults With Poor Sleep Quality.

This study included 52 Japanese older adults with Pittsburgh Sleep Quality Index (PSQI) scores > 5 and 52 healthy controls (HCs) with PSQI score ≤ 5. Diffusion-weighted imaging (DWI) and 3D T1-weighted imaging were acquired using 3T magnetic resonance imaging. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated using preprocessed DWI. The choroid plexus volume (CPV) was calculated using FreeSurfer 6.0. The mean ALPS index and CPV were compared between the older adults with poor sleep quality (PSQ) and HCs using a general linear model, adjusted for covariates including age, sex, years of education, total intracranial volume, systolic blood pressure, hemoglobin A1c, and white matter lesion volume. We also conducted a partial correlation analysis between the mean ALPS index and CPV, Montreal Cognitive Assessment (MoCA), and PSQI scores, adjusting for all the mentioned covariates. The PSQ group had a significantly lower mean ALPS index than HCs. The mean ALPS index in the PSQ group was negatively correlated with CPV and positively correlated with the MoCA score. Therefore, older adults with PSQ may experience dysfunction in the excretory pathway of the perivascular space around the medullary veins. This impairment may be associated with an increase in CPV and cognitive dysfunction.

Morphometry of choroid plexus epithelial cells in neurodegenerative diseases.

The choroid plexus not only secretes the majority of cerebrospinal fluid but also controls the circadian rhythm, which can be impaired in the presence of neurodegenerative diseases. In addition, many studies have reported the contribution of choroid plexus abnormalities to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Formalin-fixed paraffin-embedded blocks were obtained from the lateral ventricles of the brains of four subjects with AD, four with vascular dementia, four with Parkinson's disease, three with multiple system atrophy, and five control patients with unremarkable neuropathological findings. They were sectioned and routinely stained with hematoxylin and eosin. Morphological analysis of epithelial cells in 10 high-power fields or a total area per case was conducted using digital images. There were no significant changes in any of the measurements: epithelial cell area, long and short axes, and ratio of the epithelial cell area to total stained area among the five groups. However, a simple linear regression analysis of epithelial cells in 20 patients showed that age was significantly correlated with the cell area, long axis, and short axis but not ratio. There were no effects of hypertension, diabetes mellitus, or calcification in the stroma on the measurements. These findings indicate that age was associated with the cell area and size in choroid plexus epithelial cells, whereas no significant changes in any epithelial cell measurements were present in neurodegenerative diseases.

Relaxation-exchange magnetic resonance imaging (REXI): a non-invasive imaging method for evaluating trans-barrier water exchange in the choroid plexus.

The choroid plexus (CP) plays a crucial role in cerebrospinal fluid (CSF) production and brain homeostasis. However, non-invasive imaging techniques to assess its function remain limited. This study was conducted to develop a novel, contrast-agent-free MRI technique, termed relaxation-exchange magnetic resonance imaging (REXI), for evaluating CP-CSF water transport, a potential biomarker of CP function. REXI utilizes the inherent and large difference in magnetic resonance transverse relaxation times (T2s) between CP tissue (e.g., blood vessels and epithelial cells) and CSF. It uses a filter block to remove most CP tissue magnetization (shorter T2), a mixing block for CP-CSF water exchange with mixing time tm, and a detection block with multi-echo acquisition to determine the CP/CSF component fraction after exchange. The REXI pulse sequence was implemented on a 9.4 T preclinical MRI scanner. For validation of REXI's ability to measure exchange, we conducted preliminary tests on urea-water proton-exchange phantoms with various pH levels. We measured the steady-state water efflux rate from CP to CSF in rats and tested the sensitivity of REXI in detecting CP dysfunction induced by the carbonic anhydrase inhibitor acetazolamide. REXI pulse sequence successfully captured changes in the proton exchange rate (from short-T2 component to long-T2 component [i.e., ksl]) of urea-water phantoms at varying pH, demonstrating its sensitivity to exchange processes. In rat CP, REXI significantly suppressed the CP tissue signal, reducing the short-T2 fraction (fshort) from 0.44 to 0.23 (p < 0.0001), with significant recovery to 0.28 after a mixing time of 400 ms (p = 0.014). The changes in fshort at various mixing times can be accurately described by a two-site exchange model, yielding a steady-state water efflux rate from CP to CSF (i.e., kbc) of 0.49 s-1. A scan-rescan experiment demonstrated that REXI had excellent reproducibility in measuring kbc (intraclass correlation coefficient = 0.90). Notably, acetazolamide-induced CSF reduction resulted in a 66% decrease in kbc within rat CP. This proof-of-concept study demonstrates the feasibility of REXI for measuring trans-barrier water exchange in the CP, offering a promising biomarker for future assessments of CP function.

Optic Nerve Sheath Dilation Is aPossible Marker of CSF Dyshomeostasis in Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is acomplex neurological disease characterized by symptoms of raised intracranial pressure of unclear etiology. Although optic nerve sheath dilation is acommon MR neuroimaging feature of IIH, how and why it occurs remains poorly understood. The purpose of the presented analysis was to investigate if optic nerve sheath dilation might be associated with neuroimaging correlates of cerebrospinal and interstitial fluid homeostasis. IIH patients were retrospectively identified from 2016-2023 from our tertiary healthcare system. Brain MRIs were computationally segmented using FreeSurfer. Additionally, diffusion tensor imaging along the perivascular space (DTI-ALPS) was employed to assess cerebral glymphatic flow. The mean perioptic subarachnoid space (PSAS) to optic nerve sheath diameter (ONSD) ratio from both eyes was correlated with neuroimaging markers of CSF and interstitial fluid homeostasis (choroid plexus, ventricle, and gray and white matter volume) and glymphatic flow. All volumes of interest were normalized to total intracranial volume. Multiple linear regression was used to evaluate for associations between continuous variables accounting for covariates of patient age, sex, and body mass index. In total, 55 IIH patients (89% female; mean age: 30.3 years [SD: 7.6]) were included. Increasing PSAS/ONSD was found to be significantly associated with increasing normalized total choroid plexus volume (p = 0.001, R = 0.48) and total ventricle volume (P = 0.014, R = 0.39). Additionally, increasing PSAS/ONSD was associated with declining/worsening cerebral glymphatic clearance based on DTI-APLS (p = 0.043, R = 0.34). Additionally, there was asignificant association between increasing PSAS/ONSD and increasing normalized total gray matter volume (p = 0.025, R = 0.36) and declining normalized total white matter volume (p = 0.012, R = 0.40). These findings suggest that MR optic nerve sheath dilation in IIH might be associated with CSF dyshomeostasis with possible choroid plexus hyperplasia and impaired cerebral glymphatic flow based on DTI-ALPS. These findings encourage future research into the ocular glymphatic system in IIH patients.

Abnormal choroid plexus, hippocampus, and lateral ventricles volumes as markers of treatment-resistant major depressive disorder.

One-third of patients with major depressive disorder (MDD) do not achieve full remission and have high relapse rates even after treatment, leading to increased medical costs and reduced quality of life and health status. The possible specificity of treatment-resistant depression (TRD) neurobiology is still under investigation, with risk factors such as higher inflammatory markers being identified. Given recent findings on the role of choroid plexus (ChP) in neuroinflammation and hippocampus in treatment response, the aim of the present study was to evaluate inflammatory- and trophic-related differences in these regions along with ventricular volumes among patients with treatment-sensitive depression (TSD), TRD, and healthy controls (HCs). ChP, hippocampal, and ventricular volumes were assessed in 197 patients with MDD and 58 age- and sex-matched HCs. Volumes were estimated using FreeSurfer 7.2. Treatment resistance status was defined as failure to respond to at least two separate antidepressant treatments. Region of interest volumes were then compared among groups. We found higher ChP volumes in patients with TRD compared with patients with TSD and HCs. Our results also showed lower hippocampal volumes and higher lateral ventricular volumes in TRD compared with both patients without TRD and HCs. These findings corroborate the link between TRD and neuroinflammation, as ChP volume could be considered a putative marker of central immune activity. The lack of significant differences in all of the region of interest volumes between patients with TSD and HCs may highlight the specificity of these features to TRD, possibly providing new insights into the specific neurobiological underpinnings of this condition.

Type 2 Diabetes Mellitus and Parkinson's Disease: An Emerging Link

Parkinson’s Disease (PD) is a common neurodegenerative disease, characterized by motor deficit. Diabetes Mellitus (DM) is a metabolic condition characterized by high glucose levels in the blood. The prevalence of chronic disorders like PD has significantly risen in recent decades. Emerging research has increasingly linked PD with Type 2 Diabetes Mellitus (T2DM) in recent years. Apart from the β-cells of the pancreas, insulin is secreted by the choroid plexus in the human brain which is essential for neuroprotection which regulates neurogenesis, oxidative stress, synaptic plasticity, neuronal survival, and neuro-inflammation. The abnormalities in the insulin signaling pathway may be responsible for neurodegeneration via insulin dysregulation, from the aggregation of α-synuclein, neuroinflammation, mitochondrial dysfunction, and altered synaptic plasticity. DM or Insulin resistance is considered a risk factor for the development of PD. Due to the lack of treatment options for PD, consistent research is going on to find a potential drug as a treatment option for PD, and due to its molecular links, the antidiabetic drugs are considered as potential candidates for PD. This review will discuss the potential cellular mechanisms shared between T2DM and PD as well as the role of antidiabetics in this disease and clinical manifestations such as its severity and prognosis.

Immune cell-enriched single-cell RNA sequencing unveils the interplay between infiltrated CD8+ T resident memory cells and choroid plexus epithelial cells in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurological disorder and the leading cause of dementia. Despite significant efforts, treatment strategies targeting amyloid-β have been less successful than anticipated. Recently, the role of neuroinflammation and adaptive immune response in AD pathogenesis has gained attention. Here, we performed immune cell-enriched single-cell RNA sequencing of brain parenchymal cells from 12-month-old 5xFAD, an AD mouse model. We analyzed 11,587 single cells and found distinct differences in T cell and choroid plexus cell populations between 5xFAD mouse and littermate control. Subsequent sub-clustering of T cells in the 5xFAD mouse revealed distinct subtypes, with CD8+ resident memory T cells (TRM) being the most prevalent T cell type. In addition, we observed an increase in T cell exhaustion markers, including Pdcd1, Ctla4, and Havcr2, with a particularly significant elevation of PD-1 and TIM-3 in CD8+ TRM in 5xFAD mouse. Furthermore, choroid plexus (ChP) epithelial cells showed altered gene expression patterns, with higher expression of MHC class I and Type I IFN-stimulated genes in 5xFAD mouse compared to the control mouse, suggesting an association with clonal expansion of AD-specific T cells in the brain. Through single-cell RNA sequencing (scRNA-seq) analysis, our study highlights the potential role of resident memory CD8+ T cell and their possible interactions with ChP epithelial cells. This study provides an exploration of the brain microenvironment landscape in AD, revealing critical insights into its underlying mechanisms.

Expression of the Hippo pathway effector, TEAD1, within the developing murine forebrain

The Hippo pathway is a critical regulator of animal development. Activation of the Hippo pathway causes a cascade of phosphorylation events that culminate in the phosphorylation of the transcriptional co-factors YAP and TAZ, which limits their entry into the nucleus. When the Hippo pathway is ‘off’, however, YAP and TAZ can enter the nucleus, where they interact with the transcription factors of the TEA Domain (TEAD) family to regulate transcriptional activity. Despite the importance of the Hippo pathway for development, including within the nervous system, the expression of the TEAD family remains poorly defined in mammals. Here, we mapped the expression of TEAD1 in the developing mouse brain. We find that TEAD1 expression is confined to progenitor cells during embryonic development, namely radial glia and intermediate progenitor cells. TEAD1 expression is not evident in post-mitotic neurons of the cortical plate. We also identify expression of TEAD1 in developing and mature ependymal cells of the lateral and third ventricle, including within the subcommissural organ, as well as by cells within the choroid plexuses and the forebrain neurogenic niches. Finally, we find that adult mice conditionally heterozygous for Tead1 in the central nervous system exhibit a significantly smaller brain. Collectively, these findings reveal a specific pattern of expression for TEAD1 during telencephalic development and implicate this factor in regulating neural progenitor cell proliferation.

Choroid plexus extracellular vesicle transport of blood-borne insulin-like growth factor 1 to the hippocampus of the immature brain

Abstract Reduced serum level of insulin-like growth factor 1 (IGF-1), a major regulator of perinatal development, in extremely preterm infants has been shown to be associated with neurodevelopmental impairment. To clarify the mechanism of IGF-1 transport at the blood-cerebrospinal fluid (CSF) barrier of the immature brain, we combined studies of in vivo preterm piglet and rabbit models with an in vitro transwell cell culture model of neonatal primary murine choroid plexus epithelial (ChPE) cells. We identified IGF-1 positive intracellular vesicles in ChPE cells and provided data indicating a directional transport of IGF-1 from the basolateral to the apical media in extracellular vesicles (EVs). Exposure of the ChPE cells to human IGF-1 on the basolateral side increased the secretion of IGF-1 positive EVs in the apical media. Mass spectrometry analysis displayed similarities in protein content between EVs derived from preterm piglet CSF and ChPE derived EVs. Furthermore, exposure of ChPE cells to human IGF-1 caused an enrichment of human IGF-1 and transmembrane p24 trafficking protein 2, proteins important for perinatal development, in apical media derived EVs. Moreover, intraventricular injections of ChPE cell-derived EVs in preterm rabbit pups resulted in an uptake of EVs in the brain, displaying penetration through the ependymal lining and deep into the hippocampus. Finally, exposure of rat hippocampus neurons to ChPE cell derived EVs resulted in internalization of the EVs in hippocampal soma and neurites. In summary, we describe a transport pathway for blood-borne IGF-1 in EVs, through the blood–CSF barrier to the hippocampus in the immature brain.

NCMP-13. EXPLORING THE PATHOPHYSIOLOGY OF HYDROCEPHALUS IN CHOROID PLEXUS PAPILLOMA

Abstract BACKGROUND Choroid plexus papilloma (CPP) is a benign intraventricular lesion associated with hydrocephalus and ventricular outflow obstruction. However, the molecular mechanism by which cerebrospinal fluid (CSF) is produced by choroid plexus (CP), or by which CSF production is altered in the setting of CPP to cause hydrocephalus, is unknown. METHODS A PRISMA systematic literature review was conducted to identify gene targets associated with CSF production. Primary tissue samples of CP and CPP from the same patient were obtained, and expression of target genes was assessed using immunohistochemistry and quantified using QuPath software H-scoring. Single-nucleus sequencing of both CP and CPP was also completed, and differential expression of identified target genes was evaluated by calculating log fold change. RESULTS Systematic literature review yielded 25 studies in animal models and 18 unique gene targets. 16 targets were expressed in primary CP and CPP tissue samples upon immunohistochemistry staining. 11 of 18 targets revealed significant differential expression between CP and CPP on single-nucleus sequencing. Genes with notable expression increases in CPP included ion transporters NKCC1 (Na-K-Cl cotransporter) and TRPV4 (non-selective cation channel), as well as carbonic anhydrase II. CONCLUSIONS We present evidence that choroid plexus papilloma has altered expression of genes previously implicated in CSF production. Upregulation of membrane transporters and cytoplasmic enzymes involved in Na+, K+, Cl-, and HCO3- transport may provide a mechanistic explanation for the development of hydrocephalus in CPP. Pharmacologic inhibition of CSF production may offer a route for non-surgical management of CPP, as well as other pathologies causing hydrocephalus.

PATH-47. AGE-, SEX-, AND GRADE-ASSOCIATED MOLECULAR DIFFERENCES IN A MULTI-INSTITUTIONAL COHORT OF CHOROID PLEXUS TUMORS

Abstract BACKGROUND Choroid plexus tumors (CPT) are central nervous system tumors where prognosis has been correlated to histologic grade, with aggressive clinical behavior and reduced survival rate in higher grade cases. Here, we present a genomic survey of a large multi-institutional cohort of CPTs across all grades. MATERIAL AND METHODS Fifty-eight CPT samples were analyzed by comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform (FoundationOne®CDx). Pathology reports, histopathology reviews, and patient clinical data were assessed. RESULTS Our cohort included 11 choroid plexus papillomas (CPP; grade 1), 16 atypical CPP (grade 2), and 31 choroid plexus carcinomas (CPC; grade 3). Males were slightly more affected than females (31 vs. 27 cases). Median patient age at tissue sampling was 11 years (range: 1–72 years). Median age of patients with CPC was younger at 3 years compared CPP at 34 years (p &amp;lt; 0.01). Genomic analyses identified three frequent, mutually exclusive mutations in TP53, TERTp, and DAXX. TP53 mutations (n = 15, 26%) were significantly more prevalent in CPC (n=14 CPC, p=0.0003), and were identified predominantly in children (n=12 CPC at &amp;lt;20 years). By contrast, TERT promoter mutations (TERTp; n = 5, 8.6%) were identified exclusively in CPP (p=0.019), predominantly grade 2 (4 of 5 cases), and exclusively in adult patients, with a median age of 48 years. DAXX mutations (n=4, 6.9%) were more common in CPC (n=3). Other alterations included PTEN (n=4, all adults) and MYCN amplification (n=3, all children &amp;lt;6 years), both exclusively in CPC. In 21 cases, including 9 out of the 11 Grade 1 CPP, no known cancer mutation was detected. CONCLUSION This study provides comprehensive genomic profiling of CPTs, highlighting distinct genetic alterations associated with different histological grades and patient demographics. These findings may inform future research and therapeutic strategies targeting specific molecular pathways in CPTs.

ANGI-06. CEREBROSPINAL FLUID MAY BE THE MOST IMPORTANT PATHWAY FOR BRAIN METASTASES: A DATA-DRIVEN HYPOTHESIS AND CLINICAL IMPLICATIONS

Abstract INTRODUCTION Hematogenous spread of brain metastases represents conventional wisdom. However, compelling physiologic evidence suggests that brain metastases may reach the CNS by way of the CSF either via the choroid plexus or directly from the bone marrow. We provide clinical evidence that invasion of brain parenchyma occurs through the CSF, and we model the therapeutic implications of this novel hypothesis. METHODS First, we assessed whether brain metastases were contiguous with a CSF space in 204 consecutive patients using pre-treatment MRI. Then, CSF was examined for malignant cells in 66 consecutive brain metastasis patients. Next, we contoured normal brain MRIs of 3 patients to calculate the percentage of brain within 5 mm of a CSF space. Finally, we queried an international neoplastic meningitis registry for patients with brain metastases to evaluate response to intra-CSF chemotherapy alone. RESULTS In 204 consecutive patients with brain metastases, the mean number of metastases was 4.63 (SD 6.26), and 85% of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. In our consecutive cohort of 66 patients with CSF analysis, 44% with one, 46% with two, 63% with three, and 71% with &amp;gt;3 metastases had malignant cells in the CSF (R2=0.93, p=0.04). Brain contouring revealed that up to 75% of the brain parenchyma lies within 5 mm of a CSF space. Seven of 10 patients with both brain and CSF metastases receiving only intrathecal chemotherapy experienced disappearance or substantial reduction in the size of their metastases. CONCLUSIONS This data suggest that brain metastases may access the CNS through the CSF. Intrathecal chemotherapy can reach most brain metastases and can produce objective responses. We suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases, and true cures may require treatment of the CSF space.

NIMG-31. CASE REPORT: DIAGNOSIS OF AN INFILTRATIVE GLIOMA IN A LI-FRAUMENI SYNDROME PATIENT OBSCURED BY LESION RESPONSIVENESS TO NSCLC TREATMENT

Abstract Li-Fraumeni syndrome is a rare, autosomal dominant disorder linked to germline mutations of the TP53 suppressor gene. Patients with this syndrome are predisposed to various malignancies and a variety of brain tumors to include choroid plexus carcinoma, medulloblastoma, and glioma. We present a 46-year-old woman with a history of Li-Fraumeni syndrome which manifested with multiple systemic malignancies including breast cancer, ovarian teratoma, and leiomyosarcoma. The patient had been undergoing MRI brain surveillance since 2018, which was initially notable for a right cerebellar midline focus of enhancement associated with slowly evolving right middle cerebellar peduncle FLAIR signal, with no detectable neurologic symptoms. She underwent systemic therapy for non-small cell lung cancer (NSCLC) with pemetrexed/cisplatin. Her next MRI brain in August 2023 showed resolution of the cerebellar enhancement with small residual FLAIR signal. In April 2024, the patient presented with new neurologic symptoms to include ataxia, dizziness, difficulty swallowing, and memory loss. Repeat MRI brain revealed new infiltrative FLAIR signal throughout the right temporal lobe extending from the posterior fossa, contiguous with the previously seen cerebellar findings and consistent with infiltrative glioma. Due to fragmented records and care in multiple systems, her updated MRI initially created a diagnostic challenge with a radiographic interpretation of likely encephalitis. This is a unique case documenting a middle-aged female with Li-Fraumeni syndrome, followed for multiple cancers, presenting with new neurologic symptoms and progressive infiltrative FLAIR changes spanning from the cerebellum into the right temporal lobe. These findings highlight the natural history of a TP53 deficient tumor that ostensibly responded to a cisplatin-based regimen given for a different indication, thereby delaying time to symptom onset and need for biopsy. Surveillance of low grade lesions in patients with underlying tumor predisposition syndromes must be interpreted in context of systemic disease burden and concurrent treatments for other neoplasms.

Choroid plexus as a mediator of CNS inflammation in multiple sclerosis.

The pathophysiology of multiple sclerosis (MS) remains poorly understood despite decades of tremendous research efforts. Advances in neuroradiography coupled with availability of unbiased approaches including spatial transcriptomics, proteomics, metabolomics, and lipidomics that are compatible with brain and fluid specimens from patients raise hope that discovery of novel disease drivers is on the horizon. Once thought to be little more than salty bathwater, our modern understanding of cerebrospinal fluid (CSF) suggests the CSF as a compelling, critical regulator of brain function in health and disease. Recent studies in the field have reinvigorated interest in CSF as a medium to better understand MS and to deliver disease-modifying therapies. In turn, the choroid plexus, an epithelial tissue located within each brain ventricle that regulates CSF and forms a key blood-CSF barrier, is uniquely positioned to orchestrate neuroinflammation associated with MS. In this perspective review, we will discuss what is known about the choroid plexus as a conductor of immune responses and how it may propagate neuroinflammation associated with MS via the CSF.

Novel hypothesis and therapeutic interventions for irritable bowel syndrome: interplay between metal dyshomeostasis, gastrointestinal dysfunction, and neuropsychiatric symptoms.

Irritable bowel syndrome is a gastrointestinal disorder due to multiple pathologies. While patients with this condition experience anxiety and depressed mood more frequently than healthy individuals, it is unclear how gastrointestinal dysfunction interacts with such neuropsychiatric symptoms. Data suggest that irritable bowel syndrome patients predominantly display a lower zinc intake, which presumably impairs enterochromaffin cells producing 5-hydroxytryptamine, gut bacteria fermenting short-chain fatty acids, and barrier system in the intestine, with the accompanying constipation, diarrhea, low-grade mucosal inflammation, and visceral pain. Dyshomeostasis of copper and zinc concentrations as well as elevated pro-inflammatory cytokine levels in the blood can disrupt blood-cerebrospinal fluid barrier function, leading to locus coeruleus neuroinflammation and hyperactivation with resultant amygdalar overactivation and dorsolateral prefrontal cortex hypoactivation as found in neuropsychiatric disorders. The dysregulation between the dorsolateral prefrontal cortex and amygdala is likely responsible for visceral pain-related anxiety, depressed mood caused by anticipatory anxiety, and visceral pain catastrophizing due to catastrophic thinking or cognitive distortion. Collectively, these events can result in a spiral of gastrointestinal symptoms and neuropsychiatric signs, prompting the progression of irritable bowel syndrome. Given that the negative feedback mechanism in regulation of the hypothalamic-pituitary-adrenal axis is preserved in a subset of neuropsychiatric cases, dorsolateral prefrontal cortex abnormality accompanied by neuropsychiatric symptoms may be a more significant contributing factor in brain-gut axis malfunction than activation of the hypothalamic corticotropin-releasing hormone system. The proposed mechanistic model could predict novel therapeutic interventions for comorbid irritable bowel syndrome and neuropsychiatric disorders.