SARS-CoV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice.

The coronavirus disease of 2019 (COVID-19) pandemic has led to more than 700 million confirmed cases and nearly 7 million deaths. Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains an important question, which is also centered on the mystery of whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to neurological complications both acutely and in long COVID.

Olfactory Receptor OR2K2 Expression in Human Choroid Plexus as a Potential Marker in Early Sporadic Alzheimer's Disease.

Epithelial cells comprising the choroid plexus (CP) form a crucial barrier between the blood and the cerebrospinal fluid, thereby assuming a central position in brain homeostasis and signaling. Mounting evidence suggests that the impairment of CP function may be a significant contributor to Alzheimer's disease (AD) pathogenesis. CP function relies on the expression of specific receptors, and the potential involvement of olfactory receptors (ORs) and taste receptors (TASRs) in chemical surveillance within the CP is being investigated. Previous studies have implicated ORs and TASRs in neurodegenerative disorders like AD, although the direct evidence of their expression in the human CP remains to be established. In this study, we conducted a transcriptomic analysis encompassing eleven ORs and TASRs in the CP, comparing samples from healthy age-matched controls to those from patients with AD spanning Braak stages I to VI. Among these receptors, a striking finding emerged-OR2K2 exhibited robust expression, with a statistically significant upregulation noted at Braak stage I. Surprisingly, at the protein level, OR2K2 showed a significant decrease in both Braak stage I and VI. Additionally, we identified CP epithelial cells as the source of OR2K2 expression, where it colocalized with autophagy markers LC3 and p62. We postulate that OR2K2 could be subjected to degradation by autophagy in the early stages of AD, triggering a compensatory mechanism that leads to increased OR2K2 mRNA transcription. This study uncovers a potential role for OR2K2 in AD pathogenesis, offering a novel perspective on the intricate dynamics at play in this neurodegenerative disorder.

Ectopic CD4+ T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon-γ induced microglia activation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4+ T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4+ T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4+ T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4+ T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4+ T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4+ T cells were positive for IFN-γ. Neutralizing intracerebral IFN-γ alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-γ antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4+ T-treated mice, while ICV injection of IFN-γ mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4+ T cells contribute to NPSLE-like symptoms in mice via Interferon-γ induced microglia activation. Depleting CP-resident lupus CD4+ T cells, interferon-γ, or activated microglia may be potential therapeutic targets for NPSLE.

Enlarged choroid plexus in relapsing-remitting multiple sclerosis may lead to brain structural changes through the glymphatic impairment.

OBJECTIVES: To investigate the potential link among choroid plexus (CP) volume, glymphatic clearance and brain structural change in relapsing-remitting multiple sclerosis (RRMS) patients. MATERIALS AND METHODS: Sixty-five RRMS patients and 48 healthy controls (HC) underwent MRI examination. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) was calculated to reflect glymphatic system function. The brain structure volume and DTI-ALPS index were compared between RRMS and HC. The mediating effect of the DTI-ALPS index between CP volume and brain structural changes was further investigated. The longitudinal changes of brain structure and DTI-ALPS index were compared in 20 RRMS patients. RESULTS: Compared to HC, CP volume in RRMS was significantly increased (P < 0.001), and DTI-ALPS index was significantly decreased (P = 0.001). The volumes of white matter, thalamus, putamen and pallidum were significantly decreased in RRMS, and the volumes of lateral ventricle and third ventricle were increased. Mediation analysis showed DTI-ALPS index partially mediated the association between CP enlargement and deep gray matter (DGM) atrophy in RRMS, and between CP enlargement and ventricle enlargement. CP volume and DTI-ALPS index were also significantly correlated with Expanded Disability Status Scale (EDSS) (P = 0.006, P = 0.043). Notably, the variation of DTI_ALPS index during the follow-up period were significantly and negatively correlated with the variation of EDSS (P = 0.045). CONCLUSION: Enlarged CP volume and decreased DTI_ALPS index may be closely related to DGM atrophy and ventricular enlargement in RRMS, and may be potential imaging markers of clinical disability.

Choroid plexus calcifications are not associated with putative markers of glymphatic dysfunction: A population study in middle-aged and older adults.

BACKGROUND AND PURPOSE: Recent studies have suggested an association between dysfunction of the choroid plexus and the glymphatic system. However, information is inconclusive. Following a population-based study design, we aimed to assess the association between choroid plexus calcifications (CPCs)-as a surrogate of choroid plexus dysfunction-and severity and progression of putative markers of glymphatic dysfunction, including white matter hyperintensities (WMH) of presumed vascular origin and abnormally enlarged basal ganglia perivascular spaces (BG-PVS). METHODS: This study recruited community-dwellers aged ≥40 years living in neighboring Ecuadorian villages. Participants who had baseline head CTs and brain MRIs were included in cross-sectional analyses and those who additional had follow-up MRIs (after a mean of 6.4 ± 1.5 years) were included in longitudinal analyses. Logistic and Poisson regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess associations between CPCs and WMH and enlarged BG-PVS severity and progression. RESULTS: A total of 590 individuals were included in the cross-sectional component of the study, and 215 in the longitudinal component. At baseline, 25% of participants had moderate-to-severe WMH and 27% had abnormally enlarged BG-PVS. At follow-up, 36% and 20% of participants had WMH and enlarged BG-PVS progression, respectively. Logistic regression models showed no significant differences between CPCs volumes stratified in quartiles and severity of WMH and enlarged BG-PVS. Poisson regression models showed no association between the exposure and WMH and enlarged BG-PVS progression. Baseline age remained significant in these models. CONCLUSIONS: Choroid plexus calcifications are not associated with putative markers of glymphatic system dysfunction.

A Review of Cerebrospinal Fluid Circulation and the Pathogenesis of Congenital Hydrocephalus.

The brain's ventricles are filled with a colorless fluid known as cerebrospinal fluid (CSF). When there is an excessive accumulation of CSF in the ventricles, it can result in high intracranial pressure, ventricular enlargement, and compression of the surrounding brain tissue, leading to potential damage. This condition is referred to as hydrocephalus. Hydrocephalus is classified into two categories: congenital and acquired. Congenital hydrocephalus (CH) poses significant challenges for affected children and their families, particularly in resource-poor countries. Recognizing the psychological and economic impacts is crucial for developing interventions and support systems that can help alleviate the distress and burden faced by these families. As our understanding of CSF production and circulation improves, we are gaining clearer insights into the causes of CH. In this article, we will summarize the current knowledge regarding CSF circulation pathways and the underlying causes of CH. The main causes of CH include abnormalities in the FoxJ1 pathway of ventricular cilia, dysfunctions in the choroid plexus transporter Na+-K+-2Cl- contransporter isoform 1, developmental abnormalities in the cerebral cortex, and structural abnormalities within the brain. Understanding the causes of CH is indeed crucial for advancing research and developing effective treatment strategies. In this review, we will summarize the findings from existing studies on the causes of CH and propose potential research directions to further our understanding of this condition.

Chronic Active Lesions and Larger Choroid Plexus Explain Cognition and Fatigue in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Chronic inflammation may contribute to cognitive dysfunction and fatigue in patients with multiple sclerosis (MS). Paramagnetic rim lesions (PRLs) and choroid plexus (CP) enlargement have been proposed as markers of chronic inflammation in MS being associated with a more severe disease course. However, their relation with cognitive impairment and fatigue has not been fully explored yet. Here, we investigated the contribution of PRL number and volume and CP enlargement to cognitive impairment and fatigue in patients with MS. METHODS: Brain 3T MRI, neurologic evaluation, and neuropsychological assessment, including the Brief Repeatable Battery of Neuropsychological Tests and Modified Fatigue Impact Scale, were obtained from 129 patients with MS and 73 age-matched and sex-matched healthy controls (HC). PRLs were identified on phase images of susceptibility-weighted imaging, whereas CP volume was quantified using a fully automatic method on brain three-dimensional T1-weighted and fluid-attenuated inversion recovery MRI sequences. Predictors of cognitive impairment and fatigue were identified using random forest. RESULTS: Thirty-six (27.9%) patients with MS were cognitively impaired, and 31/113 (27.4%) patients had fatigue. Fifty-nine (45.7%) patients with MS had ≥1 PRLs (median = 0, interquartile range = 0;2). Compared with HC, patients with MS showed significantly higher T2-hyperintense white matter lesion (WM) volume; lower normalized brain, thalamic, hippocampal, caudate, cortical, and WM volumes; and higher normalized CP volume (p from <0.001 to 0.040). The predictors of cognitive impairment (relative importance) (out-of-bag area under the curve [OOB-AUC] = 0.707) were normalized brain volume (100%), normalized caudate volume (89.1%), normalized CP volume (80.3%), normalized cortical volume (70.3%), number (67.3%) and volume (66.7%) of PRLs, and T2-hyperintense WM lesion volume (64.0%). Normalized CP volume was the only predictor of the presence of fatigue (OOB-AUC = 0.563). DISCUSSION: Chronic inflammation, with higher number and volume of PRLs and enlarged CP, may contribute to cognitive impairment in MS in addition to gray matter atrophy. The contribution of enlarged CP in explaining fatigue supports the relevance of immune-related processes in determining this manifestation independently of disease severity. PRLs and CP enlargement may contribute to the pathophysiology of cognitive impairment and fatigue in MS, and they may represent clinically relevant therapeutic targets to limit the impact of these clinical manifestations in MS.

Multi-omics analyses of choroid plexus carcinoma cell lines reveal potential targetable pathways and alterations.

PURPOSE: Choroid plexus carcinomas (CPCs) are extremely rare brain tumors and carry a dismal prognosis. Treatment options are limited and there is an urgent need to develop models to further research. In the present study, we established two CPC cell lines and performed multi-omics analyses. These cell lines serve as valuable models to propose new treatments in these rare but deadly brain tumors. METHODS: Multi-omic profiling including, (i) methylation array (EPIC 850 K), (ii) whole genome sequencing (WGS), (iii) CANCERPLEX cancer genome panel testing, (iv) RNA sequencing (RNA-seq), and (v) proteomics analyses were performed in CCHE-45 and NGT131 cell lines. RESULTS: Both cell lines were classified as methylation class B. Both harbored pathogenic TP53 point mutations; CCHE-45 additionally displayed TP53 loss. Furthermore, alterations of the NOTCH and WNT pathways were also detected in both cell lines. Two protein-coding gene fusions, BZW2-URGCP, and CTTNBP2-ERBB4, mutations of two oncodrivers, GBP-4 and KRTAP-12-2, and several copy number alterations were observed in CCHE-45, but not NGT131. Transcriptome and proteome analysis identified shared and unique signatures, suggesting that variability in choroid plexus carcinoma tumors may exist. The discovered difference's importance and implications highlight the possible diversity of choroid plexus carcinoma and call for additional research to fully understand disease pathogenesis. CONCLUSION: Multi-omics analyses revealed that the two choroid plexus carcinoma cell lines shared TP53 mutations and other common pathway alterations and activation of NOTCH and WNT pathways. Noticeable differences were also observed. These cell lines can serve as valuable models to propose new treatments in these rare but deadly brain tumors.

Enlarged choroid plexus in multiple sclerosis is associated with increased lesion load and atrophy in white matter but not gray matter atrophy.

BACKGROUND: Enlargement of the choroid plexus (CP) is reported to associate with inflammatory activity and contribute to brain atrophy in patients with multiple sclerosis (pwMS). However, a recent study in healthy volunteers (HVTs) has suggested that CP enlargement can be attributed to ventriculomegaly. OBJECTIVES: To clarify the pathological significance of the enlargement of CP in multiple sclerosis (MS). METHODS: A total of 102 pwMS (89 with relapsing-remitting MS and 13 with secondary progressive MS) and 41 HVTs were cross-sectionally evaluated using brain volumetry. The CP volume was compared between disease groups and investigated for the relationships with other brain regional volumes. RESULTS: CP volume was significantly larger in pwMS than in HVTs in the univariate analysis, but not in multivariable analysis. Meanwhile, the CP and lateral ventricle (LV) volumes were significantly correlated. CP enlargement was significantly associated with increased lesion load and cerebral white matter (WM) atrophy, even after adjusting for LV volume. In contrast, multivariable analyses revealed that LV enlargement, but not CP enlargement, was associated with total gray matter (GM) atrophy. CONCLUSION: CP enlargement was closely associated with LV enlargement. After adjusting for LV volume, CP enlargement in pwMS was associated with increased lesion load and WM atrophy but not GM atrophy.

Choroid plexus mast cells drive tumor-associated hydrocephalus.

Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH in vivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.

Extracerebral choroid plexus papilloma in a newborn: a rare presentation.

Choroid plexus papillomas (CPPs) are extremely rare lesions that originate in the central nervous system. Still rarely, these can occur in heterotopic locations. We report a case of aneonate who presented at fourth week of life with a small swelling in the left side of the oropharynx. There were no other symptoms. MRI scan revealed a cystic lesion with the possibility of lymphatic malformation or teratoma. Swelling which was gradually increasing in size was electively excised. Histopathological examination revealed it to be an extracerebral CPP. Postoperative period was uneventful, and baby had no further complications. CPP is a rare lesion and, almost always, cannot be anticipated before surgery. Imaging only helps in surgical planning. Complete excision is curative.

Symptomatic intraventricular choroid plexus cysts. Illustrative case and systematic review.

Although choroid plexus cysts are a frequent incidental neuroimaging finding, symptomatic ones are rare-a series of more than five cases are hard to find. In the absence of high-volume studies, there are no generally accepted algorithms for diagnosis and treatment for this pathology. Proposed surgical techniques include microsurgical excision or fenestration and endoscopic excision or fenestration with or without additional shunting. No definitive conclusions exist about the superiority of a certain technique. Here, we introduce an illustrative case of a patient with a symptomatic choroid plexus cyst in the trigone of the lateral ventricle and a systematic review of 65 additional published cases with the aim of identifying epidemiological features, variants of localization of the cysts, their symptoms, persistence of concomitant obstructive hydrocephalus, and treatment modalities. A PRISMA-based literature search was performed on the PubMed, MEDLINE, Scopus, and Web of Knowledge databases. We include in the review case reports and case series of symptomatic choroid plexus cysts with full texts or valuable abstracts available online in English and published by April 2023. All abstracts of retrieved studies were assessed by two independent researchers to avoid bias. Only descriptive statistics were used for the presentation of the results. A total of 48 studies (39 case reports and 9 case series) with 65 depicted cases met the eligibility criteria. The review showed a slight predominance of choroid plexus cysts in men. The most common localizations of cysts were the trigone and the body of the lateral ventricle. Obstructive hydrocephalus is often present in patients with choroid plexus cysts. The most common symptoms of cysts were signs of increased ICP: headaches and vomiting. The main treatment approaches for symptomatic choroid plexus cysts were microsurgical excision, microsurgical fenestration, endoscopic fenestration, and total endoscopic excision. The tendency has been noted to shift from microsurgical to endoscopic procedures over the past two decades. Some data on the classification of cysts of the central nervous system and the underlying mechanisms of the pathogenesis of choroid plexus cysts are also presented.Although symptomatic cases of choroid plexus cysts are rare, by summarizing currently available data, one could clarify their common features and identify a preferable treatment modality.

Tractography Navigated Endoscopic En-Bloc Excision of Pediatric Giant Choroid Plexus Tumor.

Giant choroid plexus (CP) tumors in children pose a formidable surgical challenge due to extensive vascularity/blood loss, tumor size impeding early visualization of the pedicle, hydrocephalus/mass effect distorting cerebral localization, considerable prevalence of atypical tumors and carcinoma demanding excision without tumor spillage, and retraction-associated morbidity. However, total resection of CP papilloma has excellent potential for cure. This is probably the first report in the literature of diffusion tensor imaging navigation-guided tumor pedicle targeting, endoscopic devascularization and division of pedicle followed by en bloc delivery in optimally tackling most of these challenges in a 6-year-old girl presenting with a giant lateral ventricular CP tumor. Giant CP tumors pose a formidable challenge. Extensive vascularity can cause life-threatening blood loss in children.1 Large tumor size makes it impractical during microsurgery to achieve early visualization of pedicle.2 Hydrocephalus and mass effect can distort sulcal anatomy, with potentially devastating deficits.3 Still, prevalence of atypical tumors and carcinoma warrants excision without tumor spillage.4 In Video 1, we demonstrate our "10-D" steps of en-bloc excision, exploiting panoramic visualization of endoscope5: 1. Diagnosis, 2. Diffusion tensor imaging guided pedicle targeting, 3. Design position & exposure, 4. Durotomy, 5. Dissection of sulcus, 6. Delineation of pedicle, 7. Devascularization, 8. Division of pedicle, 9. Delivery of tumor, and 10. Dural & skin closure. The conventional superior parietal lobule approach to get the tumor en-bloc would have been from the posterosuperior direction, where the tumor is likely to conceal the pedicle. The trajectory to first get to the pedicle must be from an anterosuperior direction but will violate corticospinal fibers. Hence entry point was chosen in between, just posterior to the post-central sulcus. To accommodate the 'en-bloc' excision avoiding ventricular seedlings, a 5 cm mini-craniotomy was fashioned centered on the entry point planned in the navigation system. Ventricle was entered perpendicular to the sulcus through the roof of the atrium, with least cortical transgression and avoiding injury to laterally placed optic radiation and speech areas.6 A 30-degree, 4-mm endoscope was inserted anterolateral to the tumor and fixed. The wide-angled vision offered by endoscopes enhancing meticulous dissection is the likely cause of better neurological outcomes, as noted in other ventricular lesions.7 Pedicular attachment of the tumor is coagulated thoroughly and cut, ensuring initial sparing of venous drainage. The draining vein is then coagulated and divided. 'En-bloc' excision is also known in other vascular lesions to decrease the risk of bleeding.8 The angled optics & panoramic visualization helps to identify any possible tumor seedlings.9 This is probably the first report of endoscopic en-bloc excision of a giant choroid plexus tumor in literature.

Brain-derived subgroups of bipolar II depression associate with inflammation and choroid plexus morphology.

AIM: Elevated inflammation and larger choroid plexus (ChP) volume has been previously identified in mood disorders. Connections between inflammation, ChP, and clinical symptoms in bipolar II depression (BDII-D) are unclear. Data-driven clustering based on neuroanatomical phenotypes may help to elucidate neurobiological associations in BDII-D. METHODS: Inflammatory cytokines, clinical symptoms, and neuroanatomical features were assessed in 150 BDII-D patients. Sixty-eight cortical surface area (SA) and 19 subcortical volumes were extracted using FreeSurfer. The ChP volume was segmented manually using 3D Slicer. Regularized canonical correlation analysis was used to identify significantly correlated components between cortical SA and subcortical volumes (excluding the ChP), followed by k-means clustering to define brain-derived subgroups of BDII-D. Low-grade inflammation was derived by averaging the standardized z scores of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), which were computed to create a composite z-value score. Partial Pearson correlations followed by multiple comparison correction were conducted to explore associations between inflammation, clinical symptoms, and ChP volume. RESULTS: Subgroup I demonstrated smaller subcortical volume and cortical SA, higher inflammation, and larger ChP volume compared with subgroup II. Greater ChP volume was associated with a higher low-grade inflammation (mean r = 0.289, q = 0.003), CRP (mean r = 0.249, q = 0.007), IL-6 (left r = 0.200, q = 0.03), and TNF-α (right r = 0.226, q = 0.01), while greater IL-1ß was significantly associated with severe depressive symptoms in BDII-D (r = 0.218, q = 0.045). CONCLUSIONS: Neuroanatomically-derived subgroups of BDII-D differed in their inflammation levels and ChP volume. These findings suggest an important role of elevated peripheral inflammation and larger ChP in BDII-D.

Rare Case of Hemorrhagic Atypical Choroid Plexus Papilloma of Fourth Ventricle in Adult: A Diagnostic Dilemma.

Choroid plexus papillomas are highly vascular tumors, and such tumors causing subarachnoid hemorrhage have been reported in literature. Similarly, few articles have reported atypical fourth ventricular choroid plexus tumors in adults. However, such an atypical tumor presenting with grossly hemorrhagic transformation without any acute symptoms could not be found in the literature.

Targeted Knockdown of Genes in the Choroid Plexus.

The choroid plexus (ChP) serves as a critical gateway for immune cell infiltration into the central nervous system (CNS) under both physiological and pathological conditions. Recent research has shown that regulating ChP activity may offer protection against CNS disorders. However, studying the biological function of the ChP without affecting other brain regions is challenging due to its delicate structure. This study presents a novel method for gene knockdown in ChP tissue using adeno-associated viruses (AAVs) or cyclization recombination enzyme (Cre) recombinase protein consisting of TAT sequence (CRE-TAT). The results demonstrate that after injecting AAV or CRE-TAT into the lateral ventricle, the fluorescence was exclusively concentrated in the ChP. Using this approach, the study successfully knocked down the adenosine A2A receptor (A2AR) in the ChP using RNA interference (RNAi) or Cre/locus of X-overP1 (Cre/LoxP) systems, and showed that this knockdown could alleviate the pathology of experimental autoimmune encephalomyelitis (EAE). This technique may have important implications for future research on the ChP's role in CNS disorders.

Spontaneously hypertensive rats can become hydrocephalic despite undisturbed secretion and drainage of cerebrospinal fluid.

BACKGROUND: Hydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction. METHODS: Magnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay. RESULTS: SHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na+/K+/2Cl- cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats. CONCLUSION: Hydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics.

A case report of hydrocephalus due to diffuse villous hyperplasia of the choroid plexus: surgical treatment by combination a flexible videoscope with a rigid endoscope.

PURPOSE: Diffuse villous hyperplasia of the choroid plexus (DVHCP) and choroid plexus papilloma (CPP) are rare benign tumors usually diagnosed as a result of progressive hydrocephalus, especially in childhood. We present the case of a Japanese boy diagnosed with progressive hydrocephalus due to DVHCP. METHODS: Case: A 2-year and 3-month-old Japanese boy was found to have delayed motor development (equivalent to 1 year and 2 months old), an enlarged head circumference of 51 cm within + 1.5 standard deviation (S.D.), and incomplete closure of the anterior fontanel. The magnetic resonance imaging (MRI) showed lobular enlargement of the bilateral choroid plexuses extending from the trigone to the body and inferior horn of the lateral ventricle. The endoscopic choroid plexus coagulation surgery was performed to reduce the CSF formation rate. RESULTS: DVHCP was diagnosed both pathologically and clinically. Postoperatively, the patient progressed without complications, such as cerebrospinal fluid leakage. Although ventricular enlargement persisted, the anterior fontanel recessed, and the expansion of the head circumference stopped. CONCLUSION: Few cases of bilateral DVHCP and CPP have been reported in the literature. We encountered a case in which effective choroid plexus coagulation was performed for hydrocephalus due to DVHCP using less invasive endoscopic technique. It also represented an association between DVHCP and the gain of chromosome 9p.

Association of Choroid Plexus Volume With Serum Biomarkers, Clinical Features, and Disease Severity in Patients With Frontotemporal Lobar Degeneration Spectrum.

BACKGROUND AND OBJECTIVES: Choroid plexus (ChP) is emerging as a key brain structure in the pathophysiology of neurodegenerative disorders. In this observational study, we investigated ChP volume in a large cohort of patients with frontotemporal lobar degeneration (FTLD) spectrum to explore a possible link between ChP volume and other disease-specific biomarkers. METHODS: Participants included patients meeting clinical criteria for a probable syndrome in the FTLD spectrum. Structural brain MRI imaging, serum neurofilament light (NfL), serum phosphorylated-Tau181 (p-Tau181), and cognitive and behavioral data were collected. MRI ChP volumes were obtained from an ad-hoc segmentation model based on a Gaussian Mixture Models algorithm. RESULTS: Three-hundred and sixteen patients within FTLD spectrum were included in this study, specifically 135 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD), 75 primary progressive aphasia, 46 progressive supranuclear palsy, and 60 corticobasal syndrome. In addition, 82 age-matched healthy participants were recruited as controls (HCs). ChP volume was significantly larger in patients with FTLD compared with HC, across the clinical subtype. Moreover, we found a significant difference in ChP volume between HC and patients stratified for disease-severity based on CDR plus NACC FTLD, including patients at very early stage of the disease. Interestingly, ChP volume correlated with serum NfL, cognitive/behavioral deficits, and with patterns of cortical atrophy. Finally, ChP volume seemed to discriminate HC from patients with FTLD better than other previously identified brain structure volumes. DISCUSSION: Considering the clinical, pathologic, and genetic heterogeneity of the disease, ChP could represent a potential biomarker across the FTLD spectrum, especially at the early stage of disease. Further longitudinal studies are needed to establish its role in disease onset and progression. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that choroid plexus volume, as measured on MRI scan, can assist in differentiating patients with FTLD from healthy controls and in characterizing disease severity.

Comparative study of calcification in human choroid plexus, pineal gland, and habenula.

Choroid plexus, pineal gland, and habenula tend to accumulate physiologic calcifications (concrements) over a lifetime. However, until now the composition and causes of the intracranial calcifications remain unclear. The detailed analysis of concrements has been done by us using X-ray diffraction analysis (XRD), X-ray diffraction topography (XRDT), micro-CT, X-ray phase-contrast tomography (XPCT), as well as histology and immunohistochemistry (IHC). By combining physical (XRD) and biochemical (IHC) methods, we identified inorganic (hydroxyapatite) and organic (vimentin) components of the concrements. Via XPCT, XRDT, histological, and IHC methods, we assessed the structure of concrements within their appropriate tissue environment in both two and three dimensions. The study found that hydroxyapatite was a major component of all calcified depositions. It should be noted, however, that the concrements displayed distinctive characteristics corresponding to each specific structure of the brain. As a result, our study provides a basis for assessing the pathological and physiological changes that occur in brain structure containing calcifications.