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Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms 1 – 3 . However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease 4 – 6 . Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans 7 and linked to cognitive function 8 —is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date. Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

ABSTRACT Preeclampsia is a severe pregnancy complication that can cause brain injury, yet early detection of related cognitive deficits remains challenging. Therefore, in order to investigate alterations in choroid plexus volume (CPV) and susceptibility values of the choroid plexus (ChP) obtained from quantitative susceptibility mapping (QSM) in preeclampsia patients, we enrolled 281 participants, comprising 98 nonpregnant healthy controls (NPHC), 85 pregnant healthy controls (PHC), and 98 patients with preeclampsia. All participants were scanned on a 1.5 T MR scanner. The results of clinical characteristics and cognitive tests were collected from all the participants. One‐way ANOVA tests were used to analyze the differences in CPV and susceptibility values of ChP among the three groups. Multiple linear regression analysis was used to find the factors that influenced CPV and its susceptibility values, as well as cognitive decline. Additionally, receiver operating characteristic (ROC) analysis was employed to evaluate the diagnostic performance of the two imaging measures. Preeclampsia patients exhibited smaller CPV and higher susceptibility values compared to the other groups (p < 0.001; p < 0.001). Significant negative correlations were observed between body mass index (BMI), mean arterial pressure and CPV/eTIV (β = −0.100, 95% CI = −0.158 ~ −0.042, p = 0.001; β = −0.022, 95% CI = −0.033 ~ −0.011, p < 0.001). Additionally, significant positive correlations were observed between BMI (β = 0.455, 95% CI = 0.125 ~ 0.786, p = 0.007), mean arterial pressure (β = 0.170, 95% CI = 0.107 ~ 0.232, p < 0.001), hemoglobin (β = 0.152, 95% CI = 0.051 ~ 0.254, p = 0.003) and susceptibility values of ChP. Furthermore, CPV/eTIV and susceptibility values of ChP could be independent contributing factors of scores of TMT. The combination of CPV, susceptibility values of ChP, BMI and gestational week could distinguish preeclampsia from pregnant groups (AUC = 0.787, 95% CI = 0.722–0.853, p < 0.001) as well as distinguish individuals with cognitive decline from preeclampsia patients (AUC = 0.737, 95% CI = 0.621–0.844, p < 0.001). These findings indicate that smaller CPV and higher susceptibility values characterize preeclampsia and may serve as auxiliary indices for its diagnosis and related cognitive decline. Preeclampsia patients exhibit choroid plexus atrophy and iron deposition via high‐resolution T1‐weighted magnetic resonance imaging (T1WI) and quantitative susceptibility mapping, correlating with cognitive decline. Combined choroid plexus volume, susceptibility values, BMI, and gestational week serve as diagnostic biomarkers for preeclampsia and associated cognitive impairment, offering insights into glymphatic dysfunction pathophysiology.

Neuroinflammation contributes substantially to stroke pathophysiology. Cerebral invasion of peripheral leukocytes—particularly T cells—has been shown to be a key event promoting inflammatory tissue damage after stroke. While previous research has focused on the vascular invasion of T cells into the ischemic brain, the choroid plexus (ChP) as an alternative cerebral T-cell invasion route after stroke has not been investigated. We here report specific accumulation of T cells in the peri-infarct cortex and detection of T cells as the predominant population in the ipsilateral ChP in mice as well as in human post-stroke autopsy samples. T-cell migration from the ChP to the peri-infarct cortex was confirmed by in vivo cell tracking of photoactivated T cells. In turn, significantly less T cells invaded the ischemic brain after photothrombotic lesion of the ipsilateral ChP and in a stroke model encompassing ChP ischemia. We detected a gradient of CCR2 ligands as the potential driving force and characterized the neuroanatomical pathway for the intracerebral migration. In summary, our study demonstrates that the ChP is a key invasion route for post-stroke cerebral T-cell invasion and describes a CCR2-ligand gradient between cortex and ChP as the potential driving mechanism for this invasion route.

There is increasing evidence that cerebrospinal fluid (CSF) circulation plays a key role in the pathophysiology of Alzheimer’s disease (AD), although the underlying mechanisms remain poorly understood. This study evaluated CSF circulation in patients with AD using magnetic resonance imaging (MRI)-derived measures, including choroid plexus (CP) volume, CSF volume, and diffusion tensor imaging along the perivascular space (DTI-ALPS) index. The study included 188 participants: 28 with AD, 40 with mild cognitive impairment (MCI), 66 with subjective cognitive decline (SCD), and 54 normal controls (NCs). Participants underwent structural T1-weighted MRI, diffusion tensor imaging, clinical assessment, and plasma biomarker analysis. After adjustments for age, sex, and education, group differences in the DTI-ALPS index, CP volume, and CSF volume were examined. Correlation and mediation analyses were conducted to assess the relationships of clinical parameters with DTI-ALPS index, CP volume, and CSF volume. The AD group exhibited a significantly lower DTI-ALPS index and higher CP and CSF volumes compared with the MCI, SCD, and NC groups. The DTI-ALPS index showed a strong negative correlation with both CP and CSF volumes, whereas CP volume was positively correlated with CSF volume. Mediation analysis revealed interactive relationships among the DTI-ALPS index, CP volume, and CSF volume. This study demonstrates that CSF circulation is disrupted in AD patients. Additionally, CP volume influences glymphatic drainage through its effects on CSF volume, indicating a potential role in AD pathophysiology.

It has been suggested that choroid plexus calcifications (CPC) may be associated with glymphatic system dysfunction and with disturbed slow-wave (N3) sleep. If this is the case, volumetric analysis of CPC could be used to estimate the functional ability of the glymphatic system. However, data on this association is limited. This study aims to assess the association between percentages of N3 sleep – used as a putative marker of glymphatic system activity – and the volume of CPC in older adults. Community-dwelling individuals aged ≥60 years enrolled in the Atahualpa Project Cohort received head CTs (for automated determinations of CPC volume) and a single-night polysomnography (PSG) for quantification of N3 sleep percentages. Multivariate linear regression and non-parametric models were fitted to assess the association between these variables. A total of 125 older adults (median age: 65 years; 32 % males) were included. The mean percentage of N3 sleep was 12.4±9.1 %, and the mean volume of CPC was 655±345.3 µL. Non-parametric locally weighted scatterplot smoothing showed that the volume of CPC increased as the percentage of N3 sleep increased, but only when N3 sleep is reduced (up to 12 % of total sleep time). The significance disappeared when PSG parameters were included in the model as well as in participants with normal N3 sleep percentages. Study results suggest that in the presence of severe reductions in N3 sleep, increased CPC volume may be a manifestation of choroid plexus compensation or adaptation, and not necessarily dysfunction. [Display omitted] •Choroid plexus calcification (CPC) has been associated with glymphatic system dysfunction.•Glymphatic dysfunction is associated with disturbed slow wave (N3) sleep.•This study explores the association between choroid plexus calcification and disturbed N3 sleep.•125 older adults received head CTs (for CPC determinations) and PSG for quantification of N3 sleep percentages.•CPC volume increased as the percentage of N3 sleep increased, but only when N3 sleep is severely reduced.

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ . Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss‐of‐function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53‐fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz ‐linked hydrocephalus. Synopsis Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice. Contrast medium leaks from the choroid plexus into the lateral ventricles of Mpdz −/− mice. Transmitted electron microscopy (TEM) of the CP of Mpdz −/− mice shows that intercellular junctions between the CP epithelial cells (CPECs) are structurally defective. The receptor to low‐density lipoprotein is overabundant in CPECs of Mpdz −/− mice by approximately 40%, and its constitutive transcytosis higher by more than 50% compared to CPECs of Mpdz +/+ mice. Fluid‐phase uptake is approximately two‐fold higher than Mpdz +/+ mice. Comparative proteomic analysis of the cerebrospinal fluid of Mpdz +/+ and Mpdz −/− mice finds protein overabundance in the latter, including more than 50‐fold abundance of ApoE. Graphical Abstract Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.

To clarify the pathogenesis of two different types of adult-onset normal-pressure hydrocephalus (NPH), we investigated cerebrospinal fluid distribution on the high-field three-dimensional MRI. The subarachnoid spaces in secondary NPH were smaller than those in the controls, whereas those in idiopathic NPH were of similar size to the controls. In idiopathic NPH, however, the basal cistern and Sylvian fissure were enlarged in concurrence with ventricular enlargement towards the z-direction, but the convexity subarachnoid space was severely diminished. In this article, we provide evidence that the key cause of the disproportionate cerebrospinal fluid distribution in idiopathic NPH is the compensatory direct CSF communication between the inferior horn of the lateral ventricles and the ambient cistern at the choroidal fissure. In contrast, all parts of the subarachnoid spaces were equally and severely decreased in secondary NPH. Blockage of CSF drainage from the subarachnoid spaces could cause the omnidirectional ventricular enlargement in secondary NPH.

Purpose SMARCB1 encodes a subunit of the SWI/SNF complex involved in chromatin remodeling. Pathogenic variants (PV) in this gene can give rise to three conditions. Heterozygous loss-of-function germline PV cause rhabdoid tumor predisposition syndrome and schwannomatosis. Missense PV and small in-frame deletions in exons 8 and 9 result in Coffin–Siris syndrome, which is characterized by intellectual disability (ID), coarse facial features, and fifth digit anomalies. Methods By a gene matching approach, individuals with a similar SMARCB1 PV were identified. Informed consent was obtained and patient data were collected to further establish genotype–phenotype relationship. Results A recurrent de novo missense PV (c.110G>A;p.Arg37His) in exon 2 of SMARCB1 , encoding the DNA-binding domain, was identified in four individuals from different genetic centers. They shared a distinct phenotype consisting of profound ID and hydrocephalus due to choroid plexus hyperplasia. Other shared features include severe neonatal feeding difficulties; congenital heart, kidney, and eye anomalies; obstructive sleep apnea; and anemia. Conclusion The p.Arg37His PV in the DNA-binding domain of SMARCB1 causes a distinctive syndrome, likely through a gain-of-function or dominant-negative effect, which is characterized by severe ID and hydrocephalus resulting from choroid plexus hyperplasia. This report broadens the phenotypic spectrum associated with PV in SMARCB1 .

While the impact of hemorrhagic and ischemic strokes on the blood–brain barrier has been extensively studied, the impact of these types of stroke on the choroid plexus, site of the blood-CSF barrier, has received much less attention. The purpose of this review is to examine evidence of choroid plexus injury in clinical and preclinical studies of intraventricular hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage and ischemic stroke. It then discusses evidence that the choroid plexuses are important in the response to brain injury, with potential roles in limiting damage. The overall aim of the review is to highlight deficiencies in our knowledge on the impact of hemorrhagic and ischemic strokes on the choroid plexus, particularly with reference to intraventricular hemorrhage, and to suggest that a greater understanding of the response of the choroid plexus to stroke may open new avenues for brain protection.