Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordThere is another record in ORE for this publication: http://hdl.handle.net/10871/33419The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute

Cerebral microbleeds in a neonatal rat model.

BACKGROUND:In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter. METHODS:Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks. RESULTS:mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls. CONCLUSIONS:In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development

Correction: Cerebral microbleeds in a neonatal rat model.

[This corrects the article DOI: 10.1371/journal.pone.0171163.]

Frailty predicts worse outcomes after intracranial meningioma surgery irrespective of existing prognostic factors

OBJECTIVE: Frailty has been recognized as a predictor of adverse surgical outcomes across multiple surgical disciplines, but until now the relationship between frailty and intracranial meningioma surgery has not been studied. The goal of the present study was to determine the relationship between increasing frailty (determined using the modified Frailty Index [mFI]) and intracranial meningioma resection outcomes (including hospital length of stay [LOS], discharge location, and reoperation and readmission rates). METHODS: This is a single-center retrospective cohort study of patients who underwent intracranial meningioma resection between August 2012 and May 2018. Seventy-six patients met the inclusion criteria. RESULTS: Frailty was associated with increased hospital LOS (p = 0.0218), increased reoperation rate (p = 0.029), and discharge to a higher level of care: an inpatient rehabilitation facility or a skilled nursing facility (p = 0.0002). After multivariable analysis, frailty was determined to be an independent risk factor for increased LOS, worse discharge disposition, and subsequent readmission. CONCLUSIONS: Frailty is an independent risk factor for worse outcomes following intracranial meningioma resection, including increased LOS, reoperations, and worse discharge disposition. Frailty may help stratify preoperative surgical risk, and thus may provide important clinical information to help neurosurgeons and elderly patients weigh the risks and benefits of resection

Frailty Predicts Worse Outcomes After Intracranial Meningioma Surgery Irrespective of Existing Prognostic Factors

OBJECTIVE: Frailty has been recognized as a predictor of adverse surgical outcomes across multiple surgical disciplines, but until now the relationship between frailty and intracranial meningioma surgery has not been studied. The goal of the present study was to determine the relationship between increasing frailty (determined using the modified Frailty Index [mFI]) and intracranial meningioma resection outcomes (including hospital length of stay [LOS], discharge location, and reoperation and readmission rates). METHODS: This is a single-center retrospective cohort study of patients who underwent intracranial meningioma resection between August 2012 and May 2018. Seventy-six patients met the inclusion criteria. RESULTS: Frailty was associated with increased hospital LOS (p = 0.0218), increased reoperation rate (p = 0.029), and discharge to a higher level of care: an inpatient rehabilitation facility or a skilled nursing facility (p = 0.0002). After multivariable analysis, frailty was determined to be an independent risk factor for increased LOS, worse discharge disposition, and subsequent readmission. CONCLUSIONS: Frailty is an independent risk factor for worse outcomes following intracranial meningioma resection, including increased LOS, reoperations, and worse discharge disposition. Frailty may help stratify preoperative surgical risk, and thus may provide important clinical information to help neurosurgeons and elderly patients weigh the risks and benefits of resection