Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter

Abstract

Background Hydrocephalus is a neurological disease with an incidence of 80–125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. Methods Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19–40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. Results The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. Conclusion The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation.

AQP4, Astrogenesis, and Hydrocephalus: A New Neurological Perspective

“…Hydrocephalus is an abnormal build-up of cerebrospinal fluid associated with distension of the ventricular system due to impairments in CSF circulation [ 40 , 41 ]. Inflammatory response plays a fundamental role in acquired conditions such as postinfectious and posthemorrhagic hydrocephalus [ 42 , 43 , 44 , 45 , 46 ]. Reactive astrogliosis (one of the primary expressions of neuroinflammation) is associated with both congenital and acquired hydrocephalus [ 45 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…Inflammatory response plays a fundamental role in acquired conditions such as postinfectious and posthemorrhagic hydrocephalus [ 42 , 43 , 44 , 45 , 46 ]. Reactive astrogliosis (one of the primary expressions of neuroinflammation) is associated with both congenital and acquired hydrocephalus [ 45 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Historically, the neurodevelopmental consequences of pediatric hydrocephalus are attributed to parenchymal stretch and periventricular white matter injury secondary to ventricular enlargement and elevated intracranial pressure [ 55 ].…”

Notch inhibition rescues TNF-α mediated block in multiciliated ependymal cell differentiation: Implications for hydrocephalus therapy

“…Researchers observed significant loss of multicilia in ependymal cells or the absence of MECs from the ventricular wall in patients with congenital hydrocephalus. More recent observations using confocal microscopy and antibody staining have confirmed major disorganization of the ependymal lining in cases of human nonobstructive congenital hydrocephalus (Saugier-Veber et al, 2017, Garcia-Bonilla et al, 2022.…”

“…Researchers observed significant loss of multicilia in ependymal cells or the absence of MECs from the ventricular wall in patients with congenital hydrocephalus. More recent observations using confocal microscopy and antibody staining have confirmed major disorganization of the ependymal lining in cases of human non-obstructive congenital hydrocephalus (Saugier-Veber et al, 2017, Garcia-Bonilla et al, 2022). Animal models that block the formation of motile cilia or maturation of MECs consistently result in congenital hydrocephalus in mice, confirming motile cilia’s essential role in maintaining normal CSF dynamics and ventricular homeostasis.…”

AQP4 labels a subpopulation of white matter-dependent glial radial cells affected by pediatric hydrocephalus, and its expression increased in glial microvesicles released to the cerebrospinal fluid in obstructive hydrocephalus

“…In general, the neuropathology of hydrocephalus involves neuroinflammation, alterations in the periventricular white matter, parenchymal stretch associated with compression, and axonal loss. It is also related to neurodevelopmental alterations such as ventricular zone disruption and impairments in neuronal differentiation, including glial radial cell (GRC) loss or dendritic and synaptic atrophy [ 20 , 26 , 34 , 35 , 61 ]. All these phenomena are accompanied by reactive astrogliosis [ 29 , 44 ].…”