Date of Completion

Spring 5-1-2020

Project Advisor(s)

Joanne C. Conover, David Goldhamer, Thomas Peters, Elizabeth Schifano

University Scholar Major

Molecular and Cell Biology

Second University Scholar Major

Statistics

Disciplines

Developmental Neuroscience

Abstract

Fetal-onset hydrocephalus is a relatively common birth defect occurring in 1-2 cases per thousand births and is characterized by abnormally expanded brain ventricles. Current diagnosis for this complex pathology often involves relatively simple metrics and heavy reliance on clinician experience over objective measures. Those affected often suffer chronic headaches and cognitive deficits and may present with a bulging skill. Shunting is considered the standard treatment for communicating hydrocephalus (i.e. cerebrospinal fluid flow is physically unobstructed in the ventricular system). Shunting remains a highly invasive procedure often performed during the critical period of infancy and has a high failure rate of up to 40% within one year, often requiring multiple revision surgeries.

Although shunting can successfully reduce ventricle size, shunted patients often still suffer from associated cognitive deficits. In a series of studies, we analyzed the relationship between fetal-onset hydrocephalus and alterations to normal developmental patterns within the ventricular-subventricular zone (V-SVZ) stem cell niche – located subjacent to the lateral ventricles (LV).22 We utilized archival, periventricular human tissue and MRI scans from periods covering fetal through early adolescent development to: 1) develop a model of normal (non-hydrocephalic) development of the human brain’s LV and the subjacent V-SVZ, and 2) analyze alterations to normal V-SVZ development in hydrocephalus subjects. We have analyzed LV morphology changes, including volume and surface area metrics, in relation to changes in cell type distributions within the V-SVZ.

In our recently published paper, Coletti et al. (2018), we have shown that during normal neural development: 1) ependymal cell formation (ependymogenesis) proceeds in a posterior-to-anterior wave, 2) human LV ependymogenesis occurs through “pinwheel” cytoarchitecture similar to that in other mammals, 3) LV volume and surface area growth plateau at approximately 1.5-years, and 4) no pinwheel-core stem cells are detected by the same 1.5-year timepoint. Collectively, our findings suggest that fetal V-SVZ development in humans mirrors that in other rodents, but with a postnatal decline in proliferative and neurogenic potential leading to no stem cell retention or neurogenesis in the V-SVZ by 1.5-years. Additionally, we document an association between LV volume/surface area changes (observed through non-invasive MRI) and V-SVZ cell type changes at the cellular level.

In hydrocephalus patient case studies, we used the aforementioned methods to document: 1) reduced ventricle-surface stem cell counts per unit area, 2) variable degrees of astrogliosis, and 3) extensive micro-convolutions of the ventricular lining associated with shunting. In fetal stages, hyperproliferative V-SVZ phenotypes have been observed. Collectively, these findings illuminate the interactions between LV morphology and V-SVZ histology and have the potential to accelerate hydrocephalus research by emphasizing the consideration of cellular neurodevelopmental processes during hydrocephalus treatment. Our findings raise questions about how refining shunting parameters such as shunt tip approaches, age of shunting, and shunt flow rates can best facilitate cellular neurodevelopment.

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