Objective Although MRI is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of pre-oligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. Methods We employed a preterm fetal sheep model of global cerebral ischemia where acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically defined lesions with contrast- and diffusion-weighted high-field ex vivo MRI data. Results Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, pre-myelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined two novel hypo-intense signal abnormalities on T2-weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. Interpretation These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.

Objective Recently we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry and Golgi staining defined CN growth, cell death, proliferation and dendritic maturation in preterm fetal sheep four weeks after HI. Patch-clamping recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Neither was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity.

The COVID-19 global pandemic will require that most educators move instruction online, at least temporarily. As many of us pivot from physical to virtual classrooms, we need to focus on preserving the "high-impact educational practices" that promote deep student engagement with their learning (Kuh, 2008). Some high-impact practices, such as experiential education and research, are likely to

Background and PurposeAlthough the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.MethodsWe employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter. ResultsA spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.ConclusionsOur results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.

Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objectives: To characterize CSF proteomic changes as a function of APOE4 copy number. Methods: We analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons. Results: In the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusions: Increasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.