Microstructural Periventricular White Matter Injury in Post-Hemorrhagic Ventricular Dilatation

Background and Objectives:The neurological deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extra-fiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of post-mortem white matter histology from similar cases.Methods:A prospective cohort of infants born very preterm underwent term equivalent MRI, including infants with PHH, high-grade intraventricular hemorrhage without hydrocephalus (IVH), and controls (VPT). DBSI metrics extracted from the corpus callosum, corticospinal tracts, and optic radiations included fiber axial diffusivity, fiber radial diffusivity, fiber fractional anisotropy, fiber fraction (fiber density), restricted fractions (cellular infiltration), and non-restricted fractions (vasogenic edema). Measures were compared across groups and correlated with ventricular size. Corpus callosum postmortem immunohistochemistry in infants with and without PHH assessed intra- and extra-fiber pathologies.Results:Ninety-five infants born very preterm were assessed (68 VPT, 15 IVH, 12 PHH). Infants with PHH had the most severe white matter abnormalities and there were no consistent differences in measures between IVH and VPT groups. Key tract-specific white matter injury patterns in PHH included reduced fiber fraction in the setting of axonal and/or myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. Specifically, measures of axonal injury were highest in the corpus callosum; both axonal and myelin injury were observed in the corticospinal tracts; and axonal and myelin integrity were preserved in the setting of increased extra-fiber cellular infiltration and edema in the optic radiations. Increasing ventricular size correlated with worse DBSI metrics across groups. On histology, infants with PHH had high cellularity, variable cytoplasmic vacuolation, and low synaptophysin marker intensity.Discussion:PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathological effects of PHH on neonatal brain development.

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Diffusion basis spectrum imaging in post-hemorrhagic hydrocephalus of prematurity

10.1101/2021.01.12.21249706 ◽

2021 ◽

Author(s):

Albert M. Isaacs ◽

Jeffrey J. Neil ◽

James P. McAllister ◽

Sonika Dahiya ◽

Leandro Castaneyra-Ruiz ◽

...

Keyword(s):

White Matter ◽

Axonal Injury ◽

White Matter Injury ◽

Periventricular White Matter ◽

Cellular Infiltration ◽

Ventricular Size ◽

Fiber Density ◽

Spectrum Imaging ◽

Subventricular Zones ◽

Myelin Injury

ABSTRACTObjectiveThe debilitating neurological deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of the deleterious mechanisms underlying PHH-related brain injury, this study applied diffusion basis spectrum imaging (DBSI) for the first time in neonates, modeling white matter fibers to assess axonal and myelin integrity, fiber density, and extra-fiber pathologies including cellularity, edema, and inflammation. The objectives of the study were to characterize DBSI measures in key periventricular white matter tracts of PHH infants, associate those diffusion measures with ventricular size, and utilize postmortem white matter histology to compare with the MRI findings.MethodA prospective cohort of very preterm infants (n=95) underwent MRI at term equivalent age, of which 68 were controls (VPT group), 15 had high-grade intraventricular hemorrhage without hydrocephalus (IVH group), and 12 had PHH (PHH group). DBSI metrics extracted from manually segmented corpus callosum (CC), corticospinal tracts (CST), and optic radiations (OPRA) included fiber level axial diffusivity (FAD), fiber radial diffusivity (FRD), fiber fractional anisotropy (FFA), fiber fraction (FF), restricted fractions (RF), and non-restricted fractions (NRF). All measures were contrasted across groups and correlated with frontal occipital horn ratio (FOHR), a measure of ventricular size. Postmortem immunohistochemistry was performed on the CC of 10 preterm infants (five VPT, three IVH, and two PHH) and two full-term infants who died from non-neurologic causes assessing white matter intra- and extra-fiber pathologies, as well as the integrity of the adjoining ventricular and subventricular zones.ResultsExcept for FF in the CC, there were no differences in all measures between IVH and VPT infants. In the unmyelinated CC, PHH had the lowest FF, FAD, and FFA and the highest RF. In the CC, FOHR related negatively with FAD, FFA, and FF and positively with RF. In the myelinated CST, PHH had the lowest FAD, FFA, and FF and the highest FRD and RF. FOHR related negatively to FAD and FFA and positively with NRF and FRD. In the OPRA, PHH was associated with the lowest FF and the highest RF, NRF, and FAD. FOHR related positively with FAD and NRF and negatively with FF. On postmortem tissues, PHH was associated with the highest white matter cellularity counts, variable amounts of cytoplasmic vacuolation, and the lowest synaptophysin marker intensity. The adjoining ventricular and subventricular zones in PHH had poor cytoarchitecture on H&E staining and relatively increased expression of GFAP and IBA1.ConclusionsThis initial utilization of DBSI to investigate neonatal brain development and injury demonstrated that PHH was associated with diffuse periventricular white matter injury, with tract-specific microstructural patterns and severity of axonal injury, myelin injury, white matter fiber loss, hypercellularity, and inflammation. While axonal injury was present in the CST and unmyelinated CC, myelin injury occurred only in the CST. The OPRA predominantly showed inflammation with myelin preservation. White matter cellular infiltration occurred in all tracts. Postmortem immunohistochemistry confirmed the imaging findings of decreased axonal fiber density, sparser fiber architecture, and increased cellular infiltration. Larger ventricular size was associated with greater white matter disruption. Building upon these results, DBSI provides an innovative approach for investigating the complex neuropathological effects of PHH on periventricular white matter microstructure.

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Combining Hypothermia and Oleuropein Subacutely Protects Subcortical White Matter in a Swine Model of Neonatal Hypoxic-Ischemic Encephalopathy

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa132 ◽

2020 ◽

Author(s):

Jennifer K Lee ◽

Polan T Santos ◽

May W Chen ◽

Caitlin E O’Brien ◽

Ewa Kulikowicz ◽

...

Keyword(s):

White Matter ◽

Motor Cortex ◽

Corpus Callosum ◽

Internal Capsule ◽

Subcortical White Matter ◽

White Matter Injury ◽

Swine Model ◽

Cortex Neuron ◽

Motor Cortex Neuron ◽

Ischemic Encephalopathy

Abstract Neonatal hypoxia-ischemia (HI) causes white matter injury that is not fully prevented by therapeutic hypothermia. Adjuvant treatments are needed. We compared myelination in different piglet white matter regions. We then tested whether oleuropein (OLE) improves neuroprotection in 2- to 4-day-old piglets randomized to undergo HI or sham procedure and OLE or vehicle administration beginning at 15 minutes. All groups received overnight hypothermia and rewarming. Injury in the subcortical white matter, corpus callosum, internal capsule, putamen, and motor cortex gray matter was assessed 1 day later. At baseline, piglets had greater subcortical myelination than in corpus callosum. Hypothermic HI piglets had scant injury in putamen and cerebral cortex. However, hypothermia alone did not prevent the loss of subcortical myelinating oligodendrocytes or the reduction in subcortical myelin density after HI. Combining OLE with hypothermia improved post-HI subcortical white matter protection by preserving myelinating oligodendrocytes, myelin density, and oligodendrocyte markers. Corpus callosum and internal capsule showed little HI injury after hypothermia, and OLE accordingly had minimal effect. OLE did not affect putamen or motor cortex neuron counts. Thus, OLE combined with hypothermia protected subcortical white matter after HI. As an adjuvant to hypothermia, OLE may subacutely improve regional white matter protection after HI.

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164: Glial fibrillary acidic protein as a serum biomarker for the early identification of neonatal periventricular white matter injury in preterm neonates

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2011.10.182 ◽

2012 ◽

Vol 206 (1) ◽

pp. S86

Author(s):

Amanda Stewart ◽

Jacky Jennings ◽

Aylin Tekes ◽

Huisman Thierry ◽

Frances Northington ◽

...

Keyword(s):

White Matter ◽

Glial Fibrillary Acidic Protein ◽

Early Identification ◽

Acidic Protein ◽

White Matter Injury ◽

Serum Biomarker ◽

Preterm Neonates ◽

Periventricular White Matter

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Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15608862 ◽

2015 ◽

Vol 36 (8) ◽

pp. 1396-1411 ◽

Cited By ~ 14

Author(s):

Mojgan Ezzati ◽

Alan Bainbridge ◽

Kevin D Broad ◽

Go Kawano ◽

Aaron Oliver-Taylor ◽

...

Keyword(s):

White Matter ◽

Corpus Callosum ◽

Grey Matter ◽

Ischemia Reperfusion ◽

Ischemic Postconditioning ◽

White Female ◽

Resonance Spectroscopy ◽

Periventricular White Matter ◽

Remote Ischemic Postconditioning ◽

Hypoxia Ischemia

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention ( n = 8); (ii) RIPostC – with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI ( n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate ( p = 0.005) and increased whole brain phosphorus-31 MRS ATP ( p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter ( p = 0.03), internal capsule ( p = 0.002) and corpus callosum ( p = 0.021); there was reduced microglial activation in corpus callosum ( p = 0.001) and more surviving oligodendrocytes in corpus callosum ( p = 0.029) and periventricular white matter ( p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.

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525: Peripheral glucose levels at birth and diagnosis of periventricular white matter injury in premature neonates

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2012.10.691 ◽

2013 ◽

Vol 208 (1) ◽

pp. S225

Author(s):

Sarahn Wheeler ◽

Elisabeth Nigrini ◽

Andrew Satin ◽

Michael Johnston ◽

Ernest Graham ◽

...

Keyword(s):

White Matter ◽

White Matter Injury ◽

Periventricular White Matter ◽

Premature Neonates ◽

Glucose Levels

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Periventricular White Matter Injury in the Premature Infant Is Associated with a Reduction in Cerebral Cortical Gray Matter Volume at Term

Pediatric Research ◽

10.1203/00006450-199904020-02039 ◽

1999 ◽

Vol 45 (4, Part 2 of 2) ◽

pp. 343A-343A

Author(s):

Terrie E Inder ◽

Petra S Huppi ◽

Simon Warfield ◽

Ron Kikinis ◽

Gary P Zientara ◽

...

Keyword(s):

White Matter ◽

Premature Infant ◽

Gray Matter ◽

Gray Matter Volume ◽

White Matter Injury ◽

Periventricular White Matter ◽

Matter Volume ◽

Cortical Gray Matter

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LIFESPAN AGE-RELATED DIFFERENCES IN THE REGIONAL WHITE MATTER MICROSTRUCTURE OF THE HUMAN CORPUS CALLOSUM

Innovation in Aging ◽

10.1093/geroni/igz038.3435 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S945-S945

Author(s):

John Lynn ◽

Chaitali Anand ◽

Muzamil Arshad ◽

Dalal Khatib ◽

Jeffrey Stanley ◽

...

Keyword(s):

White Matter ◽

Corpus Callosum ◽

Geometric Mean ◽

Age Groups ◽

Fiber Density ◽

Linear Effect ◽

Water Fraction ◽

General Linear Model Analysis ◽

Age Related ◽

Axonal Density

Abstract The corpus callosum (CC) connects homologous cortical structures across hemispheres and is the largest white matter tract in the human brain. Post-mortem studies suggest that CC myelination begins in infancy, reaches a plateau in the middle age, and declines in the later years. The latter is accompanied by myelin disruption and reduction in fiber density and diameter, i.e. changes in intra-/extracellular water space. We used multi-echo T2 imaging to estimate, via multi-exponential T2 relaxation of water, the myelin water fraction (MWF), a direct proxy for myelin content, and geometric mean T2 (geomT2IEW) that reflects water in the intra-/extracellular space, to investigate age differences in five CC regions covering its anterior to posterior span in 395 healthy individuals (7-85 years; 161M+235F). The general linear model analysis of MWF showed main effects of age and age-squared conditioned on interactions by CC region. Univariate polynomial regressions on three age groups (7-29, 30-59, and 60-85 years) revealed the overall quadratic association between age and MWF as mainly driven by the positive linear relationship in the youngest group and minimal differences in the remainder of the lifespan, save for two weak negative linear associations in the anterior/middle CC body. With geomT2, a main linear effect of age, and significant interactions between age and age-squared by region were observed. The positive linear association was especially prominent in the regions with greater fiber density. The results are consistent with CC myelination into adulthood and decreased axonal density and diameter but not prominent myelin degeneration in elderly individuals.

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Fiber-specific white matter reductions in Parkinson hallucinations and visual dysfunction

Neurology ◽

10.1212/wnl.0000000000009014 ◽

2020 ◽

Vol 94 (14) ◽

pp. e1525-e1538 ◽

Cited By ~ 4

Author(s):

Angeliki Zarkali ◽

Peter McColgan ◽

Louise-Ann Leyland ◽

Andrew J. Lees ◽

Geraint Rees ◽

...

Keyword(s):

White Matter ◽

Corpus Callosum ◽

Parkinson Disease ◽

Fiber Bundle ◽

Visual Performance ◽

Visual Hallucinations ◽

Fiber Density ◽

Left Posterior ◽

Parkinson Dementia ◽

Attentional Models

ObjectiveTo investigate the microstructural and macrostructural white matter changes that accompany visual hallucinations and low visual performance in Parkinson disease, a risk factor for Parkinson dementia.MethodsWe performed fixel-based analysis, a novel technique that provides metrics of specific fiber-bundle populations within a voxel (or fixel). Diffusion MRI data were acquired from patients with Parkinson disease (n = 105, of whom 34 were low visual performers and 19 were hallucinators) and age-matched controls (n = 35). We used whole-brain fixel-based analysis to compare microstructural differences in fiber density (FD), macrostructural differences in fiber bundle cross section (FC), and the combined FD and FC (FDC) metric across all white matter fixels. We then performed a tract-of-interest analysis comparing the most sensitive FDC metric across 11 tracts within the visual system.ResultsPatients with Parkinson disease hallucinations exhibited macrostructural changes (reduced FC) within the splenium of the corpus callosum and the left posterior thalamic radiation compared to patients without hallucinations. While there were no significant changes in FD, we found large reductions in the combined FDC metric in Parkinson hallucinators within the splenium (>50% reduction compared to nonhallucinators). Patients with Parkinson disease and low visual performance showed widespread microstructural and macrostructural changes within the genu and splenium of the corpus callosum, bilateral posterior thalamic radiations, and left inferior fronto-occipital fasciculus.ConclusionsWe demonstrate specific white matter tract degeneration affecting posterior thalamic tracts in patients with Parkinson disease with hallucinations and low visual performance, providing direct mechanistic support for attentional models of visual hallucinations.

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