Evidence Of White Matter Damage Research Articles

Microstructural Changes in Normal-Appearing White Matter in Pediatric X-Linked Adrenoleukodystrophy: A Diffusion Tensor Imaging Study

Abstract Objective Diffusion tensor imaging (DTI) is an advanced magnetic resonance imaging (MRI) technique that provides quantitative diffusion data of water molecules in tissue. Usage of DTI in pediatric X-linked adrenoleukodystrophy (X-ALD) may adjunct earlier detection of brain involvement. This study aimed to analyze the normal-appearing white matter in pediatric patients with X-ALD using DTI. Materials and Methods A retrospective database search was performed. Children with genetically diagnosed X-ALDs with a reportedly normal brain MRI between January 2010 and September 2021 were included. Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and apparent diffusion coefficient were serially measured in 8 regions of the brain, and these measurements were compared with those in control patients. Results The study group included 21 X-ALD patients and 11 control patients. The mean age was 6.64 ± 5.14 years. FA values of the genu and body of the corpus callosum were significantly lower in the ALD group than controls. There was also a statistically significant difference in FA, AD, and RD values of cerebellar white matter in the two groups. Conclusion There is evidence of white matter damage on DTI in X-ALD patients with the normal-appearing white matter on conventional MRI sequences. The inclusion of DTI in routine MRI examinations of X-ALD patients may provide additional insight into possible white matter damage in that population.

Mild, moderate and severe: terminology implications for clinical and experimental traumatic brain injury.

When describing clinical or experimental traumatic brain injury (TBI), the adjectives 'mild,' 'moderate' and 'severe' are misleading. 'Mild' clinical TBI frequently results in long-term disability. 'Severe' rodent TBI actually resembles mild or complicated mild clinical TBI. Many mild TBI patients appear to have recovered completely but have postconcussive symptoms, deficits in cognitive and executive function and reduced cerebral blood flow. After moderate TBI, 31.8% of patients died or were discharged to skilled nursing or hospice. Among survivors of moderate and severe TBI, 44% were unable to return to work. On MRI, 88% of mild TBI patients have evidence of white matter damage, based on measurements of fractional anisotropy and mean diffusivity/apparent diffusion coefficient. After sports concussion, clinically recovered patients have abnormalities in functional connectivity on functional MRI. Methylphenidate improved fatigue and cognitive impairment and, combined with cognitive rehabilitation, improved memory and executive functioning. In comparison to clinical TB, because the entire spectrum of experimental rodent TBI, although defined as moderate or severe, more closely resembles mild or complicated mild clinical TBI. Many patients after mild or moderate TBI suffer long-term sequelae and should be considered a major target for translational research. Treatments that improve outcome in rodent TBI, even when the experimental injuries are defined as severe, might be most applicable to mild or moderate TBI.

Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha concentration and combined outcome of death or abnormal neuroimaging in preterm neonates with early-onset clinical sepsis.

Prematurity and sepsis are the major contributors of neonatal mortality and neurodevelopmental sequelae. The present study was conducted to measure the plasma and cerebrospinal fluid (CSF) concentration of interleukin (IL)-1β and tumor necrotic factor (TNF)-α in preterm neonates with early-onset clinical sepsis (EOCS), and to find out their association with combined outcome of death or abnormal neuroimaging. Thirty-two preterm (⩽34 weeks) neonates with EOCS and 32 gestational age-matched, healthy neonates served as cases and controls, respectively. Samples were collected soon after birth. Neonates were followed up clinically and by serial cranial ultrasonography (CUS) until discharge and subsequently by magnetic resonance imaging (MRI) of brain until 1 year. Developmental screening was done by Denver Developmental Screening test-II. In EOCS group, no neonate had any clinical/microbiological evidence of meningitis. Blood culture was positive in 17 (53%). CUS was abnormal in 12 (37%) (intracranial hemorrhage-11, periventricular leukomalacia-1). Ten (31%) neonates expired. Significant elevation of plasma and CSF IL-1β and TNF-α was observed in the EOCS group. On follow-up, seven (22%) neonates showed evidence of white matter damage in MRI, two of them had developmental delay and microcephaly. Plasma and CSF IL-1β and TNF-α concentration were significantly elevated in deceased neonates and those with abnormal neuroimaging. Both biomarkers demonstrated high predictive accuracy for poor outcome in receiver-operating curve analysis. Elevation of plasma and CSF IL-1β and TNF-α is associated with an increase in the combined outcome of death or abnormal neuroimaging in preterm neonates with EOCS in the absence of clinical/microbiological evidence of meningitis with high predictive accuracy.

Use of a minimally invasive tubular retraction system for deep-seated tumors in pediatric patients

Microsurgical removal is the preferred treatment for most deep-seated, intraaxial tumors in the pediatric population. The feasibility of surgery as an option has improved with advances in surgical technology and technique. Tubular retractors disperse retraction forces over a greater surface area than do conventional retractors, which can lower the risk of ischemic complications. The authors describe their experience utilizing a new tubular retractor system specifically designed for cranial applications in conjunction with frameless neuronavigation. The Vycor ViewSite retractor was used in 4 pediatric patients (ages 15 months and 9, 10, and 16 years) with deep-seated intraaxial tumors. The lesions included a papillary tumor of the pineal region, a low-grade astrocytoma in the occipital lobe, a dysembryoplastic neuroepithelial tumor arising from the basal ganglia, and an intraventricular low-grade glioma. The extent of white matter damage along the surgical trajectory (based on T2 or FLAIR and diffusion restriction/apparent diffusion coefficient signals) and the extent of resection were assessed on postoperative imaging. Satisfactory resection or biopsy was achieved in all patients. A comparison of pre- and postoperative MR imaging studies revealed evidence of white matter damage along the surgical trajectory in 1 patient. None of the patients demonstrated new neurological deficits postoperatively. Obtaining surgical access to deep-seated, intraaxial tumors is challenging. In this small series of pediatric patients, the combination of the ViewSite tubular retractor and frameless neuronavigation facilitated the surgical approach. The combination of these technologies adds to the armamentarium to safely approach tumors in deep locations.

Minimally Invasive Trans-Portal Resection of Deep Intracranial Lesions

The surgical management of deep intra-axial lesions still requires microsurgical approaches that utilize retraction of deep white matter to obtain adequate visualization. We report our experience with a new tubular retractor system, designed specifically for intracranial applications, linked with frameless neuronavigation for a cohort of intraventricular and deep intra-axial tumors. The ViewSite Brain Access System (Vycor, Inc) was used in a series of 9 adult and pediatric patients with a variety of pathologies. Histological diagnoses either resected or biopsied with the system included: colloid cyst, DNET, papillary pineal tumor, anaplastic astrocytoma, toxoplasmosis and lymphoma. The locations of the lesions approached include: lateral ventricle, basal ganglia, pulvinar/posterior thalamus and insular cortex. Post-operative imaging was assessed to determine extent of resection and extent of white matter damage along the surgical trajectory (based on T (2)/FLAIR and diffusion restriction/ADC signal). Satisfactory resection or biopsy was obtained in all patients. Radiographic analysis demonstrated evidence of white matter damage along the surgical trajectory in one patient. None of the patients experienced neurological deficits as a result of white matter retraction/manipulation. Based on a retrospective review of our experience, we feel that this access system, when used in conjunction with frameless neuronavigational systems, provides adequate visualization for tumor resection while permitting the use of standard microsurgical techniques through minimally invasive craniotomies. Our initial data indicate that this system may minimize white matter injury, but further studies are necessary.

MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of NBS1, Nbn, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. In this study we used MRI to study the brain morphology and organization of Nbn deleted mice. Using conventional T2-weighted magnetic resonance, we found that the brains of the mutant mice (Nbs1-CNS-del) were significantly smaller than those of the wild-type animals, with marked mal-development of the cerebellum. Region of interest analysis of the T2 maps revealed significant T2 increase in the areas of white matter (corpus callosum, internal capsule and midbrain), with minor changes, if any, in gray matter. Diffusion tensor imaging (DTI) data confirmed that fractional anisotropy values were significantly reduced in these areas, mainly due to increased radial diffusivity (water diffusion perpendicular to neuronal fibers). Biochemical analysis showed low and dispersed staining for MBP and GalC in Nbs1-CNS-del brains, indicating defects in myelin formation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of Nbs1 in the development and organization of the white matter.

White matter volume and concentration reductions in adolescents with history of very preterm birth: A voxel-based morphometry study

Very preterm birth (VPTB) is an important risk factor for white matter (WM) damage. We used voxel-based morphometry (VBM) to examine regional WM brain abnormalities in 50 adolescents with antecedents of very preterm birth (VPTB) without evidence of WM damage on T2-weighted MRI. This group was compared with a group of 50 subjects born at term and matched for age, handedness and socio-cultural status. We also examined the relationship between WM changes and gestational age (GA) and weight (GW) at birth in VPTB subjects. Both modulated and unmodulated VBM analyses showed significant abnormalities in several WM brain regions in the VPTB group, involving all the cerebral lobes. However, density analyses (unmodulated data) mainly identified periventricular damage and the involvement of the longitudinal fascicles while volume analyses (modulated data) detected WM decreases in regions distant from the ventricular system, located at the origin and end of the long fascicles. A significant correlation was found between WM decreases and both GA and GW in various brain regions: the lower the GA and GW, the lower the WM integrity. This study supports the current view that widespread white matter impairment is associated with immature birth.

No phenotype associated with established lipopolysaccharide model for cerebral palsy

Cerebral palsy (CP) is associated with childhood spasticity, seizures, and paralysis. Oligodendrocyte damage resulting in periventicular leukomalacia (PVL) in the developing brain has been implicated. Animal models of CP have used prenatal hypoxia and infection with histopathology of PVL as the end point. To evaluate whether this histologic end point is associated with a CP phenotype, we reproduced a lipopolysaccharide (LPS) model for PVL, 1 and evaluated developmental, behavioral, and motor outcomes. On gestational day 15, Fischer 344 rats were intracervically injected with .1 mg/kg LPS (n = 5) or saline (n = 4). After delivery, evaluation for developmental milestones was performed on days 1 to 21 (LPS = 45; control = 30 pups). Males were also tested at 2.5 months using open-field, rotarod, and anxiety tests. On day 21, 2 pups/litter were perfused for immunohistochemistry, and stained with 2 oligodendrocyte antibodies: 2', d'-cyclic nucleotide phosphodiesterase (CNP), and myelin proteolipid protein (PLP) with relative densities of staining assessed using NIH Image software. Statistical analysis included Mann-Whitney U and analysis of variance (ANOVA). LPS pups demonstrated decreased CNP (P = .04) and PLP (P = .06) staining, replicating the model. There was no difference seen in neonatal weight, righting, negative geotaxis, cliff aversion, rooting, forelimb grasp, audio startle, air righting, eye opening, and activity. Surprisingly, LPS-exposed neonatal rats mastered forelimb placement (P < .01) and surface righting (P = .02) earlier than control rats. There were no differences between adult groups in open field distance traveled (P = .8), open-field locomotion time (P = .6), rotarod (P = .6), or anxiety (P = .7). Histologic evidence of white matter damage can be replicated using an LPS model for intrauterine inflammation. Significant phenotypic differences consistent with the motor and cognitive damage sequelae of such lesions (ie, CP) were not demonstrated. When evaluating animal models, it is important to assess not only biochemical markers for human disease, but also clinically relevant phenotypes.

Global hypoxia per se is an unusual cause of axonal injury.

Irreversible hypoxic brain damage and axonal injury are present in over 90% of fatal blunt head injuries. Given the frequency of each, difficulties arise as to whether or not they are due to different mechanisms and, as such, can be separately recognised and quantified. Recent literature has raised the possible role of hypoxia in the formation of axonal bulbs. The present study of 17 cases of cardio-respiratory arrest, 12 of status epilepticus, 3 of carbon monoxide poisoning and 12 controls was designed to test the relationship between hypoxia and axonal injury and to test the hypothesis whether or not the two entities can be separated into primary and secondary forms of traumatic brain injury. Axonal damage was seen in 9/17 and 7/12 of the cases with cardiac arrest and status epilepticus, respectively, in most of whom there was also evidence of raised intracranial pressure (ICP). All 3 cases of carbon monoxide poisoning had evidence of white matter damage in keeping with the classical pattern of selective vulnerability. It is concluded that the great majority of axonal damage identified in cases dying after cardiac arrest and status epilepticus can be attributed to raised ICP and the vascular complications of internal herniation. However, in some cases, axonal damage was seen in the absence of an elevated ICP, although its amount and distribution were different from diffuse axonal injury. In many cases there was an increase in expression of neuronal beta amyloid precursor protein.

Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits

OBJECTIVE: Periventricular leukomalacia, a common brain white matter lesion in preterm neonates, is a major risk factor for cerebral palsy. Epidemiologic studies have demonstrated an association between infection and periventricular leukomalacia. The purpose of this study was to determine whether ascending intrauterine infection could cause brain white matter lesions in the fetal rabbit. STUDY DESIGN: Rabbits with timed pregnancies underwent hysteroscopy at 20 to 21 days of gestation (70%). Animals were allocated in a ratio of 2:1 for inoculation with either Escherichia coli (0.2 ml containing 10 3 to 10 4 colony-forming units) or sterile saline solution. Both groups were treated with ampicillin-sulbactam (Unasyn, 100 mg/kg per day; Pfizer, Seoul) every 8 hours until they were killed 5 to 6 days after hysteroscopy. Histologic examination of the placentas and fetal brains was conducted. RESULTS: Forty-five animals underwent hysteroscopy; 31 were inoculated with E. coli and 14 with sterile saline solution. At the time the animals were killed, the rate of intrauterine infection was higher and there were fewer live fetuses in the E. coli–inoculated animals than in the saline solution group. Histologic evidence of brain white matter damage was identified in 12 fetuses born to 10 E. coli–inoculated rabbits but none in the saline solution group ( p < 0.05). All rabbits with brain white matter lesions had evidence of intrauterine infection. Evidence of white matter damage included increased karyorrhexis, rarefaction, and disorganization of white matter. Apoptosis was demonstrated in areas of white matter damage by immunohistochemical studies. CONCLUSION: Experimental ascending intrauterine infection can cause fetal brain white matter lesions. (Am J Obstet Gynecol 1997;177:797-802.)