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Nitrosative stress and inducible nitric oxide synthase expression in periventricular leukomalacia
Haynes, Robin L; Folkerth, Rebecca D; Trachtenberg, Felicia L; Volpe, Joseph J; Kinney, Hannah C
Periventricular leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29-51 postconceptional (PC) weeks] and 16 control cases (20-144 PC weeks). Using a standardization score of 0-3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 +/- 0.3) cases compared to controls (score of 0.7 +/- 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL's pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.
PMCID:2909016
PMID: 19415311
ISSN: 1432-0533
CID: 2177182
Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity
Ligam, Poonam; Haynes, Robin L; Folkerth, Rebecca D; Liu, Lena; Yang, May; Volpe, Joseph J; Kinney, Hannah C
Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
PMCID:2713790
PMID: 19127204
ISSN: 1530-0447
CID: 2177192
Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia
Ferland, Russell J; Batiz, Luis Federico; Neal, Jason; Lian, Gewei; Bundock, Elizabeth; Lu, Jie; Hsiao, Yi-Chun; Diamond, Rachel; Mei, Davide; Banham, Alison H; Brown, Philip J; Vanderburg, Charles R; Joseph, Jeffrey; Hecht, Jonathan L; Folkerth, Rebecca; Guerrini, Renzo; Walsh, Christopher A; Rodriguez, Esteban M; Sheen, Volney L
Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.
PMCID:2722192
PMID: 18996916
ISSN: 1460-2083
CID: 2177722
Meningioangiomatosis associated with meningioma: a case report [Case Report]
Saad, Ali; Folkerth, Rebecca; Poussaint, Tina; Smith, Edward; Ligon, Keith
BACKGROUND: Meningioangiomatosis is a meningovascular disorder that only rarely occurs in association with a meningioma. Occasionally, as in this case, imaging studies do not readily identify this disorder as a benign process. In addition, this disorder may infiltrate the underlying cerebral cortex, simulating, intraoperatively, a malignant infiltrative process. To allow better recognition of this disorder, we report a case with emphasis on the unique cytologic features of the 2 components (meningioangiomatosis and meningioma) and potential pitfalls in diagnosis. CASE: A 3-year-old girl was examined in the neurosurgery service for history of refractory seizure. Neuroimaging showed an ill-defined signal abnormality in the left frontal lobe suggestive of a high-grade tumor. Tumor resection was performed, and intraoperative smear preparation showed meningioangiomatosis associated with meningioma. CONCLUSION: Familiarity with cytologic preparations of this rare variant is very important in providing accurate intraoperative consultation. To our knowledge, this is the first description of the cytologic features on smear preparation of meningioangiomatosis occurring in association with meningioma.
PMID: 19248561
ISSN: 0001-5547
CID: 2177712
The development of ring-shaped contrast enhancement in a case of cerebellar dysembryoplastic neuroepithelial tumor: case report [Case Report]
Tailor, Jignesh K; Kim, Albert H; Folkerth, Rebecca D; Black, Peter M
OBJECTIVE: Dysembryoplastic neuroepithelial tumor (DNT) occurs rarely in the cerebellum. We describe a rare case of cerebellar DNT that developed contrast enhancement after long-term observation and discuss the underlying mechanism and clinical relevance of this unusual phenomenon. CLINICAL PRESENTATION: A 34-year-old woman with known cystic cerebellar lesions presented with increased frequency of vertigo and new onset of truncal ataxia. Magnetic resonance imaging revealed new contrast enhancement in the dominant cystic lesion of the cerebellar vermis without any change in size and shape or evidence of edema. INTERVENTION: The lesions were resected under magnetic resonance imaging guidance. Histological assessment revealed populations of small, round cells in a microcystic background containing "floating" neurons, diagnostic of DNT. Microvascular proliferation and pigmented neurons were also present. CONCLUSION: This is the first report of the development of contrast enhancement in a previously nonenhancing case of cerebellar DNT. The acquisition of ring-shaped contrast enhancement may be associated with microvascular proliferation, but otherwise no evidence of malignant progression. In addition, this case presents the novel pathological finding of pigmented neurons in DNT.
PMID: 18812941
ISSN: 1524-4040
CID: 2177202
Oxidative injury in the cerebral cortex and subplate neurons in periventricular leukomalacia
Folkerth, Rebecca D; Trachtenberg, Felicia L; Haynes, Robin L
We previously identified immunocytochemical evidence of nitrative and oxidative injury in premyelinating oligodendrocytes in periventricular leukomalacia (PVL). Here, we tested the hypothesis that free radical injury occurs in the overlying cerebral cortex and subplate neurons in PVL. We immunostained for nitrotyrosine, malondialdehyde, and hydroxynonenal adducts and scored neuron staining density in PVL (n = 11) and non-PVL (n = 15) cases (postconceptional ages from 34 to 109 weeks). Analysis of covariance controlled for age. Mean malondialdehyde scores in PVL cases were increased over controls (p = 0.005). Hydroxynonenal scores increased with age only in PVL cases (diagnosis vs age interaction; p = 0.024). Nitrotyrosine scores were not significantly increased. In 11 PVL and 23 control cases between 20 and 183 postconceptional weeks, cells morphologically consistent with subplate and Cajal-Retzius neurons showed qualitatively increased free radical modification in PVL over control cases with statistically significant odds ratios for hydroxynonenal and nitrotyrosine in both subplate neurons and Cajal-Retzius cells. Glial fibrillary acidic protein and CD68 scores for reactive astrocytes and microglia, respectively, were not significantly increased, suggesting a minimal inflammatory response. Thus, oxidative/nitrative damage to cortical and "pioneer" neurons, although mild overall, may contribute to cortical volume loss and cognitive/behavioral impairment in survivors of prematurity.
PMCID:2831221
PMID: 18596545
ISSN: 0022-3069
CID: 2177212
Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia
Billiards, Saraid S; Haynes, Robin L; Folkerth, Rebecca D; Borenstein, Natalia S; Trachtenberg, Felicia L; Rowitch, David H; Ligon, Keith L; Volpe, Joseph J; Kinney, Hannah C
The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.
PMCID:2770329
PMID: 18177464
ISSN: 1015-6305
CID: 2177222
Genomic and functional profiling of human Down syndrome neural progenitors implicates S100B and aquaporin 4 in cell injury
Esposito, Giuseppe; Imitola, Jaime; Lu, Jie; De Filippis, Daniele; Scuderi, Caterina; Ganesh, Vijay S; Folkerth, Rebecca; Hecht, Jonathan; Shin, Soojung; Iuvone, Teresa; Chesnut, Jonathan; Steardo, Luca; Sheen, Volney
Down syndrome (DS) is caused by trisomy of chromosome 21 and is characterized by mental retardation, seizures and premature Alzheimer's disease. To examine neuropathological mechanisms giving rise to this disorder, we generated multiple human DS neural progenitor cell (NPC) lines from the 19-21 week frontal cortex and characterized their genomic and functional properties. Microarray profiling of DS progenitors indicated that increased levels of gene expression were not limited to chromosome 21, suggesting that increased expression of genes on chromosome 21 altered transcriptional regulation of a subset of genes throughout the entire genome. Moreover, many transcriptionally dysregulated genes were involved in cell death and oxidative stress. Network analyses suggested that upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 (AQP4). We further demonstrate in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression. In addition, AQP4 expression could be induced by direct exposure to ROS, and siRNA inhibition of AQP4 resulted in elevated levels of ROS following S100B exposure. Finally, elevated levels of S100B-induced ROS and loss of AQP4 expression led to increased programmed cell death. These findings suggest that dysregulation of chromosome 21 genes in DS neural progenitors leads to increased ROS and thereby alters transcriptional regulation of cytoprotective, non-chromosome 21 genes in response to ongoing cellular insults.
PMID: 17984171
ISSN: 1460-2083
CID: 2177732
Neuronal cell death in the arcuate nucleus of the medulla oblongata in stillbirth
Folkerth, Rebecca D; Zanoni, Sallie; Andiman, Sarah E; Billiards, Saraid S
The hypothesis that unexplained stillbirth arises in a similar manner as the sudden infant death syndrome (SIDS) is based in part on shared neuropathologic features between the two entities, including hypoxic-ischemic lesions such as white matter and brainstem gliosis, as well as aplasia or hypoplasia of the arcuate nucleus on the ventral surface of the medulla. The arcuate nucleus is the putative homologue of the respiratory chemosensory region at the ventral medullary surface in animals that is involved in central chemosensitivity. To determine arcuate nucleus pathology in stillbirth, and its co-occurrence with evidence of hypoxia-ischemia, we reviewed brain specimens from the archives of our hospitals from 22 consecutive stillbirths from 22 to 41 gestational weeks. Explained causes of death (n=17) included nuchal cord, acute chorioamnionitis, placental abruption, and fetal glomerulosclerosis; 5 cases were unexplained. In 12 brains, we observed nuclear karyorrhexis and/or pyknosis with cytoplasmic hypereosinophilia in neurons in the arcuate nucleus in both explained (n=8) and unexplained (n=4) cases (54.5% of total cases). Three additional cases had arcuate aplasia (n=1) or hypoplasia (n=2) (13.6% of total cases); one of the latter cases also had neuronal necrosis in the hypoplastic arcuate. The degree of gliosis in the region of the arcuate nucleus was variable across all cases, without statistically significant differences between groups with and without arcuate nucleus necrosis. Other lesions in association with (n=14) and without (n=8) arcuate nucleus abnormalities were diffuse cerebral white matter gliosis, periventricular leukomalacia (PVL), and neuronal necrosis in the hippocampus, basal ganglia, thalamus, basis pontis, and brainstem tegmentum. In 16/20 (80.0%) cases (with or without histologic necrosis of the arcuate), immunostaining with caspase-3 demonstrated positive neurons. Our findings suggest that neuronal pathology in the arcuate nucleus may be both developmental (13.6%) and acquired (54.5%). The association of neuronal necrosis and apoptosis in the arcuate nucleus with systemic entities involving fetal ischemia, and with other brain lesions consistent with ischemia, e.g., cerebral white matter gliosis, suggests that ischemia plays a role in the arcuate nucleus damage as well. Thus, the underpopulation of arcuate neurons detected postnatally in some SIDS infants may be secondary to an acquired insult in mid- or late gestation, and in other cases, a primary developmental lesion in early gestation, or both. The role of arcuate nucleus pathology in the pathogenesis of fetal demise remains to be determined.
PMID: 17950558
ISSN: 0736-5748
CID: 2177232
Thalamic damage in Periventricular Leukomalacia (PVL) [Meeting Abstract]
Ligam, Poonam; Folkerth, Rebecca D; Haynes, Robin L; Liu, Lena; Volpe, Joseph J; Kinney, Hannah C
ISI:000255442300030
ISSN: 0022-3069
CID: 2178032