Transient ischemic attack without self-awareness of symptoms witnessed by bystanders: analysis of the PROMISE-TIA registry.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) can occur without self-awareness of symptoms. We aimed to investigate characteristics of patients with a tissue-based diagnosis of TIA but having no self-awareness of their symptoms and whose symptoms were witnessed by bystanders. METHODS: We used data from the multicenter registry of 1414 patients with a clinical diagnosis of TIA. For patients without evidence of ischemic lesions on imaging, clinical characteristics were compared between patients with and without self-awareness of their TIA symptoms. RESULTS: Among 896 patients (559 men, median age of 70 years), 59 (6.6%) were unaware of their TIA symptoms, but had those symptoms witnessed by bystanders. Patients without self-awareness of symptoms were older and more frequently female, and more likely to have previous history of stroke, premorbid disability, and atrial fibrillation, but less likely to have dyslipidemia than those with self-awareness. Patients without self-awareness of symptoms arrive at hospitals earlier than those with self-awareness (P < 0.001). ABCD2 score was higher in patients without self-awareness of symptoms than those with self-awareness (median 5 vs. 4, P = 0.002). Having no self-awareness of symptoms was a significant predictor of ischemic stroke within 1 year after adjustment for sex, ABCD2 score, and onset to arrival time (hazard ratio = 2.44, 95% confidential interval: 1.10-4.83), but was not significant after further adjustment for arterial stenosis or occlusion. CONCLUSIONS: Patients with a TIA but having no self-awareness of their symptoms might have higher risk of subsequent ischemic stroke rather than those with self-awareness, suggesting urgent management is needed even if patients have no self-awareness of symptoms.

Differences between primary central nervous system lymphoma and glioblastoma: topographic analysis using voxel-based morphometry.

AIM: To evaluate the diagnostic feasibility of probabilistic analysis using voxel-based morphometry (VBM) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). MATERIALS AND METHODS: In total, 118 patients with GBM (57 males, 61 females; mean [± standard deviation] age, 56.9±19.3 years; median, 61 years) and 52 patients with PCNSL (37 males, 15 females; mean age, 62±13.3 years, median, 66 years) were studied retrospectively. Each patient underwent preoperative contrast-enhanced T1-weighted imaging (CE-T1WI) using a 1.5 or 3 T magnetic resonance imaging (MRI) system. To assess preferential occurrence sites, images from CE-T1WI were co-registered and spatially normalised using the MNI152 T1 template. Subsequently, a region of interest (ROI) was placed in the centre of the enhancing tumour in normalised images with 1-mm isotropic resolution. The same ROI between normalised and T1 template images was set up using an ROI manager function in ImageJ software. A spherical volume of interest (VOI) with a radius of 10 mm was determined. A probability map was created by overlaying each image with the VOI. Each VOI was removed from T1 template images for VBM analysis. VBM analysis was performed using statistical parametric mapping (SPM) 12 software under default settings. RESULTS: VBM analysis showed significantly higher frequency in the splenium of the corpus callosum among PCNSL patients than among GBM patients (p<0.05; family-wise error correction). CONCLUSION: Topographic analysis using VBM provides useful information for differentiating PCNSL from GBM.

Radiation-Induced Changes Associated with Obliteration of Brain AVMs after Repeat Radiosurgery.

BACKGROUND AND PURPOSE: Radiation-induced changes can occur after stereotactic radiosurgery for brain AVMs, potentially causing symptomatic complications. We evaluated the incidence of such changes and the efficacy of repeat gamma knife radiosurgery for incompletely obliterated AVMs. MATERIALS AND METHODS: We retrospectively evaluated 150 patients who underwent gamma knife radiosurgery for AVMs between 2002 and 2020; twenty-five underwent further radiosurgical procedures for incompletely obliterated AVMs. We recorded the median margin doses at the first (median, 20 Gy; range, 12-23 Gy; AVM volume, 0.026-31.3 mL) and subsequent procedures (median, 18 Gy; range, 12-23 Gy; AVM volume, 0.048-9.2 mL). RESULTS: After the first treatment, radiologic radiation-induced changes developed in 48 (32%) patients, eight of whom had symptomatic changes. After repeat gamma knife radiosurgery, 16 of 25 patients achieved complete AVM obliteration (64%). The development of radiation-induced changes after the first treatment was significantly associated with successful obliteration by subsequent radiosurgery (OR = 24.0, 95% CI 1.20-483, P = .007). Radiation-induced changes occurred in only 5 (20%) patients who underwent a second gamma knife radiosurgery, one of whom experienced transient neurologic deficits. Between the first and repeat gamma knife radiosurgery procedures, there was no significant difference in radiologic and symptomatic radiation-induced changes (P = .35 and P = 1.0, respectively). CONCLUSIONS: Radiation-induced changes after the first gamma knife radiosurgery were associated with AVM obliteration after a repeat procedure. The risk of symptomatic radiation-induced changes did not increase with retreatment. When the first procedure fails to achieve complete AVM obliteration, a favorable outcome can be achieved by a repeat gamma knife radiosurgery, even if radiation-induced changes occur after the first treatment.

Complications of Endovascular Treatments for Brain Arteriovenous Malformations: A Nationwide Surveillance.

BACKGROUND AND PURPOSE: Embolization is widely performed to treat brain arteriovenous malformations, but little has been reported on factors contributing to complications. We retrospectively reviewed a nationwide surveillance to identify risk factors contributing to complications and short-term clinical outcomes in the endovascular treatment of brain arteriovenous malformations. MATERIALS AND METHODS: Data for endovascular treatment of brain arteriovenous malformations were extracted from the Japanese nationwide surveillance. Patient characteristics, brain arteriovenous malformation features, procedures, angiographic results, complications, and clinical outcomes at 30 days postprocedure were analyzed. RESULTS: A total of 1042 endovascular procedures (788 patients; mean, 1.43 ± 0.85 procedures per patient) performed in 111 institutions from 2010 to 2014 were reviewed. Liquid materials were used in 976 procedures (93.7%): to perform presurgical embolization in 638 procedures (61.2%), preradiosurgical embolization in 160 (15.4%), and as sole endovascular treatment in 231 (22.2%). Complete or near-complete obliteration of brain arteriovenous malformations was obtained in 386 procedures (37.0%). Procedure-related complications occurred in 136 procedures (13.1%), including hemorrhagic complications in 59 (5.7%) and ischemic complications in 57 (5.5%). Univariate analysis identified deep venous drainage, associated aneurysms, infratentorial location, and preradiosurgical embolization as statistically significant risk factors for complications. Multivariate analysis showed that embolization of brain arteriovenous malformations in the infratentorial location was significantly associated with complications. Patients with complications due to endovascular procedures had worse clinical outcomes 30 days after the procedures than those without complications. CONCLUSIONS: Complications arising after endovascular treatment of brain arteriovenous malformations are not negligible even though they may play a role in adjunctive therapy, especially in the management of infratentorial brain arteriovenous malformations.

Predictors of Cerebral Aneurysm Rupture after Coil Embolization: Single-Center Experience with Recanalized Aneurysms.

BACKGROUND AND PURPOSE: Recanalization after coil embolization is widely studied. However, there are limited data on how recanalized aneurysms rupture. Herein, we describe our experience with the rupture of recanalized aneurysms and discuss the type of recanalized aneurysms at greatest rupture risk. MATERIALS AND METHODS: A total of 426 unruptured aneurysms and 169 ruptured aneurysms underwent coil embolization in our institution between January 2009 and December 2017. Recanalization occurred in 38 (8.9%) of 426 unruptured aneurysms (unruptured group) and 37 (21.9%) of 169 ruptured aneurysms (ruptured group). The Modified Raymond-Roy classification on DSA was used to categorize the recanalization type. Follow-up DSA was scheduled until 6 months after treatment, and follow-up MRA was scheduled yearly. If recanalization was suspected on MRA, DSA was performed. RESULTS: In the unruptured group, the median follow-up term was 74.0 months. Retreatment for recanalization was performed in 18 aneurysms. Four of 20 untreated recanalized aneurysms (0.94% of total coiled aneurysms) ruptured. In untreated recanalized aneurysms, class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (P = .025). In the ruptured group, the median follow-up term was 28.0 months. Retreatment for recanalization was performed in 16 aneurysms. Four of 21 untreated recanalized aneurysms (2.37% of total coiled aneurysms) ruptured. Class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (P = .02). CONCLUSIONS: The types of recanalization after coil embolization may be predictors of rupture. Coiled aneurysms with class IIIb recanalization should undergo early retreatment because of an increased rupture risk.

Intravoxel Incoherent Motion MR Imaging of Pediatric Intracranial Tumors: Correlation with Histology and Diagnostic Utility.

BACKGROUND AND PURPOSE: Intravoxel incoherent motion imaging, which simultaneously measures diffusion and perfusion parameters, is promising for brain tumor grading. However, intravoxel incoherent motion imaging has not been tested in children. The purpose of this study was to evaluate the correlation between intravoxel incoherent motion parameters and histology to assess the accuracy of intravoxel incoherent motion imaging for pediatric intracranial tumor grading. MATERIALS AND METHODS: Between April 2013 and September 2015, 17 children (11 boys, 6 girls; 2 months to 15 years of age) with intracranial tumors were included in this retrospective study. Intravoxel incoherent motion parameters were fitted using 13 b-values for a biexponential model. The perfusion-free diffusion coefficient, pseudodiffusion coefficient, and perfusion fraction were measured in high- and low-grade tumors. These intravoxel incoherent motion parameters and the ADC were compared using the unpaired t test. The correlations between the intravoxel incoherent motion parameters and microvessel density or the MIB-1 index were analyzed using the Spearman correlation test. Receiver operating characteristic analysis was used to evaluate diagnostic performance. RESULTS: The perfusion-free diffusion coefficient and ADC were lower in high-grade than in low-grade tumors (perfusion-free diffusion coefficient, 0.85 ± 0.40 versus 1.53 ± 0.21 × 10-3 mm2/s, P < .001; ADC, 1.04 ± 0.33 versus 1.60 ± 0.21 × 10-3 mm2/s, P < .001). The pseudodiffusion coefficient showed no difference between the groups. The perfusion fraction was higher in high-grade than in low-grade tumors (21.7 ± 8.2% versus 7.6 ± 4.3%, P < .001). Receiver operating characteristic analysis found that the combined perfusion-free diffusion coefficient and perfusion fraction had the best diagnostic performance for tumor differentiation (area under the curve = 0.986). CONCLUSIONS: Intravoxel incoherent motion imaging reflects tumor histology and may be a helpful, noninvasive method for pediatric intracranial tumor grading.

Predicting TERT promoter mutation using MR images in patients with wild-type IDH1 glioblastoma.

PURPOSE: The purpose of this study was to identify magnetic resonance imaging (MRI) features that are associated with telomerase reverse transcriptase promoter mutation (TERTm) in glioblastoma. MATERIALS AND METHODS: A total of 112 patients with glioblastoma who had MRI at 1.5- or 3.0-T were retrospectively included. There were 43 patients with glioblastoma with wild-type TERT (TERTw) (22 men, 21 women; mean age, 47±25 [SD] years; age range: 3-84 years) and 69 patients with glioblastoma with TERTm (34 men, 35 women; mean age 64±11 [SD] years; age range, 41--85 years). The feature vectors consist of 11 input units for two clinical parameters (age and gender) and nine MRI characteristics (tumor location, subventricular extension, cortical extension, multiplicity, enhancing volume, necrosis volume, the percentage of necrosis volume, minimum apparent diffusion coefficient [ADC] and normalized ADC). First, the diagnostic performance using univariate and multivariate logistic regression analyses was evaluated. Second, the cross-validation of the support vector machine (SVM) was performed by using leave-one-out method with 43 TERTw and 69 TERTm to evaluate the diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for the differentiation between TERTw and TERTm were compared between logistic regression analysis and SVM. RESULTS: With multivariate analysis, the percentage of necrosis volume and age were significantly greater in TERTm glioblastoma than in TERTw glioblastoma. SVM allowed discriminating between TERTw glioblastoma and TERTm glioblastoma with sensitivity, specificity, PPV, NPV, and accuracy of 85.7% [60/70; 95% confidence interval (CI): 75.3-92.9%], 54.8% (23/42; 95% CI: 38.7-70.2%), 75.9% (60/79; 95% CI: 69.1-81.7%), 69.7% (23/33; 95% CI: 54.9-81.3%) and 74.1% (83/112; 95% CI: 65.0-81.9%), respectively. CONCLUSION: The percentage of necrosis volume and age may surrogate for predicting TERT mutation status in glioblastoma.

Association between signal hyperintensity on T1-weighted MR imaging of carotid plaques and ipsilateral ischemic events.

BACKGROUND AND PURPOSE: To investigate associations between cerebral ischemic events and signal hyperintensity in T1-weighted MR imaging (T1WI) of carotid plaque according to stenosis severity and to estimate persistence of T1WI signal hyperintensity. METHODS: A total of 222 patients (392 atherosclerotic carotid arteries) underwent plaque imaging using 3D inversion-recovery-based T1WI (magnetization-prepared rapid acquisition with gradient-echo [MPRAGE]). Carotid plaque with intensity on MPRAGE of >200% that of adjacent muscle was categorized as "high signal intensity" and correlated with ipsilateral ischemic events within the previous 6 months. A total of 58 arteries (35 patients) underwent repeat MR imaging a total of 70 times at a median interval of 279 days (range, 10-1037 days). RESULTS: Ipsilateral ischemic events were more frequent in patients with MPRAGE high signals than in patients with low signals in the 0%-29%, 30%-69%, and 70%-99% stenosis groups: Relative risk (95% confidence interval) was 2.50 (0.96-6.51), 7.55 (1.84-31.04), and 1.98 (1.01-3.90), respectively. In the 70 cases of repeat MR imaging, 29 of 30 cases with high signals on the preceding MR imaging maintained high signals. Of the 58 arteries that underwent repeat MR imaging, 4 of 22 carotid arteries with high signals developed ipsilateral subsequent ischemic events within 1 year, whereas none with low signals developed subsequent events. CONCLUSIONS: Carotid plaque signal hyperintensity on T1WI is strongly associated with previous ipsilateral ischemic events, persisting over a period of months, and may indicate risk of subsequent events. Larger clinical trials are warranted to clarify associations between signal hyperintensity and risk of subsequent cerebral ischemic events.

Correlation between E-cadherin expression and invasiveness in vitro in a human esophageal cancer cell line.

E-cadherin, a member of the cadherin family, plays a major role in cell-cell adhesion of normal epithelium. Recent studies have shown that reduction or loss of E-cadherin expression in carcinomas have some relationship with their clinicopathological manifestation including invasion and metastasis. In the present study, we have established cell clones with different E-cadherin expression from human esophageal cancer, TE-2, and examined their adhesive capacity and invasiveness in vitro. Cell clones with positive E-cadherin expression [ECD(+) cells] were round and formed cobblestone colonies, while cell clones negative for E-cadherin [ECD(-) cells] had spindle shapes and formed dispersed colonies. ECD(+) cells showed higher adhesive capacity than ECD(-) cells, in both an aggregation assay with gyratory shaking culture and a dissociation assay of cells passing through the micropore membrane. Monoclonal antibody against human E-cadherin (HECD1) effectively diminished the mutual adhesion of ECD(+) cells but did not affect that of ECD(-) cells. Tumor invasiveness was evaluated with organotypic raft culture which is a coculture system consisting of two layers, a collagen gel layer containing fibroblasts and overlying reconstituted stratified squamous epithelium. ECD(+) cells formed complete stratified epithelium, but ECD(-) cells did not. ECD(+) cells did not invade the collagen/fibroblast gel, but ECD(-) cells did. Furthermore, ECD(+) cells showed invasion when an antibody against E-cadherin was used. Thus, loss or dysfunction of E-cadherin diminishes intercellular adhesion and results in the acquisition of invasive capacity in the cell line we examined.

E-cadherin and alpha-catenin expression in human esophageal cancer.

Intercellular adhesion of the epithelial tissue is mainly regulated by the E-cadherin (E-cad) molecule. alpha-Catenin (alpha-cat) is one of the E-cad-associated cytoplasmic proteins that forms a linkage to the cytoskeleton and regulates E-cad function. To investigate the mechanism of dysfunction in cell-cell adhesion in cancerous tissues, we examined E-cad and alpha-cat expression by immunohistochemical staining on 46 human esophageal cancers using our specific monoclonal antibodies. By grading of E-cad and alpha-cat expression as uniformly positive (+), heterogeneous (+/-), or uniformly negative (-), the 46 tumors could be classified into 9 (20%) E-cad(+)/alpha-cat(+), 15 (33%) E-cad(+/-)/alpha-cat(+/-), 21 (46%) E-cad(+/-)/alpha-cat(-), and 1 (2%) E-cad(-)/alpha-cat(-). Twenty-five (54%) of the 46 tumors showed a similar expression of both molecules, while the other 21 tumors (46%) showed E-cad(+/-)/alpha-cat(-). Thus, although the expression of alpha-cat was significantly correlated with that of E-cad, in some tumors the reduction of alpha-cat was greater. Regarding the clinicopathological features, the reduction of alpha-cat expression, as well as that of E-cad, was significantly associated with tumor dedifferentiation, infiltrative growth, and lymph node metastasis (P < 0.01). Furthermore, the frequency of lymph node metastasis in E-cad(+/-)/alpha-cat(-) tumors was significantly higher (90%) than in E-cad(+)/alpha-cat(+) tumors (22%) (P < 0.01) or in E-cad(+/-)/alpha-cat(+/-) tumors (47%) (P < 0.05). These results suggest that not only E-cad but also alpha-cat are important regulators of intercellular adhesion and that alpha-cat is also involved in invasion and metastasis. In particular, reduction of alpha-cat expression is more correlated with invasive phenotype and lymph node metastasis than E-cad expression in human esophageal cancer.

The influence of glutamate receptor 2 expression on excitotoxicity in Glur2 null mutant mice.

AMPA receptor (AMPAR)-mediated ionic currents that govern gene expression, synaptic strength, and plasticity also can trigger excitotoxicity. However, native AMPARs exhibit heterogeneous pharmacological, biochemical, and ionic permeability characteristics, which are governed partly by receptor subunit composition. Consequently, the mechanisms governing AMPAR-mediated excitotoxicity have been difficult to elucidate. The GluR2 subunit is of particular interest because it influences AMPAR pharmacology, Ca(2+) permeability, and AMPAR interactions with intracellular proteins. In this paper we used mutant mice lacking the AMPAR subunit GluR2 to study AMPAR-mediated excitotoxicity in cultured cortical neurons and in hippocampal neurons in vivo. We examined the hypothesis that in these mice the level of GluR2 expression governs the vulnerability of neurons to excitotoxicity and further examined the ionic mechanisms that are involved. In cortical neuronal cultures AMPAR-mediated neurotoxicity paralleled the magnitude of kainate-evoked AMPAR-mediated currents, which were increased in neurons lacking GluR2. Ca(2+) permeability, although elevated in GluR2-deficient neurons, did not correlate with excitotoxicity. However, toxicity was reduced by removal of extracellular Na(+), the main charge carrier of AMPAR-mediated currents. In vivo, the vulnerability of CA1 hippocampal neurons to stereotactic kainate injections and of CA3 neurons to intraperitoneal kainate administration was independent of GluR2 level. Neurons lacking the GluR2 subunit did not demonstrate compensatory changes in the distribution, expression, or function of AMPARs or of Ca(2+)-buffering proteins. Thus GluR2 level may influence excitotoxicity by effects additional to those on Ca(2+) permeability, such as effects on agonist potency, ionic currents, and synaptic reorganization.

Induction of platelet-derived growth factor beta-receptor in focal ischemia of rat brain.

Our previous study on the ischemia-induced expression of platelet-derived growth factor (PDGF)-B chain in the rat brain prompted us to examine expression of PDGF beta-receptor in the ischemic brain. Focal ischemia was induced by permanent tandem occlusion of middle cerebral and common carotid arteries in spontaneously hypertensive rats. Northern analysis revealed that ischemia significantly increased expression of the receptor in the ischemic neocortex at 4 and 7 days (328 +/- 109%; 323 +/- 119%, respectively, over control: n = 4, p < 0.05 versus sham). Neurons in infarct transiently showed increased immunostaining for the receptor at 1 day, whereas neurons in periinfarct area showed sustained and increased immunoreactivity from 1 to 14 days post-ischemia. Reactive glial cells in the external capsule and in molecular layer of the neocortex adjacent to infarct possessed enhanced immunoreactivity from 1 to 21 days. Furthermore, marked immunoreactivity was observed on brain macrophages in infarct and on the abluminal side of capillaries surrounding infarct from 4 to 7 days. These results demonstrated that ischemic insult increases expression of the PDGF beta-receptor at both the mRNA and protein level in the brain, suggesting its important role in cellular cascade of the ischemic brain.

Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo.

To elucidate the role of the platelet-derived growth factor (PDGF)-B chain in the brain, we examined its expression in rat brains with focal ischemia. Focal ischemia was induced by permanent tandem occlusion of the middle cerebral and common carotid arteries in spontaneously hypertensive rats (SHRs). Northern analysis demonstrated that ischemia transiently increased mRNA expression of the PDGF-B chain, but not the PDGF-A chain, in the injured neocortex. The larger transcript (3.5 kb) of the B chain gradually increased to threefold by 16 h, whereas the smaller transcript (2.6 kb) of the B chain markedly increased sixfold by 4 h. Immunohistochemistry revealed enhanced immunoreactivity in the neurons in the infarct and in the periinfarct area from 16 h to days 4-7, with a peak at 24 h. Furthermore, the brain macrophages that accumulated in the infarct showed intense immunostaining in their perinuclear region from days 2 to 14, with a peak at days 5-6. The present study demonstrates that ischemia induces the expression of the PDGF-B chain, first in neurons and later in brain macrophages, and suggests an important role of the PDGF-B chain in the healing process of the injured brain.

Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats.

Our previous studies demonstrated coordinate expression of platelet-derived growth factor (PDGF) -B chain and beta-receptor in neurons at risk in the rat brain with focal ischemia. To clarify a role of the -B chain in the brain further, we examined whether PDGF-A or -B chain protects CA1 pyramidal neurons from delayed neuronal death after forebrain ischemia in rats. Pretreatment with PDGF-BB, but not -AA, at 120 ng/d for 2 days until forebrain ischemia was performed markedly ameliorated delayed neuronal death in CA1 pyramidal neurons on day 7 after ischemia. This neuroprotective effect of PDGF-BB was dose-dependent, and pretreatment with PDGF-BB at 240 ng/d showed almost complete inhibition of delayed neuronal death. In contrast, posttreatment with PDGF-BB at 120 ng/d starting 20 minutes after ischemia demonstrated no significant neuroprotective effect. The current study established marked neuroprotective actions of PDGF-BB in ischemic neuronal damage.

Relationship between e-cadherin expression and lymph-node metastasis in human esophageal cancer.

Expression of E-cadherin in esophageal carcinoma was studied immunohistochemically in 65 patients using an anti-human E-cadherin monoclonal antibody (HECD-1). In normal esophageal epithelium, E-cadherin was strongly expressed on cell-cell boundaries. On the contrary, a reduced E-cadherin expression (Rd-type) was frequently observed in cancer tissues (56/65, 88%). The frequency of Rd-type was much higher in cases with deeper invasion (48/52, 92%) than that in cases with superficial invasion (8/13, 62%) (p<0.05). Concerning lymph node metastasis, the frequency of Rd-type in the metastatic tumor group (47/49, 96%) was significantly higher than that in the non-metastatic tumor group (9/16, 56%) (p<0.01). These results suggest that E-cadherin might play a key role in the progression of carcinogenesis and that the reduction of E-cadherin expression is associated with malignant potential such as invasion and metastasis in human esophageal cancer.

Expression of platelet-derived growth factor B-chain in the mature rat brain and pituitary gland.

For better understanding of the role of platelet-derived growth factor (PDGF) B-chain in the brain, the expression of PDGF B-chain was studied in the mature rat brain at both protein and mRNA levels, by assay of PDGF B-chain-related mitogenic activity, Northern blot, in situ hybridization and immunohistochemistry. It was shown that (1) mature rat brain contained substantial PDGF B-chain-related mitogenic activity, (2) significant amounts of two sizes of transcripts (3.5 kb, widely, and 2.6 kb, weakly and in narrower areas) were expressed in the brain, and (3) the transcripts were localized in ubiquitous neurons by in situ hybridization, with the strongest signal in hippocampal pyramidal cells, which distribution almost corresponded with that of the immunoreactive products. The abundant neuronal localization of the transcript and protein, as well as the neuronal expression of the receptor reported elsewhere, suggests the role of the growth factor in neuronal cells as a neuronal regulatory and/or trophic agent acting by autocrine loop or by neuron to neuron interaction. However, there was an apparent discrepancy in part, in the distribution between transcripts and immunoreactivity; that is, transcripts were expressed intensely in the intermediate pituitary lobe with only a scattered immunoreactivity, and the opposite situation was observed in the accessory olfactory nerve and posterior pituitary lobe. This might suggest that PDGF B-chain is transported or secreted in these foci.

Increases in levels of brain-derived neurotrophic factor mRNA and its promoters after transient forebrain ischemia in the rat brain.

Expression of brain-derived neurotrophic factor (BDNF) may play a role in the mechanism of neuronal cell death after cerebral ischemia. We investigated the changes in levels of mRNAs encoding BDNF and its promoters in the rat brain after transient forebrain ischemia. Transient forebrain ischemia was induced by occlusion of bilateral common carotid arteries and systemic hypotension for 8 min. The alterations in BDNF gene expression in the hippocampus and in the cerebral cortex were examined by in situ hybridization using a mouse BDNF cDNA probe and cDNA probes including exon-specific promoters. BDNF transcripts were rapidly enhanced after the ischemic insult, both in the hippocampus and the cerebral cortex. NBQX suppressed the enhanced gene expression of BDNF markedly in the dentate gyrus (DG). In contrast, MK-801 had little effect on BDNF expression. In the piriform cortex, MK-801 or NBQX reduced the expression only moderately. After the ischemic insult, promoter specific BDNF 5'-exon I and exon III were increased remarkably in the DG. The increase in exon I in DG was suppressed partially by MK-801 and NBQX, while the increase in exon III in CA3 was suppressed by MK-801 but that in DG was not suppressed by either antagonist. In the piriform cortex, exon III was increased remarkably and this increase was not influenced by either agonist. These results suggest that the gene expression of BDNF was enhanced by transient ischemia both in the hippocampus and the cerebral cortex and that the cerebral ischemia stimulated at least two different promoter- and neuron type-specific pathways regulating expression of the BDNF gene mediated by glutamate receptors of non-NMDA type and NMDA type.

Platelet-derived growth factor B-chain-like immunoreactivity in injured rat brain.

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells and glial cells. For a better understanding of the role of PDGF B-chain in the brain, the expression of PDGF B-chain was examined immunohistochemically in penetrating injury to the rat brain. Shrunken neurons were distributed with enhanced PDGF B-chain-related immunoreactivity (PBRI) in the vicinity of the lesion during a period from day 1 to day 4 post injury. Platelet-derived growth factor B-chain-related immunoreactivity was transiently observed also in the cytoplasm of the numerous brain macrophages in the lesion on day 3 and day 4. These distributions of PBRI in the lesion were closely related to the neovascularization and astrogliosis there. The close time and spatial correlation between the expression of PBRI and cellular responses to injury seen in this study suggests PDGF B-chain has an important role in the healing process of cerebral wound.