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Background: The content and composition of cerebrospinal fluid (CSF) is determined in large part by the choroid plexus (CP) and specifically, a specialized epithelial cell (CPe) layer that responds to, synthesizes, and transports peptide hormones into and out of CSF. Together with ventricular ependymal cells, these CPe relay homeostatic signals throughout the central nervous system (CNS) and regulate CSF hydrodynamics. One new candidate signal is augurin, a newly recognized 14 kDa protein that is encoded by esophageal cancer related gene-4 (Ecrg4), a putative tumor suppressor gene whose presence and function in normal tissues remains unexplored and enigmatic. The aim of this study was to explore whether Ecrg4 and its product augurin, can be implicated in CNS development and the response to CNS injury.Methods: Ecrg4 gene expression in CNS and peripheral tissues was studied by in situ hybridization and quantitative RT-PCR. Augurin, the protein encoded by Ecrg4, was detected by immunoblotting, immunohistochemistry and ELISA. The biological consequence of augurin over-expression was studied in a cortical stab model of rat CNS injury by intra-cerebro-ventricular injection of an adenovirus vector containing the Ecrg4 cDNA. The biological consequences of reduced augurin expression were evaluated by characterizing the CNS phenotype caused by Ecrg4 gene knockdown in developing zebrafish embryos.Results: Gene expression and immunohistochemical analyses revealed that, the CP is a major source of Ecrg4 in the CNS and that Ecrg4 mRNA is predominantly localized to choroid plexus epithelial (CPe), ventricular and central canal cells of the spinal cord. After a stab injury into the brain however, both augurin staining and Ecrg4 gene expression decreased precipitously. If the loss of augurin was circumvented by over-expressing Ecrg4 in vivo, BrdU incorporation by cells in the subependymal zone decreased. Inversely, gene knockdown of Ecrg4 in developing zebrafish embryos caused increased proliferation of GFAP-positive cells and induced a dose-dependent hydrocephalus-like phenotype that could be rescued by co-injection of antisense morpholinos with Ecrg4 mRNA.Conclusion: An unusually elevated expression of the Ecrg4 gene in the CP implies that its product, augurin, plays a role in CP-CSF-CNS function. The results are all consistent with a model whereby an injury-induced decrease in augurin dysinhibits target cells at the ependymal-subependymal interface. We speculate that the ability of CP and ependymal epithelium to alter the progenitor cell response to CNS injury may be mediated, in part by Ecrg4. If so, the canonic control of its promoter by DNA methylation may implicate epigenetic mechanisms in neuroprogenitor fate and function in the CNS. © 2011 Gonzalez et al; licensee BioMed Central Ltd.

Glioblastoma (GB) is a highly heterogeneous type of incurable brain cancer with a low survival rate. Intensive ongoing research has identified several potential targets; however, GB is marred by the activation of multiple pathways, and thus common targets are highly sought. The signal regulatory scaffold IQGAP1 is an oncoprotein implicated in GB. IQGAP1 nucleates a myriad of pathways in a contextual manner and modulates many of the targets altered in GB like MAPK, NF-κB, and mTOR/PI3K/Akt1, thus positioning it as a plausible common therapeutic target. Here, we review the targets that are subjects of GB treatment clinical trials and the commonly used animal models that facilitate target identification. We propose a model in which the dysfunction of various IQGAP1 pathways can explain to a larger extent some of the GB heterogeneity and offer a platform for personalized medicine., (© 2024. The Author(s).)

Background: It is well known that rare cases of Alzheimer's disease (AD) pathology may cause corticobasal or posterior cortical atrophy syndromes, and that cases with advanced AD may develop parkinsonism. However, reports of parkinsonism as an initial manifestation of AD have rarely been documented., Objectives: To demonstrate that a syndrome meeting all criteria for a clinical diagnosis of idiopathic Parkinson's disease (PD) may be an initial and years-long sustained manifestation of pathologically confirmed AD., Methods: Clinico-pathological case., Results: We present a case with a 12-year clinical presentation consistent with a typical course of idiopathic Parkinson's disease, including dementia developing 6 years after the PD diagnosis. The patient improved, but only mildly, to standard treatment for PD motor symptoms. The neuropathological examination identified AD changes, and no evidence to support a concomitant diagnosis of PD., Conclusions: The absence of alpha-synucleinopathy, coupled with the patient's dementia history and AD changes in neuropathological examination, indicated the diagnosis of AD and no supplementary explanation. Neuronal loss with neurofibrillary tangles and amyloid plaques in the brainstem, substantia nigra, and locus coeruleus likely contributed to Parkinsonism features., (© 2024 International Parkinson and Movement Disorder Society.)

Background: Suprasellar masses commonly include craniopharyngiomas and pituitary adenomas. Suprasellar glioblastoma is exceedingly rare with only a few prior case reports in the literature. Suprasellar glioblastoma can mimic craniopharyngioma or other more common suprasellar etiologies preoperatively., Observations: A 65-year-old male with no significant history presented to the emergency department with a subacute decline in mental status. Work-up revealed a large suprasellar mass with extension to the right inferior medial frontal lobe and right lateral ventricle, associated with significant vasogenic edema. The patient underwent an interhemispheric transcallosal approach subtotal resection of the interventricular portion of the mass. Pathological analysis revealed glioblastoma, MGMT partially methylated, with a BRAF V600E mutation., Lessons: Malignant glioblastomas can mimic benign suprasellar masses and should remain on the differential for a diverse set of brain masses with a broad range of radiological and clinical features. For complex cases accessible from the ventricle where the pituitary complex cannot be confidently preserved via a transsphenoidal approach, an interhemispheric approach is also a practical initial surgical option. In addition to providing diagnostic value, molecular profiling may also reveal therapeutically significant gene alterations such as BRAF mutations.

This study investigated the prevalence of embryonic and connective tissue elements in the filum terminale (FT) of patients with tethered cord syndrome (TCS), examining both typical and pathological histology. The FT specimens from 288 patients who underwent spinal cord detethering from 2013 to 2021 were analyzed. The histopathological examination involved routine hematoxylin and eosin staining and specific immunohistochemistry when needed. The patient details were extracted from electronic medical records. The study found that 97.6% of the FT specimens had peripheral nerves, and 70.8% had regular ependymal cell linings. Other findings included ependymal cysts and canals, ganglion cells, neuropil, and prominent vascular features. Notably, 41% showed fatty infiltration, and 7.6% had dystrophic calcification. Inflammatory infiltrates, an underreported finding, were observed in 3.8% of the specimens. The research highlights peripheral nerves and ganglion cells as natural components of the FT, with ependymal cell overgrowth and other tissues potentially linked to TCS. Enlarged vessels may suggest venous congestion due to altered FT mechanics. The presence of lymphocytic infiltrations and calcifications provides new insights into structural changes and mechanical stress in the FT, contributing to our understanding of TCS pathology.

Abstract: Suicide rapidly increased in the United States by 30% from 2000 to 2020, accounting for more than 800,000 deaths ( Neurosci Res Program Bull . 1972; 10: 384-8). Studies have shown that there are a multitude of underlying issues, including mental illness, that elevate an individual's risk of dying by suicide ( CDC WONDER: Underlying cause of death, 1999-2019 . Atlanta, GA: US Department of Health and Human Services, CDC; 2020). Presented here is a case of Bing Neel syndrome (BNS) found in a 69-year-old man who died by suicide by jumping off a 135' bridge. His medical history was significant for traumatic brain injury, Waldenstrom macroglobulinemia (WM), major depressive disorder, suicidal ideation, and anxiety. Bing Neel syndrome is a rare central nervous system complication of WM. His wife reported an abrupt mental deterioration starting 5 years before his death, characterized by paranoia, depression, and insomnia. He had been a high-functioning university professor. His decline culminated with the loss of independence in his activities of daily living. At autopsy, it was found that he experienced blunt force injuries related to the fall, causing his death. A neuropathologic examination revealed a brisk and fulminant clonal CD20 + /immunoglobulin M+ lymphocytic infiltrate, involving all sampled regions of his brain, consistent with WM. This workup was critical to obtaining an accurate pathologic diagnosis of BNS and understanding his full clinical status before death. Although BNS was not the proximate cause of death, this diagnosis aided the death investigation as a causal factor in his suicidality and was vital to providing his family closure., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor., Methods: Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies., Results: An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85-90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53 . Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section., Conclusion: Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different., Competing Interests: Authors DB, MC, and WK were employed by Caris Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mondia, Kritselis, Donahue, Elinzano, Sarangi, Bryant, Capelletti, Korn, Yu, Yan, Toms and Wong.)

Meningioma is the most common intracranial neoplasm, yet there is no effective therapy for recurrent/refractory meningiomas after surgery and radiation. Prostate-specific membrane antigen (PSMA) is an enzyme upregulated on endothelial cells of multiple neoplasms and is being investigated as a theranostic target. Until now, PSMA has not been studied in meningiomas. We aimed to verify PSMA endothelial expression in meningiomas, detect tumor grade variability, and investigate the relationship of PSMA signal with tumor recurrence. We analyzed 96 archival meningiomas including 58 de novo and 38 recurrent specimens. All specimens were stained routinely and immunostained for CD31 and PSMA. Slides were scanned and analyzed producing raw data for images of PSMA, CD31, PSMA/CD31, and PSMA/vasculature. PSMA expression was seen within 98.9% of meningioma samples. In the total cohort, higher-grade tumors had increased expression of raw PSMA and PSMA/CD31, and PSMA/vasculature ratios compared to grade 1 tumors. PSMA expression and PSMA/vasculature ratios (p = 0.0015) were higher in recurrent versus de novo tumors among paired samples. ROC curves demonstrated PSMA/CD31, PSMA/vasculature, and raw CD31 as indicators of tumor recurrence. Thus, PSMA is expressed within endothelial cells of meningiomas, is increased with tumor grade and recurrence, and persists with prior irradiation., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Background: Neural components of the fibrous filum terminale (FT) are well known but are considered as embryonic remnants without functionality., Objective: To investigate the ultrastructure of human FT specimens for sensory nerve endings and record paraspinal muscle activity on electrostimulation of the FT., Methods: We prospectively investigated a cohort of 53 patients who underwent excision of the FT for the treatment of tethered cord syndrome. Surgical FT specimens were investigated by light and transmission electron microscopy. Intraoperative electrophysiological routine monitoring was extended by recording paraspinal muscles above and below the laminotomy level., Results: Light microscopy revealed tiny peripheral nerves piercing the pia mater of the FT and entering its fibrous core. Transmission electron microscopy unveiled within the fibrous core of the FT myelinated nerve structures in 8 of the 53 patients and unmyelinated ones in 10 of the 53 patients. Both nerve endings encapsulated in fibrous tissue or unencapsulated nonmyelinated Schwann cell nerve bundles, that is, Remak cells, were found. Those nerve endings resembled mechanoreceptor and nociceptive receptor structures found in human skin, muscle tendons, and skeletal ligaments. Specifically, we found Ruffini mechanoreceptors and in addition nerve endings which resembled nociceptive glioneural structures of the skin. Bipolar electrostimulation of the FT was associated with paraspinal muscle activity above and below the spinal segment at which the FT was stimulated., Conclusion: Morphological and electrophysiological results indicate the presence of functional sensory nerve endings in the FT. Like other spine ligaments, the FT may serve as a proprioceptive element but may also contribute to back pain in spine disorders., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background: Patients with hypermobile Ehlers-Danlos syndrome (hEDS), a heritable connective tissue disorder, present frequently with symptoms of tethered cord syndrome (TCS) but without a low-lying conus. Currently, surgical treatment of such cases is controversial. Because connective tissue disorder affects fibrous structures, we hypothesized that a diseased filum terminale (FT) might cause TCS in hEDS, justifying surgical transection for treatment., Methods: We investigated FT pathology, FT biomechanics, clinical presentation, and outcome following FT excision in 78 radiologically occult hEDS-TCS cases and for comparison in 38 typical TCS cases with low-lying conus and/or fatty FT infiltration but without hEDS., Results: In hEDS-TCS, electron microscopy revealed inherited collagen fibril abnormalities and acquired fibril damage. Biomechanical tension tests revealed elastic properties of the FT in both study groups, but they were impaired in the hEDS TCS. Follow-up examinations at 3 and 12 months after FT excision showed statistically significant improvement of urinary, bowel, and neurologic symptoms in both study groups; intergroup comparison revealed no differences in outcome except more pronounced neurologic improvement in the hEDS-TCS group., Conclusions: Both morphologic findings and biomechanical tests indicate limited elastic properties of the FT in hEDS, which is no more able to dampen but still transmitting spine movement-related stretch forces. That mechanism exposes the conus medullaris to unphysiologic stretch forces, causing TCS, especially when considering the hypermobile spine in hEDS. This notion is supported by the observed clinical improvement following FT resection in hEDS-TCS cases without a low-lying conus., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mucormycosis can lead to fatal rhinocerebral infection., Case: A 53-year-old male with diabetes presented with altered mental status. He had been recently discharged from an admission for COVID-19 pneumonia treated with remdesivir and methylprednisolone. Imaging demonstrated a large left frontal mass with midline shift suspicious for a primary brain neoplasm. His neurologic exam rapidly declined and the patient was taken to the operating room for decompressive hemicraniectomy. Post-operatively, the patient remained comatose and failed to improve. Autopsy revealed a cerebral mucormycosis infection., Discussion: Despite concern for a primary brain neoplasm the patient was diagnosed postmortem with a mucormycosis infection. Other features supporting this diagnosis included nasal sinusitis on initial scans, his fulminant clinical decline, rapidly progressive imaging findings, and persistent hyperglycemia throughout his clinical course., Conclusion: In an era of high steroid usage to treat COVID-19, mucormycosis infection must be considered in high-risk patients demonstrating disproportionate clinical decline.

The objectives of this study were to describe the anatomy, histology, and ultrastructure of the equine filum terminale (FT) and to describe the FT in hereditary equine regional dermal asthenia (HERDA), a model of human Ehlers-Danlos syndromes (EDS). Those humans suffer from tethered cord syndrome (TCS) caused by an abnormally structured FT wherein its attachment at the base of the vertebral column leads to long-term stretch-induced injury to the spinal cord. The pathophysiology of TCS in EDS is poorly understood, and there is a need for an animal model of the condition. Histopathologic and ultrastructural examinations were performed on FT from HERDA ( n = 4) and control horses ( n = 5) and were compared to FT from human TCS patients with and without EDS. Adipose, fibrous tissue, and neuronal elements were assessed. CD3 and CD20 immunohistochemistry was performed to clarify cell types (HERDA n = 2; control n = 5). Collagen fibrils were assessed in cross-section for fibril diameter and shape, and in longitudinal section for fibril disorganization, swelling, and fragmentation. The equine and human FT were similar, with both containing fibrous tissue, ependyma, neuropil, and nerve twigs. Hypervascularity was observed in both HERDA horses and human EDS-TCS patients and was not observed in equine or human controls. Moderate to severe abnormalities in collagen fibril orientation and architecture were observed in all HERDA horses and were similar to those observed in human EDS-TCS patients.

Objective: The craniocervical junction (CCJ) is anatomically complex and comprises multiple joints that allow for wide head and neck movements. The thecal sac must adjust to such movements. Accordingly, the thecal sac is not rigidly attached to the bony spinal canal but instead tethered by fibrous suspension ligaments, including myodural bridges (MDBs). The authors hypothesized that pathological spinal cord motion is due to the laxity of such suspension bands in patients with connective tissue disorders, e.g., hypermobile Ehlers-Danlos syndrome (EDS)., Methods: The ultrastructure of MDBs that were intraoperatively harvested from patients with Chiari malformation was investigated with transmission electron microscopy, and 8 patients with EDS were compared with 8 patients without EDS. MRI was used to exclude patients with EDS and craniocervical instability (CCI). Real-time ultrasound was used to compare the spinal cord at C1-2 of 20 patients with EDS with those of 18 healthy control participants., Results: The ultrastructural damage of the collagen fibrils of the MDBs was distinct in patients with EDS, indicating a pathological mechanical laxity. In patients with EDS, ultrasound revealed increased cardiac pulsatory motion and irregular displacement of the spinal cord during head movements., Conclusions: Laxity of spinal cord suspension ligaments and the associated spinal cord motion disorder are possible pathogenic factors for chronic neck pain and headache in patients with EDS but without radiologically proven CCI.

Background: Gastrointestinal (GI) symptoms are common in Parkinson disease (PD), often preceding neurological manifestations; however, early diagnostic utility of GI biopsies remains controversial. Studies suggest aberrant deposition of alpha-synuclein (α-syn) follows step-wise progression in central nervous system though histologic interpretation of normal and aberrant staining patterns have shown variable results. This study examines whether GI α-syn mRNA expression combined with standard α-syn immunohistochemical staining enhance the role of GI biopsy in PD., Materials and Methods: Four groups were examined, including pediatric (21) and adult control patients (18), PD clinic patients (17), and pathologically confirmed PD cases from hospital archives (16). Enteric nervous system α-syn staining was evaluated by immunohistochemistry in 33 PD and 39 controls. α-Syn mRNA levels were compared between patient groups using quantitative polymerase chain reaction and stomach and colon levels in PD., Results: PD patients had Lewy bodies (LB) and diffuse neuronal α-syn staining. GI tissues from elderly controls, children, and young adults exhibited diffuse positivity. LB were limited to PD. Myenteric plexus immunoreactivity varied in different regions. Widespread staining was noted within stomach and colon. Immunoreactivity was present within esophagus, appendix, and small bowel. α-Syn mRNA expression was highest in PD; however, levels varied between proximal and distal GI tract., Conclusions: α-Syn is normally present within young and elderly enteric nervous system; furthermore, while α-syn mRNA is always detectable, levels are highest and most variable in PD. This suggests that enteric α-syn may be altered in neurodegenerative disease. The presence of LB in the GI tract, not solely α-syn expression, may prove useful, distinguishing neurodegenerative disease patients from normal controls.

Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems occurring in the perinatal period. Hypothermia is the only approved intervention for neonatal HI encephalopathy. However, this treatment is only partially protective, has a narrow therapeutic time window after birth and only can be used to treat full-term infants. Consequently, additional therapies are critically needed. Inflammation is an important contributing factor to the evolution of HI brain injury in neonates. Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins with anti-inflammatory properties. We have previously shown that IAIPs reduce neuronal cell death and improve behavioral outcomes when given after carotid artery ligation, but before hypoxia in male neonatal rats. The objective of the current study was to investigate the neuroprotective effects of treatment with IAIPs given immediately or 6 h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After ligation of the right common carotid artery, P7 rats were exposed to 90 min of hypoxia (8% oxygen). Human plasma-derived IAIPs or placebo (phosphate buffered saline) was given at zero, 24, and 48 h after HI. Brains were perfused, weighed and fixed 72 h after HI at P10. In a second, delayed treatment group, the same procedure was followed except that IAIPs or placebo were given at 6, 24 and 48 h after HI. Separate sham-operated, placebo-treated groups were exposed to identical protocols but were not exposed to carotid artery ligation and remained in room air. Rat sex was recorded. The effects of IAIPs on HI brain injury were examined using histopathological scoring and immunohistochemical analyses of the brain and by using infarct volume measurements on frozen tissue of the entire brain hemispheres ipsilateral and contralateral to HI injury. IAIPs given immediately after HI improved (P < 0.050) histopathological brain injury across and within the cingulate, caudate/putamen, thalamus, hippocampus and parietal cortex in males, but not in females. In contrast, IAIPs given immediately after HI reduced (P < 0.050) infarct volumes of the hemispheres ipsilateral to HI injury in similarly both the males and females. Treatment with IAIPs also resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI group, reduced (P < 0.050) neuronal and non-neuronal cell death in the cortex and total hemisphere, and also increased the total area of oligodendrocytes determined by CNPase in the ipsilateral hemisphere and corpus callosum (P < 0.050) of male, but not female subjects exposed to HI. Delayed treatment with IAIPs 6 h after HI did not improve histopathological brain injury in males or females, but resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI males. Therefore, treatment with IAIPs immediately after HI improved brain weights and reduced neuropathological brain injury and cell death in male rats, and reduced infarct volume in both male and female neonatal rats. We conclude that IAIPs exert neuroprotective effects after exposure to HI in neonatal rats and may exhibit some sex-related differential effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Perineural cysts are a benign spine pathology but, when they become symptomatic and require surgical treatment, represent a significant challenge to the spine surgeon. Here we describe our experience with a novel endoscopic approach to the biopsy, drainage, resection of the cyst wall, and direct cyst fenestration to the subarachnoid space., Methods: A transforaminal endoscopic approach to a large lumbar 2-3 perineural cyst is presented here in a 25-year-old patient. A step-by-step technique for the biopsy, drainage, and resection of the cyst wall is presented., Results: The patient underwent cyst resection and fenestration into the subarachnoid space without complication, with immediate relief of his preoperative symptoms and after 1 year remains symptom-free., Conclusions: Surgical treatment of perineural cysts in the spine represent a significant challenge to the surgeon, principally due to the risk of spinal fluid leak in the postoperative period. Transforaminal endoscopic surgical access to this disease pathology is a novel minimally invasive surgical approach presented here that allows diagnosis and treatment of a perineural cyst and can be performed in an awake patient., (Copyright © 2019. Published by Elsevier Inc.)

Primitive round- or spindle-cell EWSR1-negative undifferentiated sarcomas harboring CIC-DUX4 gene fusion are the most common form of Ewing-like sarcomas. These tumors primarily occur in peripheral soft tissues, but examples have been described within viscera and the brain. As far as we are aware, CIC-DUX4 positive primary epidural spinal sarcoma has not been reported. Herein, we describe a T5-T6 epidural tumor in a 15-year-old girl in which many neoplastic cells had moderate and focally abundant cytoplasm, including plasmacytoid or rhabdoid cells, rather than the more common Ewing-like morphology described in the majority of such tumors. The diagnosis was confirmed by fluorescent in situ hybridization after the tumor was found to be WT-1 positive, and comprehensive genomic profiling demonstrated breakpoints in exon 20 and exon 1 of the CIC and DUX4 genes, respectively. After treatment with local radiation and systemic chemotherapy, resected recurrent tumor demonstrated more pleomorphic neoplastic cells as well as intracytoplasmic eosinophilic globules and nuclear pseudoinclusions which may reflect therapy-related changes. Unfortunately, there was further progression of tumor including the development of intracranial lesions, and the patient succumbed to her tumor 22 months after the original resection.

Background: In Alzheimer's disease, there are striking changes in CSF composition that relate to altered choroid plexus (CP) function. Studying CP tissue gene expression at the blood-cerebrospinal fluid barrier could provide further insight into the epithelial and stromal responses to neurodegenerative disease states., Methods: Transcriptome-wide Affymetrix microarrays were used to determine disease-related changes in gene expression in human CP. RNA from post-mortem samples of the entire lateral ventricular choroid plexus was extracted from 6 healthy controls (Ctrl), 7 patients with advanced (Braak and Braak stage III-VI) Alzheimer's disease (AD), 4 with frontotemporal dementia (FTD) and 3 with Huntington's disease (HuD). Statistics and agglomerative clustering were accomplished with MathWorks, MatLab; and gene set annotations by comparing input sets to GeneGo ( http://www.genego.com ) and Ingenuity ( http://www.ingenuity.com ) pathway sets. Bonferroni-corrected hypergeometric p-values of < 0.1 were considered a significant overlap between sets., Results: Pronounced differences in gene expression occurred in CP of advanced AD patients vs. Ctrls. Metabolic and immune-related pathways including acute phase response, cytokine, cell adhesion, interferons, and JAK-STAT as well as mTOR were significantly enriched among the genes upregulated. Methionine degradation, claudin-5 and protein translation genes were downregulated. Many gene expression changes in AD patients were observed in FTD and HuD (e.g., claudin-5, tight junction downregulation), but there were significant differences between the disease groups. In AD and HuD (but not FTD), several neuroimmune-modulating interferons were significantly enriched (e.g., in AD: IFI-TM1, IFN-AR1, IFN-AR2, and IFN-GR2). AD-associated expression changes, but not those in HuD and FTD, were enriched for upregulation of VEGF signaling and immune response proteins, e.g., interleukins. HuD and FTD patients distinctively displayed upregulated cadherin-mediated adhesion., Conclusions: Our transcript data for human CP tissue provides genomic and mechanistic insight for differential expression in AD vs. FTD vs. HuD for stromal as well as epithelial components. These choroidal transcriptome characterizations elucidate immune activation, tissue functional resiliency, and CSF metabolic homeostasis. The BCSFB undergoes harmful, but also important functional and adaptive changes in neurodegenerative diseases; accordingly, the enriched JAK-STAT and mTOR pathways, respectively, likely help the CP in adaptive transcription and epithelial repair and/or replacement when harmed by neurodegeneration pathophysiology. We anticipate that these precise CP translational data will facilitate pharmacologic/transgenic therapies to alleviate dementia.

Purpose: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation., Materials and Methods: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS)., Results: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation., Conclusions: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

Perinatal hypoxic-ischemic reperfusion (I/R)-related brain injury is a leading cause of neurologic morbidity and life-long disability in children. Infants exposed to I/R brain injury develop long-term cognitive and behavioral deficits, placing a large burden on parents and society. Therapeutic strategies are currently not available for infants with I/R brain damage, except for hypothermia, which can only be used in full term infants with hypoxic-ischemic encephalopathy (HIE). Moreover, hypothermia is only partially protective. Pro-inflammatory cytokines are key contributors to the pathogenesis of perinatal I/R brain injury. Interleukin-1β (IL-1β) is a critical pro-inflammatory cytokine, which has been shown to predict the severity of HIE in infants. We have previously shown that systemic infusions of mouse anti-ovine IL-1β monoclonal antibody (mAb) into fetal sheep resulted in anti-IL-1β mAb penetration into brain, reduced I/R-related increases in IL-1β expression and blood-brain barrier (BBB) dysfunction in fetal brain. The purpose of the current study was to examine the effects of systemic infusions of anti-IL-1β mAb on short-term I/R-related parenchymal brain injury in the fetus by examining: 1) histopathological changes, 2) apoptosis and caspase-3 activity, 3) neuronal degeneration 4) reactive gliosis and 5) myelin basic protein (MBP) immunohistochemical staining. The study groups included non-ischemic controls, placebo-treated ischemic, and anti-IL-1β mAb treated ischemic fetal sheep at 127days of gestation. The systemic intravenous infusions of anti-IL-1β mAb were administered at fifteen minutes and four hours after in utero brain ischemia. The duration of each infusion was two hours. Parenchymal brain injury was evaluated by determining pathological injury scores, ApopTag® positive cells/mm 2 , caspase-3 activity, Fluoro-Jade B positive cells/mm 2 , glial fibrillary acidic protein (GFAP) and MBP staining in the brains of fetal sheep 24h after 30min of ischemia. Treatment with anti-IL-1β mAb reduced (P<0.05) the global pathological injury scores, number of apoptotic positive cells/mm 2 , and caspase-3 activity after ischemia in fetal sheep. The regional pathological scores and Fluoro-Jade B positive cells/mm 2 did not differ between the placebo- and anti-IL-1β mAb treated ischemic fetal sheep. The percent of the cortical area stained for GFAP was lower (P<0.05) in the placebo ischemic treated than in the non-ischemic group, but did not differ between the placebo- and anti-IL-1β mAb treated ischemic groups. MBP immunohistochemical expression did not differ among the groups. In conclusion, infusions of anti-IL-1β mAb attenuate short-term I/R-related histopathological tissue injury, apoptosis, and reduce I/R-related increases in caspase-3 activity in ovine fetal brain. Therefore, systemic infusions of anti-IL-1β mAb attenuate short-term I/R-related parenchymal brain injury in the fetus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: CNS toxoplasmosis and lymphoma are often indistinguishable by conventional contrast-enhanced MRI. There is limited literature on the diagnostic efficacy of dynamic susceptibility contrast (DSC) MRI for differentiating these entities. This study assesses the clinical utility of relative cerebral blood volume (rCBV) for making a diagnosis and determines rCBV thresholds for differentiation using contemporary DSC-MRI., Patients and Methods: Thirteen patients with 25 lesions (13 toxoplasmosis and 12 lymphoma) and pre-treatment DSC-MRI were identified retrospectively. Volumetric regions of interest of segmented enhancement were used to extract mean rCBV normalized to normal-appearing white matter for each lesion. We compared average mean rCBV between all toxoplasmosis and lymphoma lesions using a general mixed model. Three models were also compared for evaluating rCBV-based disease status in each patient: 1) mean rCBV of each lesion using a generalized estimating equation, 2) volume-weighted mean rCBV, and 3) maximum mean rCBV of all lesions using logistic regression., Results: The average mean rCBV for all toxoplasmosis lesions was 0.98 (95% CI 0.55-1.41) compared to 2.07 (95% CI 1.71-2.43) for all lymphoma lesions, a significant difference (1.09, 95% CI 0.53-1.65, p=0.0013). For the three models used to evaluate rCBV-based disease status in each patient, a significant relationship was observed, with an optimal rCBV threshold of approximately 1.5 for distinguishing lymphoma from toxoplasmosis in each model., Conclusion: RCBV derived from contemporary DSC-MRI is helpful for distinguishing between cerebral toxoplasmosis and cerebral lymphoma on an individual patient basis and may facilitate more timely initiation of appropriate directed therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Expression of the orphan C2orf40 gene is associated with the aggregation of the neurofibrillary tangle-protein tau in transgenic mice, tumor suppression, the induction of senescence in CNS, and the activation of microglia and peripheral mononuclear leukocytes. This gene also encodes several secreted pro- and anti-inflammatory neuropeptide-like cytokines, suggesting they might be implicated in the inflammatory component(s) of Alzheimer's disease (AD). Accordingly, we evaluated human AD and control brains for expression changes by RT-qPCR, Western blot, and histological changes by immunolabeling. RT-qPCR demonstrated increased cortical gene expression in AD. The molecular form of Ecrg4 detected in cortex was 8-10 kDa, which was shown previously to interact with the innate immunity receptor complex. Immunocytochemical studies showed intensely stained microglia and intravascular blood-borne monocytes within cerebral cortical white matter of AD patients. Staining was diminished within cortical neurons, except for prominent staining in neurofibrillary tangles. Choroid plexuses showed a decreasing trend. These findings support our hypothesis that c2orf40 participates in the neuroimmune response in AD.

Central nervous system (CNS) tumors are a heterogeneous group of neoplasms divided into two broad categories, glial and non-glial. Non-glial tumors are derived from such diverse structures as the pineal gland, meninges, germ cells, and hematopoietic cells, as well as metastases. Primary glial neoplasms, or those which originate from astrocytes, oligodendrocytes, or ependymal cells, include astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas. Each entity has a unique morphology and pattern of biologic behavior which portends a distinct prognosis and outcome. Individual outcomes show some variability based on tumor location and age of symptom onset; however, the underlying aggressiveness of the tumor often dictates the time course of the disease. With the advent and widespread use of fluorescent in-situ hybridization and polymerase chain reaction (PCR) techniques, molecular phenotyping of brain tumors has become mainstream and is now an integral part of patient care. The molecular genetics of CNS tumors is a rapidly growing field, and the volume of discoveries is growing at an ever increasing rate, compelling the need for updates in this exciting area of science.

The inhibin/activin family of proteins is known to have a broad distribution of synthesis and expression in many species, as well as a variety of functions in reproductive and other physiological systems. Yet, our knowledge regarding the production and function of inhibin and activin in the central nervous system is relatively limited, especially in humans. The present study aimed to explore the distribution of inhibin/activin protein subunits and receptors in the adult human brain. The human hypothalamus and surrounding basal forebrain was examined using post-mortem tissues from 29 adults. Immunocytochemical studies were conducted with antibodies directed against the inhibin/activin α, βA, and βB subunits, betaglycan and the activin type IIA and IIB receptors. An immunoassay was also utilised to measure dimeric inhibin A and B levels in tissue homogenates of the infundibulum of the hypothalamus. Robust βA subunit immunoreactivity was present in the paraventricular, supraoptic, lateral hypothalamic, infundibular, dorsomedial and suprachiasmatic nuclei of the hypothalamus, in the basal ganglia, and in the nucleus basalis of Meynert. A similar staining distribution was noted for the βB subunit, betaglycan and the type II receptor antibodies, whereas α subunit staining was not detected in any of the major anatomical regions of the human brain. Inhibin B immunoreactivity was present in all tissues, whereas inhibin A levels were below detectable limits. These studies show for the first time that the inhibin/activin protein subunits and receptors can be co-localised in the human brain, implicating potential, diverse neural functions., (© 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.)

By virtue of its ability to regulate the composition of cerebrospinal fluid (CSF), the choroid plexus (CP) is ideally suited to instigate a rapid response to traumatic brain injury (TBI) by producing growth regulatory proteins. For example, Esophageal Cancer Related Gene-4 (Ecrg4) is a tumor suppressor gene that encodes a hormone-like peptide called augurin that is present in large concentrations in CP epithelia (CPe). Because augurin is thought to regulate senescence, neuroprogenitor cell growth and differentiation in the CNS, we evaluated the kinetics of Ecrg4 expression and augurin immunoreactivity in CPe after CNS injury. Adult rats were injured with a penetrating cortical lesion and alterations in augurin immunoreactivity were examined by immunohistochemistry. Ecrg4 gene expression was characterized by in situ hybridization. Cell surface augurin was identified histologically by confocal microscopy and biochemically by sub-cellular fractionation. Both Ecrg4 gene expression and augurin protein levels were decreased 24-72 hrs post-injury but restored to uninjured levels by day 7 post-injury. Protein staining in the supraoptic nucleus of the hypothalamus, used as a control brain region, did not show a decrease of auguin immunoreactivity. Ecrg4 gene expression localized to CPe cells, and augurin protein to the CPe ventricular face. Extracellular cell surface tethering of 14 kDa augurin was confirmed by cell surface fractionation of primary human CPe cells in vitro while a 6-8 kDa fragment of augurin was detected in conditioned media, indicating release from the cell surface by proteolytic processing. In rat CSF however, 14 kDa augurin was detected. We hypothesize the initial release and proteolytic processing of augurin participates in the activation phase of injury while sustained Ecrg4 down-regulation is dysinhibitory during the proliferative phase. Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation.

Reduced clearance of amyloid β peptides (Aβ) across the blood-brain barrier contributes to amyloid accumulation in Alzheimer disease. Amyloid β efflux transport is via the endothelial low-density lipoprotein receptor-related protein 1 (LRP-1) and P-glycoprotein (P-gp), whereas Aβ influx transport is via the receptor for advanced glycation end products. Because age is the major risk factor for developing Alzheimer disease, we measured LRP-1 and P-gp expression and associated transporter expression with Aβ accumulation in aging rats. Quantitative LRP-1 and P-gp microvessel expression was measured by immunohistochemistry (IHC); LRP-1 and P-gp expression were assessed in microvessel isolates by Western blotting. There was an age-dependent loss of capillary LRP-1 across all ages (3-36 months) by IHC (linear trend p = 0.0004) and between 3 and 20 months by Western blotting (linear trend p < 0.0001). There was a late (30-36 months) P-gp expression loss by IHC (p < 0.05) and Western blotting (p = 0.0112). Loss of LRP-1 correlated with Aβ42 accumulation (p = 0.0121) and very nearly with Aβ40 (p = 0.0599) across all ages. Expression of LRP-1 correlated negatively with the expression of receptor for advanced glycation end products (p < 0.0004). These data indicate that alterations in LRP-1 and P-gp expression seem to contribute progressively to Aβ accumulation in aging.

Objective: The purpose of this study was to determine whether the preoperative MRI findings of enhanced diffusivity, macrocyst content, and internal hemorrhage in pituitary macroadenomas are predictive of successful transsphenoidal hypophysectomy., Materials and Methods: We retrospectively reviewed the preoperative and postoperative sella protocol MR images of 28 patients who underwent transsphenoidal hypophysectomy for chiasm-compressing macroadenoma. Chiasmatic decompression defined surgical success. Two neuroradiologists differentiated nonsolid (macrocystic and macrohemorrhagic) from solid tumors, computed apparent diffusion coefficient (ADC) and T2-weighted signal intensity normalized to pons in solid tumors, and measured change in tumor height. A neuropathologist graded reticulin content in tumor specimens. Categorical and dichotomous variables were examined with the chi-square or Fisher's exact test; continuous-scale data were analyzed with the Student's t test, analysis of variance, or linear regression., Results: Transsphenoidal hypophysectomy succeeded in the management of 10 of 11 nonsolid tumors and nine of 17 solid tumors (p = 0.049). The ratios of tumor to brainstem ADC in the nine successfully resected solid tumors were higher than in the eight cases of failed treatment (p = 0.008) with no significant difference in ratio of tumor to brainstem T2-weighted signal intensity (p = 0.76). All six solid tumors with enhanced diffusivity (ratio of tumor to brainstem ADC > 1.1) were successfully managed with transsphenoidal hypophysectomy, compared with three of 11 with an ADC ratio less than 1.1 (p = 0.009). There was a significant main effect of ADC ratio groupings on change in tumor height (p = 0.02), and a linear relation was found between ADC ratio and change in tumor height (p = 0.04). Taken together, tumors with nonsolid features or an ADC ratio greater than 1.1 were highly resectable (p < 0.001; sensitivity, 0.84; specificity, 0.89). ADC ratios in reticulin-poor solid tumors were higher than those in reticulin-rich tumors (p = 0.024)., Conclusion: Macrocystic and macrohemorrhagic adenomas and solid tumors with enhanced diffusivity are more likely to be successfully managed with transsphenoidal hypophysectomy. Transsphenoidal hypophysectomy of solid, enhancing tumors with restricted diffusion is more likely to fail, possibly because of the greater reticulin content of the tumor; initial transcranial surgery may be appropriate in these cases.

A unique form of chronic, active, granulomatous herpes simplex type 2 encephalitis is described in an asymptomatic, immunocompetent 8-year-old girl who acquired the virus as a neonate. The extensive, bilateral cerebral parenchymal involvement was discovered incidentally. Diagnosis was confirmed by a combination of serial neuroimaging, brain biopsy, and quantitative polymerase chain reaction targeted to DNA sequences in the glycoprotein G gene, allowing differentiation between herpes simplex virus types 1 and 2. The clinical course over a 5-year period, treatment with intermittent intravenous steroids, and daily valacyclovir, diagnostic imaging, and laboratory studies are reviewed in detail. This form of herpes simplex virus type 2 encephalitis hasn't been described previously and is significant because of its prolonged indolent course, absence of neurological findings or suggestive history, and benign behavior in this child, who is now 14 years old. The authors believe this entity can be unsuspected and underdiagnosed in the general pediatric population, especially in those with a prior maternal history of herpes simplex virus type 2 infection.

The frequent co-occurrence of Alzheimer's disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-beta peptide (Abeta) in CSF in preclinical and early AD. CSF biomarker data (Abeta, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Abeta in APOE epsilon4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Abeta in epsilon4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Abeta in preclinical AD. The basis for the apparent effect of APOE epsilon4 genotype on the relationship of ventricular volume to Abeta and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease.

Aging is the most important single risk factor for developing Alzheimer disease. We measured amyloid-beta peptide (Abeta) levels in rat cerebral cortex and hippocampus during normal aging of Brown-Norway/Fischer rats. Amyloid-beta accumulation was associated with expression of the Abeta influx transporter, the receptor for advanced glycation end-products (RAGEs) at the blood-brain barrier. Rats at selected ages from 3 to 36 months were analyzed by 1) immunohistochemistry for amyloid deposition and quantitative microvessel surface area RAGE expression, 2) ELISA for cortical Abeta40 and Abeta42 concentrations, and 3) Western blotting of microvessel proteins for RAGE expression. Immunohistochemistry showed increasing accumulation of brain Abeta with aging. By ELISA analysis, both Abeta40 and Abeta42 concentrations in cortical homogenates rose sharply from 9 to 12 months. The Abeta42 continued to rise up to age 30 months, whereas Abeta40 stabilized after 12 months. The expression of RAGE initially decreased between 3 and 12 months but then increased between 12 and 34 months by immunohistochemistry. On immunoblotting, RAGE decreased up to 9 months and then progressively increased up to 36 months. These data indicate an association between amyloid and microvessel RAGE during aging. An increase in capillary RAGE expression seems to play a role in the later Abeta accumulation but not in the initial increase.

Converging evidence suggests a possible link between thyroid state and Alzheimer's disease (AD), including a higher probability of dementia in individuals with higher TSH levels and a two-fold risk of AD in patients with hypothyroidism. Thyroid hormones modulate factors associated with AD, including amyloid precursor protein expression in the brain, suggesting a possible role for thyroid hormone in AD pathology. The present study is the first to directly evaluate brain thyroid hormone levels in AD. Triiodothyronine (T(3)) and thyroxine (T(4)) levels were measured with radioimmunoassay (RIA) in post-mortem samples of prefrontal cortex of patients with pathologically confirmed AD, including Braak stage I-II (n=8), Braak stage V-VI (n=8), and controls without any primary neurological disease (n=8). T(4) levels did not differ between groups. T(3) levels were significantly lower in Braak stage V-VI brains relative to controls, but there was no statistically significant difference between T(3) levels in Braak stage I-II versus controls. Results suggest that the conversion of T(4) to T(3) may be affected in advanced AD, perhaps due to alterations in deiodinase activity. Reduced conversion of T(4) to T(3) in AD may be associated with both AD pathology and the clinical presentation of dementia.

Microvascular accumulation and neuronal overproduction of amyloid-beta peptide (Abeta) are pathologic features of Alzheimer's disease (AD). In this study, we examined the receptor for advanced glycation endproducts (RAGE), a multi-ligand receptor found in both neurons and cerebral microvascular endothelia that binds Abeta. RAGE expression was assessed in aged controls (n = 6), patients with early AD-like pathology (n = 6), and severe, Braak V-VI AD (n = 6). Human hippocampi were stained with a specific polyclonal antibody directed against RAGE (Research Diagnostics, Flanders, NJ). Immunoreactivity was localized in both neurons and cerebral endothelial cells. Quantitative image-analyses were performed on grayscale images to assess the total surface area of endothelial RAGE immunoreaction product in cross sections of cerebral microvessels (5-20 microm). Confocal images were acquired for confirmation of RAGE immunoreactivity in both microvessels and neurons by coupling RAGE with CD-31 and neurofilament, respectively. A significant increase in endothelial RAGE immunoreactivity was found in severe Braak V-VI AD patients when compared to aged controls (p < 0.001), and when compared to patients with early AD pathology (p = 0.0125). In addition, a significant increase in endothelial RAGE immunoreactivity was witnessed when comparing aged controls having no reported AD pathology with patients having early AD-like pathology (p = 0.038). Our data suggest that microvascular RAGE levels increase in conjunction with the onset of AD, and continue to increase linearly as a function of AD pathologic severity (p < 0.0001).

There is increasing evidence for blood-brain barrier (BBB) compromise in Alzheimer disease (AD). The presence of the epsilon4 allele of the apolipoprotein E (apoE) gene is a risk factor for sporadic AD. Apolipoprotein E is essential both for maintenance of BBB integrity and for the deposition of fibrillar amyloid-beta (Abeta) that leads to the development of Abeta plaques in AD and to cerebral amyloid angiopathy. This review investigates the relationships between apoE, Abeta, and the BBB in AD. Alterations in the expression and distribution of the BBB Abeta transporters receptor for advanced glycation end-products and low-density lipoprotein receptor-related protein 1 in AD and the potential roles of apoE4 expression in adversely influencing Abeta burden and BBB permeability are also examined. Because both apoE and Abeta are ligands for low-density lipoprotein receptor-related protein 1, all 3 molecules are present in AD plaques, and most AD plaques are located close to the cerebral microvasculature. The interactions of these molecules at the BBB likely influence metabolism and clearance of Abeta and contribute to AD pathogenesis. Therapeutic alternatives targeting apoE/Abeta and sealing a compromised BBB are under development for the treatment of AD.

The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.

Background: Neurofibromatosis Type 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized by neoplasms involving the nervous system which typically present in children. The development of intracranial tumors in adults with NF1 is uncommon and to our knowledge, siblings with adult onset gliomas have not been previously reported., Objective: To perform pathological, clinical and genetic analysis of an unusual family with NF1 and adult onset intracranial gliomas., Results: A 39-year-old woman presented with seizures and aphasia and was diagnosed with an intracerebral tumor. Although there was no family history, she met the accepted clinical criteria for NF1. A biopsy was performed and pathological examination revealed an anaplastic pleomorphic xanthoastrocytoma (PXA). In spite of therapy, she died from complications of tumor recurrence. Her 32-year-old sister developed headaches and was diagnosed with a glioma. Although she did not meet the accepted clinical criteria for NF1, given that she has a sibling with NF1 and a malignancy observed in this disorder, we hypothesize that she also has NF1. Our genetic analysis indicated a shared haplotype in these siblings who developed brain tumors but not in an unaffected sister suggesting that both carry the NF1 disease-producing allele. This haplotype was inherited from their unaffected father indicating a paternal origin of the spontaneous putative mutation in the NF1 gene in this family., Conclusion: NF1 should be a diagnostic consideration when siblings develop intracranial brain tumors even when they develop in adults. Our study supports and extends other reports that broaden the clinical and pathological spectrum of manifestations that can occur in NF1 to include not only adult-onset gliomas but uncommon histological subtypes such as PXA.