Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AßO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors.

OBJECTIVE: Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown. METHODS: To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies. RESULTS: A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124 was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors AMPA2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors, and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes. INTERPRETATION: We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.

Cortical remyelination: a new target for repair therapies in multiple sclerosis.

OBJECTIVE: Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter. METHODS: Postmortem brain tissue from 22 patients with MS (age 27-77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination. RESULTS: New oligodendrocytes that were actively forming myelin sheaths were identified in 30 of 42 remyelinated subpial cortical lesions, including lesions from 3 patients in their 70s. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes, and fewer reactive astrocytes. Astrocytes in the white matter, but not in cortical portions of these lesions, significantly upregulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination. INTERPRETATION: Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.

Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients.

OBJECTIVE: Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. Although the clinical impact of gray matter pathology in MS brains is unknown, 30 to 40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients. METHODS: To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains. RESULTS: Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis, and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains. INTERPRETATION: Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.

Beta4 tubulin identifies a primitive cell source for oligodendrocytes in the mammalian brain.

We have identified a novel population of cells in the subventricular zone (SVZ) of the mammalian brain that expresses beta4 tubulin (betaT4) and has properties of primitive neuroectodermal cells. betaT4 cells are scattered throughout the SVZ of the lateral ventricles in adult human brain and are significantly increased in the SVZs bordering demyelinated white matter in multiple sclerosis brains. In human fetal brain, betaT4 cell densities peak during the latter stages of gliogenesis, which occurs in the SVZ of the lateral ventricles. betaT4 cells represent <2% of the cells present in neurospheres generated from postnatal rat brain but >95% of cells in neurospheres treated with the anti-mitotic agent Ara C. betaT4 cells produce oligodendrocytes, neurons, and astrocytes in vitro. We compared the myelinating potential of betaT4-positive cells with A2B5-positive oligodendrocyte progenitor cells after transplantation (25,000 cells) into postnatal day 3 (P3) myelin-deficient rat brains. At P20, the progeny of betaT4 cells myelinated up to 4 mm of the external capsule, which significantly exceeded that of transplanted A2B5-positive progenitor cells. Such extensive and rapid mature CNS cell generation by a relatively small number of transplanted cells provides in vivo support for the therapeutic potential of betaT4 cells. We propose that betaT4 cells are an endogenous cell source that can be recruited to promote neural repair in the adult telencephalon.

Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development).

PURPOSE: Malformations of cortical development (MCD) (cortical dysplasias) are well-recognized causes of intractable epilepsy. Although a histologic classification system for MCD has been proposed by Palmini et al. (Neurology; 2004; 62:S2), studies to date have not assessed reproducibility. The purpose of this study was to analyze inter- and intraobserver agreement among eight experienced neuropathologists (NPs) with respect to this classification system. METHODS: Sections from 26 epilepsy resections were selected to represent the range of pathologies described by Palmini et al. Recuts of single sections from each case were sent to the NPs to classify. The slides were resent at a later date for reclassification. Kappa analysis for both inter- and intraobserver concordance was performed. RESULTS: Interobserver agreement was moderate (kappa = 0.4968). There was > or =62.5% (5 of 8 NPs) agreement for 19 of 26 cases. The greatest concordance was present when making focal cortical dysplasia (FCD) types IIA/B classifications (12 of the 14 cases with > or =75% consensus). Mild MCD (types I/II) and FCD types IA/B classifications were the least reproducible, and used most frequently in cases without consensus. Intraobserver concordance was moderate to very good (range kappa = 0.4654-0.8504). The category with the fewest classification changes made on reevaluation was FCD type IIB (4.2%), whereas that with the most changes was mild MCD (types I/II) (52.9%). DISCUSSION: Interobserver concordance using this approach was moderate. The classification categories with the greatest concordance were FCD type IIA/B, and the least, mild MCD and FCD types IA/B. In addition, difficulty in differentiating Mild MCD/FCD type I lesions from normal and/or gliotic tissue was noted.

Neurogenesis in the chronic lesions of multiple sclerosis.

Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.

Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study.

BACKGROUND: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination. METHODS: Brains and spinal cords were removed at autopsy from patients, who had died with multiple sclerosis, at the Cleveland Clinic in Cleveland, OH, USA. Visual examination of centimetre-thick slices of cerebral hemispheres was done to identify brains without areas of cerebral white-matter discoloration that were indicative of demyelinated lesions (referred to as myelocortical multiple sclerosis) and brains that had cerebral white-matter discolorations or demyelinated lesions (referred to as typical multiple sclerosis). These individuals with myelocortical multiple sclerosis were matched by age, sex, MRI protocol, multiple sclerosis disease subtype, disease duration, and Expanded Disability Status Scale, with individuals with typical multiple sclerosis. Demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex from individuals classed as having myelocortical and typical multiple sclerosis were compared using myelin protein immunocytochemistry. Neuronal densities in cortical layers III, V, and VI from five cortical regions not directly connected to spinal cord (cingulate gyrus and inferior frontal cortex, superior temporal cortex, and superior insular cortex and inferior insular cortex) were also compared between the two groups and with aged-matched post-mortem brains from individuals without evidence of neurological disease. FINDINGS: Brains and spinal cords were collected from 100 deceased patients between May, 1998, and November, 2012, and this retrospective study was done between Sept 6, 2011, and Feb 2, 2018. 12 individuals were identified as having myelocortical multiple sclerosis and were compared with 12 individuals identified as having typical multiple sclerosis. Demyelinated lesions were detected in spinal cord and cerebral cortex, but not in cerebral white matter, of people with myelocortical multiple sclerosis. Cortical demyelinated lesion area was similar between myelocortical and typical multiple sclerosis (median 4·45% [IQR 2·54-10·81] in myelocortical vs 9·74% [1·35-19·50] in typical multiple sclerosis; p=0·5512). Spinal cord demyelinated area was significantly greater in typical than in myelocortical multiple sclerosis (median 3·81% [IQR 1·72-7·42] in myelocortical vs 13·81% [6·51-29·01] in typical multiple sclerosis; p=0·0083). Despite the lack of cerebral white-matter demyelination in myelocortical multiple sclerosis, mean cortical neuronal densities were significantly decreased compared with control brains (349·8 neurons per mm2 [SD 51·9] in myelocortical multiple sclerosis vs 419·0 [43·6] in controls in layer III [p=0·0104]; 355·6 [46·5] vs 454·2 [48·3] in layer V [p=0·0006]; 366·6 [50·9] vs 458·3 [48·4] in layer VI [p=0·0049]). By contrast, mean cortical neuronal densities were decreased in typical multiple sclerosis brains compared with those from controls in layer V (392·5 [59·0] vs 454·2 [48·3]; p=0·0182) but not layers III and VI. INTERPRETATION: We propose that myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and can be an independent pathological event in myelocortical multiple sclerosis. Compared with control brains, cortical neuronal loss was greater in myelocortical multiple sclerosis cortex than in typical multiple sclerosis cortex. The molecular mechanisms of primary neuronal degeneration and axonal pathology in myelocortical multiple sclerosis should be investigated in future studies. FUNDING: US National Institutes of Health and National Multiple Sclerosis Society.

Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis.

Chemokines and chemokine receptors play a key role in the transmigration of leucocytes across the blood-brain barrier (BBB). CCR2 is the major receptor for CCL2, a potent monocyte and T cell chemoattractant. CCR2 and CCL2 have been consistently associated with a pathogenic role in experimental autoimmune encephalomyelitis, using knockout and transgenic mice, neutralizing antibodies, peptide antagonists and DNA vaccination. However, the significance of CCL2 and CCR2 in multiple sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues. This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the extracellular fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels. We showed that CCR2-positive T cells and monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T cells and monocytes. Next, we used a new anti-CCR2 antibody to show that CCR2-positive mononuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in multiple sclerosis lesions. We then showed that CCR2 receptor density on T cells and monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant chemokines. These findings document a novel strategy for analysing chemokine receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.

Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation.

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated on tyrosine residue 705 in response to growth factors or cytokines to form activated homodimers that drive gene expression. Because the stat3 promoter has a binding site for STAT3 dimers, the amount of STAT3 protein increases when STAT3 is activated (e.g., in response to interleukin 6). Unphosphorylated STAT1 is known to drive the expression of certain genes. To explore the possibility of a similar role for the induced expression of unphosphorylated STAT3, we overexpressed either Y705F STAT3, which can not be phosphorylated on residue 705, or wild-type STAT3 in normal human mammary epithelial cells or STAT3-null mouse cells. The levels of many mRNAs were affected strongly by high levels of either form of STAT3. Some genes whose expression was increased by overexpressed STAT3, but not by activated STAT3 dimers, encode well-known oncoproteins (e.g., MRAS and MET). In many tumors, STAT3 is activated constitutively, and thus the unphosphorylated form is likely to be expressed highly, driving oncogene expression by a novel mechanism. In addition, expression of the stat3 gene is increased strongly in response to interleukin 6, and the high levels of unphosphorylated STAT3 that result drive a substantial late phase of gene expression in response to this cytokine. Thus, unphosphorylated STAT3, which activates gene expression by a novel mechanism distinct from that used by STAT3 dimers, is very likely to be an important transcription factor both in cancer and in responses to cytokines.

Acromegaly and somatotroph hyperplasia with adenomatous transformation due to pituitary metastasis of a growth hormone-releasing hormone-secreting pulmonary endocrine carcinoma.

CONTEXT: GHRH excess from extracranial endocrine tumors is known to cause somatotroph hyperplasia and acromegaly. Hypothalamic gangliocytomas producing GHRH are also known to be associated with pituitary adenomas causing acromegaly. OBJECTIVES: The objective of this study was to describe a case of acromegaly due to a pulmonary GHRH-secreting endocrine carcinoma with metastasis to the pituitary gland and to look at the peculiar histological features of this case. SUBJECT: The patient was a 44-yr-old woman who was diagnosed with a biopsy-proven metastatic pulmonary endocrine tumor during pregnancy. After delivery, she underwent radiation and chemotherapy for pulmonary and skeletal metastases. Her disease was clinically stable for 7 yr until she developed bitemporal hemianopia. She had symptoms and signs of acromegaly. METHODS: Imaging, biochemical, and histological studies were performed. RESULTS: Magnetic resonance imaging (MRI) of the brain confirmed the presence of a 2.6-cm lesion within the sella turcica extending above the sella and compressing the optic chiasm. Endocrine studies showed elevated serum levels of GH, prolactin, alpha-subunit of glycoprotein hormones, IGF-I, chromogranin A, and GHRH. The patient underwent uneventful transsphenoidal resection of the sellar tumor. Postoperatively, she noted an improvement in symptoms of acromegaly. Histological examination confirmed metastatic endocrine carcinoma to the pituitary, and immunohistochemistry localized GHRH to the tumor cells. The adjacent pituitary exhibited somatotroph hyperplasia with abundant reactivity for GH and alpha-subunit. In addition, there was focal neoplastic transformation to a sparsely granulated somatotroph phenotype with fibrous bodies. CONCLUSION: This is the first report of a GHRH-producing endocrine tumor metastasizing to the pituitary and causing local hyperstimulation with somatotroph hyperplasia and adenomatous transformation.

The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making.

OBJECT: Oligodendrogliomas are rare primary brain tumors. They comprise approximately 5 to 33% of all glial tumors but differ from astrocytomas by being associated with a more favorable prognosis, making their correct identification important. Allelic loss of chromosome arms 1p and 19q is found in a substantial subpopulation of tumors with an oligodendroglioma phenotype. Anaplastic oligodendrogliomas with allelic loss of 1p have been associated with chemosensitivity and a longer patient survival period. METHODS: Oligodendroglial neoplasms were studied using fluorescence in situ hybridization of formalin-fixed, paraffin-embedded tissue specimens; reference and target probe sets were used to map the telomeric regions of 1p and 19q. The results were correlated with the clinical characteristics of patients treated at our institution between 1993 and 2003. Data obtained in 96 patients were analyzed. This included 63 patients (65.6%) with World Health Organization (WHO) Grade II oligodendroglioma, 22 (23%) with Grade III oligodendroglioma, and 11 (11.4%) with mixed oligoastrocytoma. Analysis of 1p in patients with pure oligodendroglioma revealed a loss of 1p in 42 patients (49.4%). In 46 of these patients 19q was lost and in 70 (82.3%) there was concordance for combined loss or retention of both 1p and 19q (p < 0.0001). Patients with oligodendroglioma in whom a loss of 1p was present fared significantly better, and this outcome was unrelated to the treatment modality or WHO grade, compared with patients in whom 1p was intact (p < 0.05). CONCLUSIONS: To the authors' knowledge, this study includes the largest published series of WHO Grade II oligodendroglioma and 1p analysis. The results suggest that the association between long-term survival and 1p loss in oligodendroglioma is unrelated to treatment. The authors of further prospective studies may better determine the true value of the allelic loss of 1p and its implication for clinical decision making.

Development of an Arthroscopic Joint Capsule Injury Model in the Canine Shoulder.

BACKGROUND: The natural history of rotator cuff tears can be unfavorable as patients develop fatty infiltration and muscle atrophy that is often associated with a loss of muscle strength and shoulder function. To facilitate study of possible biologic mechanisms involved in early degenerative changes to rotator cuff muscle and tendon tissues, the objective of this study was to develop a joint capsule injury model in the canine shoulder using arthroscopy. METHODS: Arthroscopic surgical methods for performing a posterior joint capsulectomy in the canine shoulder were first defined in cadavers. Subsequently, one canine subject underwent bilateral shoulder joint capsulectomy using arthroscopy, arthroscopic surveillance at 2, 4 and 8 weeks, and gross and histologic examination of the joint at 10 weeks. RESULTS: The canine subject was weight-bearing within eight hours after index and follow-up surgeries and had no significant soft tissue swelling of the shoulder girdle or gross lameness. Chronic synovitis and macroscopic and microscopic evidence of pathologic changes to the rotator cuff bony insertions, tendons, myotendinous junctions and muscles were observed. CONCLUSIONS: This study demonstrates feasibility and proof-of-concept for a joint capsule injury model in the canine shoulder. Future work is needed to define the observed pathologic changes and their role in the progression of rotator cuff disease. Ultimately, better understanding of the biologic mechanisms of early progression of rotator cuff disease may lead to clinical interventions to halt or slow this process and avoid the more advanced and often irreversible conditions of large tendon tears with muscle fatty atrophy.

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection.

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.

Epidermal growth factor receptor amplification does not have prognostic significance in patients with glioblastoma multiforme.

PURPOSE: There have been conflicting reports in the literature regarding the prognostic significance of epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma multiforme (GBM). The purpose of this study is to determine the prognostic significance of EGFR amplification in patients with GBM treated at the Cleveland Clinic Foundation. METHODS AND MATERIALS: A retrospective review of GBM patients treated with surgery at the Cleveland Clinic Foundation was performed. Amplification of EGFR was evaluated with fluorescence in situ hybridization in a total of 107 patients diagnosed between December 1995 and May 2003. In addition to EGFR status, various prognostic factors were evaluated to determine the factors that influenced survival and radiographic response rate. The median follow-up was 9 months. RESULTS: The overall median survival was 9.8 months, with a 1-year survival of 40%. Of the 107 patients in whom EGFR status was evaluated, 36 (33.6%) were found to have EGFR amplification. On multivariate analysis, median survival was found to be significantly improved for patients with age < 60 (12.6 months vs. 8 months, p = 0.0061), patients with Karnofsky Performance Status > or = 70 (12.1 months vs. 4.4 months, p < 0.0001), patients who had undergone subtotal resection or gross total resection (11.1 months vs. 4.1 months, p = 0.002), and patients who received a radiation dose > or = 60 Gy compared with no radiation (12.7 months vs. 3 months, p < 0.0001). There was no association of EGFR amplification with survival. When stratified by age (< 60 vs. > or = 60), EGFR status still did not reach statistical significance in predicting for survival. For the 81 patients who had radiographic follow-up, the 1-year overall local control was 14%. On univariate analysis, only treatment with radiation (< 60 Gy vs. > or = 60 Gy vs. no radiation, p = 0.03) was found to predict for improved local control. Treatment with radiation did not remain statistically significant on multivariate analysis. CONCLUSION: Epidermal growth factor receptor amplification was not found to be a significant prognostic indicator of overall survival or radiographic local control in patients with GBM treated with surgery at the Cleveland Clinic Foundation. Further studies are needed to fully delineate the significance of this molecular marker in patients with GBM.

Fatal West Nile Virus infection after rituximab/fludarabine--induced remission for non-Hodgkin's lymphoma.

West Nile virus (WNV) infections are potentially life threatening in immunocompromised hosts. Currently, the best diagnostic test is serology. Reverse-transcriptase polymerase chain reaction (RT-PCR) testing has a role, but, because WNV is a cell-associated neurotropic virus, RT-PCR results are frequently negative even in cases of active infection. We present a case in which serology results were persistently negative because the patient was immunocompromised following lymphoma treatment. The role of humoral immunity in resolution of WNV is also discussed.

Intracranial collision tumor mimicking an octreotide-SPECT positive and FDG-PET negative meningioma.

UNLABELLED: OBJECTIVE/IMPORTANCE: Cancer metastasis to a pre-existing intracranial tumor is rare, but several cases have been reported. We report an unusual case of a "collision tumor" consisting of a renal cell carcinoma metastasis to an intracranial meningioma. CLINICAL PRESENTATION: A 67-year old male with renal cell carcinoma had an asymptomatic right posterior frontal dural-based lesion identified on a screening CT scan. MRI characteristics of the tumor were consistent with meningioma. On octreotide-SPECT and F-18 fluorodeoxyglucose (FDG)-PET scans, the lesion showed octreotide uptake but did not accumulate FDG, both of which are consistent with a diagnosis of benign meningioma. One week later, he presented with a 1-day history of progressive left-sided weakness. The intracranial tumor was resected, and subacute subdural blood was found overlying a soft, reddish tumor. Microscopic examination was consistent with renal cell carcinoma with a minor portion consisting of meningioma. The meningothelial component was strongly immunoreactive to vimentin and weakly reactive to epithelial membrane antigens. Neither area reacted with glucose transporter-1 (GLUT-1), correlating with low FDG-PET uptake. CONCLUSION: Collision tumor involving metastatic renal cell carcinoma to an intracranial meningioma is a rare occurrence. Diagnosis by non-invasive means, with use of a combination of octreotide-SPECT and FDG-PET may not accurately reflect the malignant component of such a collision tumor. In this case, the collision tumor also demonstrated a propensity to undergo spontaneous hemorrhage. A high degree of suspicion of intracranial metastasis should be maintained for patients who have known systemic cancer and are found incidentally to have a dural-based mass lesion.

TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models.

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. A recent study identified 4 patterns of demyelination in active MS lesions. The characteristics of pattern II lesions suggested a primary inflammatory mechanism of myelin injury, while pattern III lesions showed features consistent with dying-back oligodendrogliopathy. The recruitment, differentiation, and activation of mononuclear phagocytes are dependent on the expression of chemokine receptors. Using immunohistochemistry we quantified cellular expression of CCR1 and CCR5 in pattern II (n = 21) and pattern III (n = 17) lesion areas of differing demyelinating activity. Infiltrating monocytes in both lesion patterns co-expressed CCR1 and CCR5, suggesting conserved mechanisms of monocyte recruitment into the CNS. In pattern II lesions, the number of cells expressing CCR1 significantly decreased while CCR5 increased in late active compared with early active demyelinating regions. In striking contrast, numbers of cells expressing CCR1 and CCR5 were equal in all regions of pattern III lesions. As hypoxia-like mechanisms may play a role in pattern III lesions, we extended these studies to white matter infarcts (n = 7) in which the expression of CCR1 better resembled pattern III than pattern II lesions. As judged by mononuclear phagocyte chemokine receptor expression, there appear to be distinct tissue environments in pattern II and III MS lesions.

Tuberculous radiculomyelitis presenting in a toddler with lower extremity weakness and seizure.

Tuberculous radiculomyelitis is an uncommon but serious complication of tuberculosis that can lead to considerable morbidity and mortality. We present the case of a 21-month-old male Congolese refugee diagnosed with tuberculous radiculomyelitis who presented with gradual motor and speech regression, and likely an infection-related seizure 2 months before diagnosis.