Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

OBJECTIVE: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. METHODS: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. RESULTS: Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. INTERPRETATION: Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.

Giant Arachnoid Granulations: A Systematic Literature Review.

Giant arachnoid granulations (GAGs) are minimally investigated. Here, we systematically review the available data in published reports to better understand their etiologies, nomenclature, and clinical significance. In the literature, 195 GAGs have been documented in 169 persons of varied ages (range, 0.33 to 91 years; mean, 43 ± 20 years; 54% female). Prior reports depict intrasinus (i.e., dural venous sinus, DVS) (84%), extrasinus (i.e., diploic or calvarial) (15%), and mixed (1%) GAG types that exhibit pedunculated, sessile, or vermiform morphologies. GAG size ranged from 0.4 to 6 cm in maximum dimension (mean, 1.9 ± 1.1 cm) and encompassed symptomatic or non-symptomatic enlarged arachnoid granulations (≥1 cm) as well as symptomatic subcentimeter arachnoid granulations. A significant difference was identified in mean GAG size between sex (females, 1.78 cm; males, 3.39 cm; p < 0.05). The signs and symptoms associated with GAGs varied and include headache (19%), sensory change(s) (11%), and intracranial hypertension (2%), among diverse and potentially serious sequelae. Notably, brain herniation was present within 38 GAGs (22%). Among treated individuals, subsets were managed medically (19 persons, 11%), surgically (15 persons, 9%), and/or by endovascular DVS stenting (7 persons, 4%). Histologic workup of 53 (27%) GAG cases depicted internal inflammation (3%), cystic change consistent with fluid accumulation (2%), venous thrombosis (1%), hemorrhage (1%), meningothelial hyperplasia (1%), lymphatic vascular proliferation (1%), and lymphatic vessel obliteration (1%). This review emphasizes heterogeneity in GAG subtypes, morphology, composite, location, symptomatology, and imaging presentations. Additional systematic investigations are needed to better elucidate the pathobiology, clinical effects, and optimal diagnostic and management strategies for enlarged and symptomatic arachnoid granulation subtypes, as different strategies and size thresholds are likely applicable for medical, interventional, and/or surgical treatment of these structures in distinct brain locations.

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma.

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology. We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions. The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain-meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified. This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways. These data raise new theories regarding glymphatic-lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.

Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency.

BACKGROUND: Polymer coating embolism due to vascular medical device use is an increasingly recognized iatrogenic complication. This phenomenon has been linked with various adverse effects including neuroinflammation, acute ischemic stroke, cerebral hemorrhage, and death. Notably, procedure- and device-specific risks of this complication are poorly investigated. In this study, we evaluate the detectable frequency of intra-arterial polymer coating delamination among patients who underwent endovascular thrombectomy for treatment of acute ischemic stroke due to large vessel occlusion. METHODS: Ninety-two cerebral thrombectomy specimens were retrospectively analyzed for the presence of polymer coating particulates. Histologic findings were correlated with demographic and procedural details and patient outcomes. RESULTS: Evidence of polymer coating deposition was found in 30 of 92 extracted thrombi (33%). No correlation between intrathrombus polymer deposition and use of a specific thrombectomy device such as a stent retriever, aspiration catheter, or guide catheter was found. However, heterogeneous patterns of device use suggest a number of culprit devices. A trend toward longer procedure times and multiple thrombectomy passes was noted in positive cases. Intrathrombus polymer deposition was not associated with adverse clinical outcomes as measured by the 90-day modified Rankin Scale (mRS); however, small sample size and follow-up intervals limit interpretation. Ninety-day outcomes based on mRS may not fully capture the clinical effects of acute and/or delayed intracerebral polymer complications. CONCLUSION: In light of documented adverse neurologic effects, the frequency of intrathrombus polymer particulates indicates the need for consensus testing methods and large-scale long-term prospective clinical device trials, with inclusion of relevant endpoints to better assess biomaterial and device risks to patients.

Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis.

BACKGROUND: In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial. METHODS: EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35-55. Glibenclamide (10 µg/day) was administered beginning 12 or 24 days later. The effects of treatment were determined by clinical scoring and tissue examination. Drug within EAE lesions was identified using bodipy-glibenclamide. The role of SUR1-TRPM4 in primary astrocytes was characterized using patch clamp and qPCR. Demyelinating lesions from MS patients were studied by immunolabeling and immunoFRET. RESULTS: Administering glibenclamide beginning 24 days after MOG35-55 immunization, well after clinical symptoms had plateaued, improved clinical scores, reduced myelin loss, inflammation (CD45, CD20, CD3, p65), and reactive astrocytosis, improved macrophage phenotype (CD163), and decreased expression of tumor necrosis factor (TNF), B-cell activating factor (BAFF), chemokine (C-C motif) ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in lumbar spinal cord white matter. Glibenclamide accumulated within EAE lesions, and had no effect on leukocyte sequestration. In primary astrocyte cultures, activation by TNF plus IFNγ induced de novo expression of SUR1-TRPM4 channels and upregulated Tnf, Baff, Ccl2, and Nos2 mRNA, with glibenclamide blockade of SUR1-TRPM4 reducing these mRNA increases. In demyelinating lesions from MS patients, astrocytes co-expressed SUR1-TRPM4 and BAFF, CCL2, and NOS2. CONCLUSIONS: SUR1-TRPM4 may be a druggable target for disease modification in MS.

α-Endosulfine (ARPP-19e) Expression in a Rat Model of Stroke.

In nutrient restricted environments, the yeast endosulfines Igo1/2 are activated via TORC1 inhibition and function critically to initiate and coordinate the cellular stress response that promotes survival. We examined expression of αEnsa, the mammalian homolog of yeast endosulfines, in rat stroke. Prominent neuronal upregulation of αEnsa was identified in 3 patterns within the ischemic gradient: (1) neurons in GFAP-/HSF1+ cortex showed upregulation and near-complete nuclear translocation of αEnsa protein within hours of ischemic onset; (2) neurons in GFAP+/HSF1+ cortex showed upregulation in cytoplasm and nuclei that persisted for days; (3) neurons in GFAP+/HSF1- cortex showed delayed cytosolic-only upregulation that persisted for days. Findings were corroborated using in situ hybridization for ENSA mRNA. Rapamycin treatment was found to reduce infarct size and behavioral deficits and, in GFAP+/HSF1+ zones, enhance αEnsa neuronal nuclear translocation and mitigate cell death, relative to controls. Based on the conservation of TOR signaling across species, and on the finding that the Rim15-Igo1/2-PP2A module is triggered by substrate deprivation in eukaryotic yeast, we speculate that αEnsa is activated by substrate deprivation, functioning through the homologous MASTL-αEnsa/ARPP19-PP2A module to promote neuronal survival. In conjunction with recent studies suggesting a neuroprotective role, our data highlight a potential function for αEnsa within ischemic brain.

Polymer-induced central nervous system complications following vascular procedures: spectrum of iatrogenic injuries and review of outcomes.

Polymer substances are commonly applied as surface coatings on endovascular catheters and vascular devices. Adverse effects related to their use have been reported, although the overall clinical significance and appropriate methods of detection of these complications have been unclear. In this analysis, we systematically reviewed clinical and diagnostic features in 32 patients (age, 36-87years; mean, 59years) in whom intracranial polymer reactions were documented following vascular interventions. Associated neuroradiologic and neuropathologic findings were variable and included cerebral vasculitis or vasculopathy (63%), abscess or granuloma formation (38%), ischemic infarcts (28%), parenchymal hematomas (28%), white matter change (25%), and/or chemical meningitis (22%). Location(s) of polymer reactions varied and included sites adjacent to and/or downstream from instrument insertion or implantation. Presenting clinical signs included focal neurologic deficits (41%), headache (22%), constitutional symptoms (19%), meningitis (16%), seizure and/or involuntary movements (9%), coma (6%), and syncope (3%). Adverse outcomes included stroke (31%), death (28%), delayed communicating hydrocephalus (9%), steroid dependency (9%), steroid complications (6%), and cerebral volume loss (3%). In some cases, these complications necessitated increased cost and length of medical care. In this review, we highlight the diverse features of polymer-induced reactions involving the central nervous system and summarize distinct diagnostic patterns that may enable earlier premortem detection of these lesions in the postprocedural clinical setting. Further work in this area is necessary to identify additional etiologic, preventative and therapeutic strategies. These data have potentially broad implications pertaining to the safety, efficacy, standards of use, storage, manufacturing, and regulation of new and emerging vascular devices and polymer nanotechnologies.

Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts.

The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.

Sulfonylurea receptor 1 expression in human cerebral infarcts.

In animal models of stroke, sulfonylurea receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neutrophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea receptor 1 immunoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction.

Rosette-forming glioneuronal tumor: a pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases.

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a mixed glio-neuronal neoplasm recently codified by the World Health Organization WHO Classification of Central Nervous System (CNS) Tumors (2007). To date, 43 cases have been described in the literature; most occurring in the fourth ventricle region. We report the fourth case involving the pineal region in a 16-year-old female with signs of increased intracranial pressure (ICP). A stereotactic biopsy of the mass was followed by a debulking procedure. Both specimens revealed classic RGNT histology. The patient had stable scans 7 months post-resection. The clinical, radiological and histopathologic features of the previously described 43 cases are reviewed along with our illustrative case. Mean age of patients was 30 ± 12.8 years with 1.9:1 female to male ratio. The most common presenting signs related to increased ICP and posterior fossa involvement, including: headache (62.8%), ataxia (39.5%) and vomiting and vertigo (both 16.3%). This tumor usually presents with cystic changes (54.5%) with focal enhancement (60.9%) and hydrocephalus (43.2%). Microcalcifications and satellite lesions were common radiographic observations. All reported cases had the classic biphasic pattern. Rosenthal fibers and eosinophilic granular bodies are each present in approximately two thirds of cases. Ki-67 labeling index is consistently low (mean (%): 1.8 ± 0.75 SD). The isocitrate dehydrogenase 1 or 2 mutation found in low grade diffuse gliomas is not identified in this RGNT case. Reported outcome is nearly uniformly excellent after complete or subtotal resection. A solitary report of recurrence after 10 years and the limited experience with this entity suggest that long term follow up is advisable.

Pathology of explanted polytetrafluoroethylene vascular grafts.

INTRODUCTION: Graft occlusion is a well-documented etiology for arteriovenous fistulae failure. However, there is little morphologic information elucidating why synthetic vascular grafts fail. The purpose of this study was to examine the tissue responses occurring within and adjacent to explanted polytetrafluoroethylene grafts that were utilized during cardiovascular procedures and subsequently removed. METHODS: Forty explanted polytetrafluoroethylene grafts (including 32 failed vascular grafts) originating from 18 females and 22 males who ranged in age from 6 to 82 years (mean age, 36 years) were evaluated. Duration of engraftment varied from 1 to 255 months (mean engraftment period, 64 months). RESULTS: In addition to neointimal hyperplasia, foreign body reaction, and thrombosis, an unexpected finding was calcification involving the graft material, as well as luminal thrombus and adjacent soft tissues. Twenty-seven of forty cases (68%) showed evidence of calcification, either within or adjacent to polytetrafluoroethylene grafts. Histologic examination revealed variable degrees and patterns of calcification within and adjacent to explanted polytetrafluoroethylene membranes and conduits (arterial, arteriovenous, or cardiac grafts). A significantly longer duration of engraftment (P=.015) was identified in calcified versus noncalcified polytetrafluoroethylene materials. Patient age, serum calcium, creatinine level, and blood urea nitrogen level showed no statistically significant differences between patients with calcified grafts and patients without calcified grafts. CONCLUSIONS: Interstitial calcification is frequently found within explanted polytetrafluoroethylene grafts and is associated with graft disruption. These findings suggest that calcification of polytetrafluoroethylene biomaterials may play a role in eventual graft failure. A better understanding of the process of polytetrafluoroethylene graft calcification may lead to novel therapies that aid in the prevention of polytetrafluoroethylene vascular graft failure.

Intrapulmonary ectopic liver after orthotopic heart transplantation.

We report a case of a 54-year-old woman who was found to have multiple intrapulmonary nodules detected on imaging 33 months after orthotopic heart transplantation. Needle biopsy of 2 discrete nodules showed benign hepatic tissue, consistent with intrapulmonary foci of ectopic liver. In this report, the clinical, radiologic, microscopic, and fluorescent in situ hybridization results of 2 biopsied nodules are described. A brief review of the published information on ectopic liver is also presented. To our knowledge, multiple ectopic foci of the liver have never been reported at any site. Furthermore, this is the first reported case that involves a transplant recipient, thereby introducing additional, unique ramifications to this rare but intriguing entity.

Hydrophilic polymer emboli: an under-recognized iatrogenic cause of ischemia and infarct.

With the increased use of percutaneous intravascular diagnostic and therapeutic devices, there is potential for embolization of materials introduced into the vasculature. We report nine cases of foreign body emboli in patients who underwent vascular procedures using hydrophilic-coated medical devices. The procedures performed included cardiac catheterization (four cases), diagnostic cerebral angiography (two cases), therapeutic cerebral angiography with coil embolization of intracerebral aneurysm (one case), lower extremity angiography (one case), and/or orthotopic cadaveric organ transplantation (three cases). Other procedures in these patients included hemodialysis and peripheral arterial or central venous catheterization. Clinical sequelae ranged from undetectable (no symptoms) to pulmonary infarction, stroke, ongoing gangrene, and/or death occurring within days to weeks of suspected embolization of foreign material. Microscopic findings in biopsy or autopsy tissue revealed aggregates of amorphous or lamellated, non-refractile, non-polarizable, predominantly basophilic foreign substances occluding intrapulmonary, intracerebral, or peripheral arteries. This is the largest series documenting embolization of polymer gel materials. Polymer gel is now widely used on several devices for interventional procedures worldwide, and we suspect that complications associated with iatrogenic embolization of this substance are under-recognized.

Primary angiitis of the CNS (PACNS) with predominant cranial neuropathy and spinal cord involvement.

We describe a 70-year old man with a history of repeated epidural injections for chronic low back pain, presenting with headache, cranial nerve palsies and progressive myelopathy. Meningeal enhancement was initially seen in the posterior epidural space of the T(10)-T(12) spine on MRI. Extensive laboratory investigation showed normal or negative results except for persistent pleocytosis, elevated protein and absence of demonstrable microorganisms on CSF studies. Despite conventional and empirical treatments, the patient developed progressive neurological deterioration leading to death. Autopsy showed Primary angiitis of the CNS (PACNS) with predominant cranial neuropathy, spinal cord involvement and extensive myelomalacia.

"Primary" leptomeningeal medulloblastoma.

We report the case of an 8-year-old boy who presented with a 2-month history of headaches and mild visual impairment and was found to have a medulloblastoma with primary leptomeningeal involvement. No mass lesion was found on imaging studies, during subsequent intraoperative surgical inspection or at autopsy. The pathologic findings were first documented on cerebrospinal fluid cytologic examination and biopsy of the cerebellum and were later confirmed at necropsy. To our knowledge, this is the third reported case of medulloblastoma identified with primary leptomeningeal involvement without a cerebellar mass and the first such case with documented autopsy findings.