Documented growth of an intracranial capillary hemangioma: A case report.

Intracranial capillary hemangiomas in adults are rare, and diagnosis can be challenging. Hemangiomas, in general (and particularly in the skin), are more often noted in the pediatric population. Due to the lack of imaging undertaken in the presymptomatic phase, the literature provides few clues on the rate of growth of these unusual tumors. Therefore, we report a case of a 64-year-old man with a medical history of Lyme disease who presented with exhaustion and confusion. Imaging demonstrated an intra-axial lesion with vascularity in the posterior right temporal lobe, raising the possibility of a glioma. Imaging two years prior revealed a very small lesion in the same location. The patient underwent a craniectomy, total resection of the lesion was completed, and his symptoms of confusion resolved. Biopsy revealed a capillary hemangioma composed of small vascular channels lined by endothelial cells and pericytes without smooth muscle. Features of glioma, vascular neoplasms or neuroborreliosis (cerebral Lyme disease) were not identified. Our case documents the growth over two years of a rare intracranial capillary hemangioma in an older adult male.

Perirhinal cortex and the recognition of relative familiarity.

Spontaneous object recognition (SOR) is a widely used task of recognition memory in rodents which relies on their propensity to explore novel (or relatively novel) objects. Network models typically define perirhinal cortex as a region required for recognition of previously seen objects largely based on findings that lesions or inactivations of this area produce SOR deficits. However, relatively little is understood about the relationship between the activity of cells in the perirhinal cortex that signal novelty and familiarity and the behavioural responses of animals in the SOR task. Previous studies have used objects that are either highly familiar or absolutely novel, but everyday memory is for objects that sit on a spectrum of familiarity which includes objects that have been seen only a few times, or objects that are similar to objects which have been previously experienced. We present two studies that explore cellular activity (through c-fos imaging) within perirhinal cortex of rats performing SOR where the familiarity of objects has been manipulated. Despite robust recognition memory performance, we show no significant changes in perirhinal activity related to the level of familiarity of the objects. Reasons for this lack of familiarity-related modulation in perirhinal cortex activity are discussed. The current findings support emerging evidence that perirhinal responses to novelty are complex and that task demands are critical to the involvement of perirhinal cortex in the control of object recognition memory.

The NMDA receptor antagonist MK-801 fails to impair long-term recognition memory in mice when the state-dependency of memory is controlled.

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory.

Evidence for Cholinergic Dysfunction in Autosomal Dominant Kufs Disease.

OBJECTIVE: Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. METHODS: We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. RESULTS: Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. CONCLUSIONS: This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain.

Incidental context information increases recollection.

The current study describes a receiver-operating characteristic (ROC) task for human participants based on the spontaneous recognition memory paradigms typically used with rodents. Recollection was significantly higher when an object was in the same location and background as at encoding, a combination used to assess episodic-like memory in animals, but not when only one of these task-irrelevant cues was present. The results show that incidentally encoded cue information can determine the degree of recollection, and opens up the possibility of assessing recollection across species in a single experimental paradigm, allowing better understanding of the cognitive and biological mechanisms at play.

Human Brain Chemokine and Cytokine Expression in Sepsis: A Report of Three Cases.

BACKGROUND: Sepsis is a systemic response to infection that can affect brain function by inducing resident cells (including astrocytes and microglia) to generate brain chemokines and cytokines. However, there are few studies on the human brain. Since this information may shed further light on pathogenesis, our study objective was to measure the expression of 36 chemokines and cytokines in autopsied brain from 3 cases of sepsis and 10 controls, and to relate this to astrocyte and microglial activation. METHODS: The right frontal pole was removed at autopsy and chemokine and cytokine expression measured by multiplexed enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (qPCR). Immunohistochemistry and image analysis were carried out to determine the expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, and CD68 and CD45, markers of activated microglial cells. RESULTS: Concentrations of the chemokines CXCL8, CXCL10, CXCL12, CCL13 and CCL22 were increased in pooled data from the three cases of sepsis (p<0.05); however, their messenger RNA (mRNA) expression was unaltered. CXCL13, CXCL1, CXCL2, CCL1, CCL2, CCL8, CCL20, (interleukin) IL-16, IL-1ß and (tumour necrosis factor) TNF concentrations showed increases in two of three sepsis cases. Additionally, individual sepsis cases showed increases in mRNA expression for HDAC (histone deacetylase) 6 and EIF (eukaryotic translation initiation factor) 4A2. Brain GFAP expression was significantly increased (p<0.05) in pooled data from the three sepsis cases. Individual sepsis cases showed increases in CD68 or CD45 expression. CONCLUSIONS: These expression patterns add to our understanding of the pathogenesis of sepsis and its effects on the brain.

Murine T cell activation is regulated by surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide).

Surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide) binds to glycosaminoglycans (GAGs) and has been shown to influence their function, and the function of proteoglycans (complexes of GAGs linked to a core protein). T cells synthesize, secrete and express GAGs and proteoglycans which are involved in several aspects of T cell function. However, there are as yet no studies on the effect of GAG-binding agents such as surfen on T cell function. In this study, surfen was found to influence murine T cell activation. Doses between 2.5 and 20 µM produced a graduated reduction in the proliferation of T cells activated with anti-CD3/CD28 antibody-coated T cell expander beads. Surfen (20 mg/kg) was also administered to mice treated with anti-CD3 antibody to activate T cells in vivo. Lymphocytes from surfen-treated mice also showed reduced proliferation and lymph node cell counts were reduced. Surfen reduced labeling with a cell viability marker (7-ADD) but to a much lower extent than its effect on proliferation. Surfen also reduced CD25 (the α-subunit of the interleukin (IL)-2 receptor) expression with no effect on CD69 expression in T cells treated in vivo but not in vitro. When receptor activation was bypassed by treating T cells in vitro with phorbyl myristate acetate (10 ng/ml) and ionomycin (100 ng/ml), surfen treatment either increased proliferation (10 µM) or had no effect (2.5, 5 and 20 µM). In vitro treatment of T cells with surfen had no effect on IL-2 or interferon-γ synthesis and did not alter proliferation of the IL-2 dependent cell line CTLL-2. The effect of surfen was antagonized dose-dependently by co-treatment with heparin sulfate. We conclude that surfen inhibits T cell proliferation in vitro and in vivo. When T cell receptor-driven activation is bypassed surfen had a neutral or stimulatory effect on T cell proliferation. The results imply that endogenous GAGs and proteoglycans play a complex role in promoting or inhibiting different aspects of T cell activation.

The episodic nature of episodic-like memories.

Studying episodic memory in nonhuman animals has proved difficult because definitions in humans require conscious recollection. Here, we assessed humans' experience of episodic-like recognition memory tasks that have been used with animals. It was found that tasks using contextual information to discriminate events could only be accurately performed using recollection, not familiarity. However, tasks using temporal information to discriminate events could be accurately performed using either recollection or familiarity. The results strengthen the position that some episodic-like recognition memory tasks are a valid model of episodic memory. However, tasks that rely on temporal information may be susceptible to nonepisodic strategies.

Regulation of permeability across the blood-brain barrier.

The blood-brain barrier refers to the very low permeability across microvessels in the Central Nervous System (CNS), created by the interaction between vascular endothelial cells and surrounding cells of the neurovascular unit. Permeability can be modulated (increased and decreased) by a variety of factors including inflammatory mediators, inflammatory cells such as neutrophils and through alterations in the phenotype of blood vessels during angiogenesis and apoptosis. In this chapter, some of these factors are discussed as well as the challenge of treating harmful increases in permeability that result in brain swelling (vasogenic cerebral edema).

A single brief stressful event time-dependently affects object recognition memory and promotes familiarity preference in marmoset monkeys.

A stressful experience can enhance information storage and impair memory retrieval in the rodent novel object recognition (NOR) task. However, recent conflicting results underscore the need for further investigation. Nonhuman primates may provide a unique, underexplored and more translational means to investigate stress-mediated changes in memory. Therefore, we assessed whether a single brief extrinsic stress event affects information encoding, storage and/or retrieval in adult marmoset monkeys submitted to the NOR task. This consisted of an initial 10 min familiarization period with two identical neutral objects. After a 6 h delay, a 10 min test trial was held where a new and familiar object could be explored. Stress was induced by a 15 min restraint event held before or after the encoding phase, or prior to retrieval. Pre-encoding stress had no effect on task performance, as this group displayed above-chance novelty preference similar to non-stressed controls. Post-encoding stress induced memory deficits, with both objects being explored equally. Interestingly, pre-retrieval stress induced an above-chance familiarity preference. A single brief stressful event thus affects recognition memory in a time-dependent manner. Also, negative discrimination ratios can be used as a measure of memory in the NOR task and a change in strategy may not mean memory failure in spontaneous learning paradigms.

The spatial layout of doorways and environmental boundaries shape the content of event memories.

Physical boundaries in our environment have been observed to define separate events in episodic memory. To date, however, there is little evidence that the spatial properties of boundaries exert any control over event memories. To examine this possibility, we conducted four experiments that took manipulations involving boundaries that have been demonstrated to influence spatial representations, and adapted them for use in an episodic object memory paradigm. Here, participants were given 15 min to freely explore an environment that contained 36 objects, equally dispersed among six discriminable buildings. In a subsequent test of object-location binding, participants were required to indicate where they remembered encountering the objects. In Experiment 1 the spatial properties of the building boundaries were identical; however, in Experiment 2 the boundaries were differentiated by their geometric shape and the location of the doorways in the buildings. In the test phases of these experiments, we observed a shift from a bias towards remembering the positions of objects within a building but not the building itself (Experiment 1), to a bias towards remembering which building an object was in but not the location within the building (Experiment 2). In Experiment 3, the buildings shared the same geometry but were differentiated by the locations of doorways, and we observed no significant differences between response types. Finally, in Experiment 4, the buildings were uniquely shaped but shared the same doorway location, and we observed a bias towards remembering the positions of objects within a building. In addition, exploratory analyses of non-spatial interference revealed more correct recall for objects housed in the first building a participant visited during exploration, compared to all other buildings. Together, our data indicates that the location of doorways in boundaries and, to a lesser extent, boundary geometries influence event models, and that a primacy effect can be observed in the recall of multiple object-location bindings.

Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory.

Loss of cholinergic cortical input is associated with diseases in which episodic memory impairment is a prominent feature, but the degree to which this neurochemical lesion can account for memory impairment in humans with neurodegenerative diseases remains unclear. Removal of cholinergic input to hippocampus impairs some of its functions in memory, perhaps by reducing the plasticity of information representation within the hippocampus, but the role of cholinergic hippocampal input in episodic-like memories has not been investigated. To address this question, we tested rats with selective lesions of basal forebrain neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), which contains hippocampal-projecting cholinergic neurons, on a task of integrated memory for objects, places, and contexts ("what-where-which" memory). This task serves as a rodent model of human episodic memory (episodic-like memory) and is sensitive to damage to the hippocampal system. Rats with lesions of cholinergic MS/VDB neurons performed as well on the what-where-which task as controls, but were impaired in a task that simply required them to associate places with contexts ("where-which" memory). Thus, episodic-like memories that rely on the hippocampus do not require cholinergic neuromodulation to be formed. Nevertheless, some more specific aspects of where-which memory, which may be more dependent on the plasticity of hippocampal spatial representations, require acetylcholine. These results suggest that cholinergic projections to hippocampus are not necessary for episodic memory and, furthermore, that hippocampal spatial representations may be to some extent dissociable from episodic memory function.

Amyloid ß-related angiitis of the central nervous system: report of 3 cases.

OBJECTIVE: Amyloid-ß (Aß) related angiitis (ABRA) is a recently described clinicopathological entity characterized by cerebrovascular Aß deposition and arteritis. Cerebral Aß deposition is commonly present in cerebal amyloid angiopathy (CAA) and Alzheimer's disease (AD) but is rarely associated with inflammatory infiltration of vessel walls. Our objective is to help clarify the clinical spectrum, radiographic findings, response to treatment, and outcomes of ABRA. The neuropathological relationship between ABRA, cerebral amyloid angiopathy, and Alzheimer's disease is discussed. METHODS: We present three cases of ABRA managed at a tertiary care centre. RESULTS: All three patients presented with seizures and cognitive dysfunction; one had multifocal neurologic findings. Brain biopsies revealed inflammatory arteritis with Aß deposits in the vessel walls. All were treated with steroids and cyclophosphamide. Two had favorable outcomes and one stabilized but with severe residual neurologic disability. CONCLUSIONS: ABRA is an unusual but likely under-recognized and potentially treatable disorder. As in other reported cases, our findings suggest that many patients respond favorably to immunosuppressive therapy. We believe that all biopsy specimens consistent with primary angiitis of the central nervous system (CNS) should be further examined for vascular Aß deposition.

Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis.

Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10(-5) mol/l) and TRAIL increased caspase-3 activity 1h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

Acetylcholine and Spontaneous Recognition Memory in Rodents and Primates.

Whilst acetylcholine has long been linked to memory, there have been significant questions about its specific role. In particular, the effects of cholinergic manipulations in primates and rodents has often been at odds. Here, we review the work in primates and rodents on the specific function of acetylcholine in memory, and episodic memory in particular. We propose that patterns of impairment can best be understood in terms of a role for hippocampal acetylcholine in resolving spatial interference and we discuss the benefits of new tasks of episodic memory in animals allowing clearer translation of findings to the clinic.

Impaired episodic simulation in a patient with visual memory deficit amnesia.

For the first time, we assess episodic simulation in a patient with visual memory deficit amnesia, following damage to visual association cortices. Compared to control participants, the patient with visual memory deficit amnesia shows severely restricted responses when asked to simulate different types of future episodic scenarios. Surprisingly, the patient's responses are more limited in cases where the scenarios require less reliance on visual information. We explain this counterintuitive finding through discussing how the severe retrograde amnesia in visual memory deficit amnesia limits the patient's access to episodic memories in which vision has not been a focus of their life. As a result, we argue that the deficits in visual memory deficit amnesia continue to distinguish it from amnesia after direct damage to the hippocampus.

Recollection is impaired, but familiarity remains intact in rats with lesions of the fornix.

It has been argued that a neural system including the hippocampus, fornix, mamillary bodies, and anterior thalamus is specifically involved in recollection, but not in familiarity based memory processes. Here we test this hypothesis using a task of episodic-like memory within an E-shaped maze. Animals seek out a preferred object (what) in a particular location (where) that is unique to a particular context (which occasion). As objects are hidden from view at the point of decision making, the animals can only base their decision on recall of their previous episode in the E-shaped maze. In contrast, once a decision has been made animals are free to explore both objects and display an object preference when objects are visible to the animal and decisions can be made on the basis of familiarity. Animals with fornix lesions are impaired at recalling a past event. However, the same animals on the same trials show no such impairment in a judgement of familiarity. We therefore demonstrate that recall is dependent upon the fornix, while familiarity based memory is not.

Cerebral Vasculitis in Ulcerative Colitis Is Predominantly Venular: Case Report and Review of the Literature.

Extraintestinal complications of ulcerative colitis include isolated case reports of cerebral vasculitis. In this case report, we describe autopsy findings in a 50-year-old female who died as a result of massive multifocal cerebral hemorrhage. Microscopic examination of the left colon showed findings typical for ulcerative colitis. Examination of the brain showed an extensive vasculitis. More affected vessels were noted in grey matter than in white matter. Many showed fibrinoid necrosis, invasion by neutrophils and thrombosis. There was extensive perivascular hemorrhage with associated infarction. Vessel analysis shows most of the vessels to have been venous rather than arterial. There were no perivascular sleeves of demyelination to suggest a primary demyelinating disorder, such as acute hemorrhagic leucoencephalitis. Our analysis shows that veins are the likely target of cerebral vasculitis in ulcerative colitis. This has clinical implications because venous occlusion generally causes massive intracerebral hemorrhage with a high mortality.