Kathy Keyvani

Molecular Classification of Low-Grade Diffuse Gliomas

The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.

Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology

Alzheimers disease (AD) is accompanied by hippocampal neuronal loss and abnormal neurogenesis, both of which probably contributing to AD-related cognitive deficits. Mounting evidence indicates that cognitive and physical stimulation provided by environmental enrichment improves neurogenesis in healthy animals and counteracts beta-amyloid pathology in mouse models of AD. Here, we hypothesized that environmental enrichment has also an impact on hippocampal neurogenesis in mice with AD-like pathology. Therefore, TgCRND8 mice and wild type littermates were either housed under standard conditions or in an enriched environment for 4 months. Standard housed TgCRND8 mice revealed diminished hippocampal cell proliferation and reduced number of mature newborn neurons compared to wild type littermates under the same housing condition. However, environmental enrichment reversed this genotype effect. Here, we show that cognitive and physical stimulation is capable of increasing the number of newborn mature hippocampal neurons in transgenic mice to wild type levels. Moreover, the expression of various plasticity associated molecules was enhanced in transgenic mice due to enriched housing. This study identifies that environmental enrichment improves diminished cellular plasticity in AD brain, probably enhancing the brain capacity to better compensate for neurodegeneration.

Naturally Occurring Autoantibodies against β-Amyloid: Investigating Their Role in Transgenic Animal and In Vitro Models of Alzheimer's Disease

Alzheimers disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against β-amyloid (Aβ) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against Aβ (NAbs–Aβ) being reduced in Alzheimers disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs–Aβ recognized the mid-/C-terminal end of Aβ and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs–Aβ were able to interfere with Aβ peptide toxicity, but NAbs–Aβ did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs–Aβ in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs–Aβ to dispose of proteins or peptides that are prone to forming toxic aggregates.

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis

Objective: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). Methods: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen–positive slides were analyzed by PCR for VZV DNA. Results: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen–positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen–positive TAs, in 6/10 (60%) VZV antigen–positive skeletal muscles, and in one VZV antigen–positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. Conclusions: Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice

After we could recently demonstrate a beneficial effect of environmental enrichment on AD-like brain pathology in female TgCRND8 mice [Ambrée O, Leimer U, Herring A, Görtz N, Sachser N, Heneka MT, et al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006;169:544-52] the present study focuses on the behavioural effects of environmental enrichment with special emphasis on learning and memory performance in this AD model. In the first experiment spontaneous exploration, locomotor activity and anxiety-related behaviour were assessed as the performance in learning tasks can be biased substantially by exploratory behavioural traits. In the second experiment spatial memory in the Barnes maze test and object recognition memory were examined. Regarding exploratory behaviour transgenic mice from standard housing condition were statistically indistinguishable from wild-type controls. Enrichment had comparable effects in both genotypes indicated by higher levels of exploration and locomotor activity. In transgenic mice the elevated plus-maze revealed less anxiety-related behaviour due to enrichment in contrast to wild-type mice that statistically did not differ in anxiety-related behaviour. Concerning learning and memory performance, cognitive deficits of standard housed transgenic mice could be demonstrated in both learning tasks. Surprisingly, in both housing conditions a significantly higher number of transgenic mice refused to explore any objects compared to wild-type mice. Furthermore, the Barnes maze test revealed deficits of the transgenic mice in spatial memory compared to wild-type mice whereas no effect of environmental enrichment was detectable. Thus environmental enrichment increased exploratory behaviour and decreased anxiety-related behaviour but could not clearly ameliorate deficits in learning and memory performance of TgCRND8 mice.

Identification of novel diagnostic markers for choroid plexus tumors: a microarray-based approach.

To identify specific markers for the diagnosis of choroid plexus tumors, gene expression profiles of choroid plexus epithelial cells (n = 8) and ependymal cells (n = 6) microdissected from human autopsy brains as well as choroid plexus papilloma tissue were investigated using DNA microarrays. Protein expression of genes overexpressed in choroid plexus was evaluated in normal choroid plexus, choroid plexus papilloma, choroid plexus carcinoma, other primary brain tumors, and cerebral metastases. Forty-six genes found to be overexpressed in normal choroid plexus epithelial cells were also present in choroid plexus papilloma. Among those, 11 were further analyzed by immunohistochemistry. Expression of inward rectifier potassium channel Kir7.1 was confirmed in normal choroid plexus (34 of 35), choroid plexus papilloma (12 of 18), and choroid plexus carcinoma (5 of 5) but was not found in 100 other primary brain tumors and cerebral metastases. Similarly, stanniocalcin-1 stained normal choroid plexus (32 of 35), choroid plexus papilloma (16 of 18), and choroid plexus carcinoma (3 of 5), whereas staining was seen in only 2 of 100 other primary brain tumors and cerebral metastases. Transthyretin stained choroid plexus (33 of 35), choroid plexus papilloma (14 of 18), and plexus carcinoma (2 of 5), but its specificity was significantly lower. Antibodies directed against coagulation factor V, glutathione peroxidase 3, pigment epithelium derived factor, serotonin receptor 5-HTR2C, lumican, fibulin-1, plastin-1, and cytokeratin 18 revealed varying degrees of specificity and sensitivity. Our data suggest that antibodies directed against Kir7.1 and stanniocalcin-1 might serve as sensitive and specific diagnostic markers for choroid plexus tumors.

Serum S100β increases in marathon runners reflect extracranial release rather than glial damage

The contribution of extracranial tissue damage to serum S100β increases was examined in 18 marathon runners without clinical or laboratory signs of brain damage. Postrace serum S100β and creatine kinase (CK) concentrations increased (p < 0.001), and areas under the curve were highly correlated (p = 0.001). To conclude, serum S100β increases after running originate from extracranial sources. CK determination may improve specificity of S100β as a marker of brain tissue damage in acute trauma.

Wheel-running in a transgenic mouse model of Alzheimer's disease: Protection or symptom?

Several studies on both humans and animals reveal benefits of physical exercise on brain function and health. A previous study on TgCRND8 mice, a transgenic model of Alzheimers disease, reported beneficial effects of premorbid onset of long-term access to a running wheel on spatial learning and plaque deposition. Our study investigated the effects of access to a running wheel after the onset of Abeta pathology on behavioural, endocrinological, and neuropathological parameters. From day 80 of age, the time when Abeta deposition becomes apparent, TgCRND8 and wildtype mice were kept with or without running wheel. Home cage behaviour was analysed and cognitive abilities regarding object recognition memory and spatial learning in the Barnes maze were assessed. Our results show that, in comparison to Wt mice, Tg mice were characterised by impaired object recognition memory and spatial learning, increased glucocorticoid levels, hyperactivity in the home cage and high levels of stereotypic behaviour. Access to a running wheel had no effects on cognitive or neuropathological parameters, but reduced the amount of stereotypic behaviour in transgenics significantly. Furthermore, wheel-running was inversely correlated with stereotypic behaviour, suggesting that wheel-running may have stereotypic qualities. In addition, wheel-running positively correlated with plaque burden. Thus, in a phase when plaques are already present in the brain, it may be symptomatic of brain pathology, rather than protective. Whether or not access to a running wheel has beneficial effects on Alzheimer-like pathology and symptoms may therefore strongly depend on the exact time when the wheel is provided during development of the disease.

Gene Expression Profiling in Perilesional and Contralateral Areas After Ischemia in Rat Brain

Structural and functional reorganization in the vicinity of damaged neocortex and other connected brain areas seems to be responsible for postlesional functional recovery. To better understand the molecular mechanisms underlying this type of plasticity, gene expression patterns were analyzed by using DNA macroarrays comprising 1176 genes. Circumscribed unilateral infarcts consistently affecting the forelimb area of the motor cortex were induced photochemically in adult rats. Ten days after lesioning, cortical gene expression fingerprints were evaluated from an area adjacent to the lesion as well as two contralateral areas of motor and somatosensory cortex. Discrete regions showed distinct expression patterns. Upregulation was observed of different members of transcription factors, immediate early genes, neuronal signaling as well as neuronal growth and structure-associated genes, ipsilaterally (six genes) and/or contralaterally (eight genes in the motor and seven in the somatosensory cortex). In contrast, downregulations were restricted to ipsilateral areas and included genes coding for ion channels, transport proteins, mediators of metabolic pathways, and intracellular transducers (14 genes). A subset of these regulations were further confirmed by real-time polymerase chain reaction (TaqMan assay). At least part of the detected regulations, in particular those of the contralateral hemisphere, are likely to underlie plasticity processes.

Environmental Enrichment Counteracts Alzheimer’s Neurovascular Dysfunction in TgCRND8 Mice

We and others have recently demonstrated that cognitive and physical stimulation in form of environmental enrichment reduces cerebral β‐amyloid (Aβ) deposition in transgenic mouse models of Alzheimer’s disease. This effect was independent from amyloid precursor protein (APP) expression or processing and rather a consequence of enhanced clearance of Aβ. However, the detailed mechanisms remain unclear. In the present study, we show that environmental enrichment in TgCRND8 mice (carrying human APPSwedish+Indiana) affect the neurovascular unit by increased angiogenesis and differential regulation of Aβ receptor/transporter molecules, namely up‐regulation of LRP1, ApoE and A2M as well as down‐regulation of RAGE so that brain to blood Aβ clearance is facilitated. These results suggest a hitherto unknown effect of environmental enrichment counteracting the vascular dysfunction in Alzheimer diseased brain.