Volume 28, No. 5/2009(Sept/Oct)
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 Clinical Neuropathology
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Neurodegeneration
Localization of disease-related PrP in Danish patients with different subtypes of prion disease
A.-L. Bergström, P.M.H. Heegaard, H. Dyrbye, P. Lind and H. Laursen
Abstract
A.-L. Bergström1,2, P.M.H. Heegaard1, H. Dyrbye2, P. Lind1 and H. Laursen2
1National Veterinary Institute, The Technical University of Denmark, and 2The Neuropathology Laboratory, Rigshospitalet, Copenhagen, Denmark
Objective: The transmissible spongiform encephalopathies are characterized by vacuolization, neuronal loss, gliosis and deposition of a misfolded and Proteinase K resistant isoform of the prion protein (PrPSc) in the central nervous system. Methods, materials and patients: Paraffin-embedded tissue blot (PET-blot), immunohistochemistry (IHC) and Western blotting (WB) were combined to study the morphology and localization of disease related PrP in Danish patients with different subtypes of sporadic Creutzfeldt-Jakob disease, familiar Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease. Results and conclusion: There was a good morphological and anatomical concordance between what was found with PET-blot and IHC in all patients. In some specific cases, the PET-blot was superior to IHC in sensitivity. To our knowledge, this is the first report where PET-blot analysis is applied to hereditary forms of human transmissible spongiform encephalopathies and compared with sporadic cases of Creutzfeldt-Jakob disease.Correspondence to:
A.-L. Bergström, PhD
National Veterinary Institute
The Technical University of Denmark
Bülowsvej 27
1790 Copenhagen V, Denmark
Email: anlb@lundbeck.com
Neurodegeneration
Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies
H. Slodzinski, L.B. Moran, G.J. Michael, B. Wang, S. Novoselov, M.E. Cheetham, R.K.B. Pearce and M.B. Graeber
Abstract
H. Slodzinski1, L.B. Moran1, G.J. Michael2, B. Wang1, S. Novoselov3, M.E. Cheetham3, R.K.B. Pearce1 and M.B. Graeber1
1University Department of Neuropathology, Imperial College, University of London and Hammersmith Hospitals Trust, 2Neuroscience Center, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, and 3Department of Molecular and Cellular Neuroscience, UCL Institute of Ophthalmology, London, UK
Background: Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins. Methods: Based on microarray expression profiling results we have predicted an increased expression of HERPUD1 in the substantia nigra of Parkinson’s disease (PD) patients. We have now used brain tissue of some of the same and additional cases of sporadic PD to localize Herp mRNA and protein in individual cell types. Results: We found expression of Herp in neurons and in glial cells including astrocytes. These findings were corroborated by in situ hybridization. Accumulation of Herp protein was also detected in the core of Lewy bodies suggesting a role in their formation. Hierarchical clustering analysis identified TWINKLE (PEO1) as the gene whose expression profile was most similar to that of Herp across the PD cohort. Conclusions: The nigral glial cells that expressed Herp at a high level resembled TUNEL-positive glia. While some of these cells likely undergo degeneration, the strong up-regulation of Herp in glia could help to explain the inflammation-like changes observed in PD (“neuroinflammation”) as it has been shown that the unfolded protein response serves as an important regulator of inflammatory genes in other organs.Correspondence to:
Prof. M.B. Graeber, MD, PhD FRCPath
The Athenaeum
Pall Mall
London SW1Y 5ER, UK
Email: manuel@graeber.net
Neurodegeneration
The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia Type 6
K. Seidel, E.R.P. Brunt, R.A.I. de Vos, F. Dijk, H.J.L. van der Want, H.H. Kampinga, U. Rüb and W.F.A. den Dunnen
Abstract
K. Seidel1, E.R.P. Brunt2, R.A.I. de Vos3, F. Dijk4, H.J.L. van der Want4, H.H. Kampinga5, U. Rüb6 and W.F.A. den Dunnen1
1Department of Pathology and Medical Biology, 2Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, 3Laboratory for Pathology Oost Nederland, Enschede, 4Cell Biology, Electron microscopy, 5Cell Biology, Radiation and Stress Cell Biology, University of Groningen, Groningen, The Netherlands, and 6Institute of Clinical Neuroanatomy, J.W. Goethe University, Frankfurt/Main, Germany
Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e. pathologically altered a-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.Correspondence to:
Dr. W.F.A. den Dunnen
Department of Pathology and Medical Biology
University Medical Center Groningen
University of Groningen
Hanzeplein 1, P.O. Box 30.001
9700 RB Groningen, The Netherlands
Email: w.f.a.den.dunnen@path.umcg.nl
Neurodegeneration
Laminar distribution of the pathological changes in frontal and temporal cortex in 8 patients with progressive supranuclear palsy
R.A. Armstrong and N.J. Cairns
Abstract
R.A. Armstrong1 and N.J. Cairns2
1Vision Sciences, Aston University, Birmingham, UK and 2Departments of Neurology and Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
Objective: To determine the laminar distribution of the pathological changes in the cerebral cortex in progressive supranuclear palsy (PSP). Method: The distribution of the abnormally enlarged neurons (EN), surviving neurons, neurofibrillary tangles (NFT), glial inclusions (GI), tufted astrocytes (TA), and neuritic plaques (NP) were studied across the cortex in tau immunolabeled sections of frontal and temporal cortex in 8 cases of PSP. Results: The distribution of the NFT was highly variable with no consistent pattern of laminar distribution. The GI were distributed either in the lower laminae or uniformly across the cortex. Surviving neurons exhibited either a density peak in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. The EN and glial cell nuclei were distributed primarily in the lower cortical laminae. There were positive correlations between the densities of the EN and glial cell nuclei and negative correlations between the surviving neurons and glial cells. No correlations were present between the densities of the NFT and GI. Conclusion: Cortical pathology in PSP predominantly affects the lower laminae but may spread to affect the upper laminae in some cases. The NFT and GI may have different laminar distributions and gliosis occurs concurrently with neuronal enlargement.Correspondence to:
Dr. R.A. Armstrong
Vision Sciences
Aston University
Birmingham, B4 7ET, UK
Email: R.A.Armstrong@aston.ac.uk
Neurodegeneration
Evaluation of brain apoptosis in a CADASIL postmortem case
C. Battisti, P. Formichi, E. Radi, A. Malandrini and A. Federico
Abstract
C. Battisti, P. Formichi, E. Radi, A. Malandrini and A. Federico
O.U. of Neurometabolic Diseases, Department of Neurological, Neurosurgical and Behavioural Sciences, Policlinico “Le Scotte”, Siena, Italy
Objective: To evaluate the role of apoptosis in the pathogenesis of brain lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary microangiopathy leading to cognitive decline and dementia, caused by mutations in the NOTCH3 gene. Materials and methods: Detection of apoptotic nuclei in temporal lobe, brain stem, medulla oblongata, hippocampus and basal ganglia from one young CADASIL patient was performed by terminal deoxynucleotidyl transferase (TdT) – mediated dUTP nick end-labeling (TUNEL). Results: Our results showed a great involvement of glial cells in apoptotic cell death in the majority of the brain regions examined; neuronal apoptosis was significantly present only in the brain stem region. Conclusions: We hypothesized that in the early stages of the disease neuronal involvement of apoptosis is limited to the cells of the brain stem, sparing the cortical area which is involved in neuronal apoptosis and cognitive decline later.Correspondence to:
Prof. A. Federico
O.U. of Neurometabolic Diseases
Department of Neurological
Neurosurgical and Behavioural Sciences
Policlinico “Le Scotte”
Viale Bracci 2, 53100 Siena, Italy
Email: federico@unisi.it
Tumor
Clinical and immunohistochemical prognostic factors in adult glioblastoma patients
S. Umesh, A. Tandon, V. Santosh, B. Anandh, S. Sampath, B.A. Chandramouli and V.R. Sastry Kolluri
Abstract
S. Umesh1, A. Tandon2, V. Santosh2, B. Anandh1, S. Sampath1, B.A. Chandramouli1 and V.R. Sastry Kolluri1
1Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), and 2Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India
Objective: Glioblastomas are the commonest and the most malignant of all adult brain tumors, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. The utility of tumor markers that reflect their underlying biology is becoming increasingly important with respect to patient prognostication and their potential role as molecular targets of therapy is being recognized. In this study, we aimed to identify the clinical factors and some immunohistochemical markers that could have an effect on patient survival in supratentorial glioblastomas. Materials and methods: We evaluated 54 cases of adult supratentorial glioblastomas operated over a span of 1 year, with respect to clinical features such as age, Karnofsky performance score(KPS), extent of resection, adjuvant therapy, and immunohistochemical expression of p53, EGFR (Epidermal Growth Factor Receptor) and PTEN (Phosphatase and Tensin homolog). Results: Radiotherapy and KPS at presentation were significant predictors of outcome in both univariate and multivariate analyses. Among immunohistochemical variables; loss of PTEN expression in association with over-expression of EGFR showed a trend towards poorer survival, in univariate analysis. Over-expression of EGFR and/or p53 emerged as significant predictors of poor outcome on multivariate analysis, despite failing to prognosticate on univariate analysis. Conclusions: Our study shows that EGFR and p53 overexpression along with loss of PTEN expression are important adjuncts to clinical variables in prognosticating glioblastoma patients.Correspondence to:
Dr. V. Santosh
Additional Professor
Department of Neuropathology
National Institute of Mental Health and Neurosciences
Bangalore – 560029, India
Email: vani@nimhans.kar.nic.in
Tumor
Podoplanin is a potential marker for the diagnosis of ependymoma: a comparative study with epithelial membrane antigen (EMA)
K. Ishizawa, T. Komori, S. Shimada and T. Hirose
Abstract
K. Ishizawa1, T. Komori2, S. Shimada1 and T. Hirose1
1Department of Pathology, Saitama Medical University, Saitama, and 2Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neurological Science, Tokyo, Japan
Podoplanin is a mucin-type transmembrane sialoglycoprotein that is characteristically expressed in lymphatic endothelia. It is also expressed in the ependyma of the central nervous system as well as in ependymomas. Particularly, membrane-bound structures along the luminal surface, ring-like structures, and dot-like structures in the cytoplasm, all of which were originally reported for epithelial membrane antigen (EMA) immunohistochemistry in ependymoma, were also reported for podoplanin immunohistochemistry in ependymoma. This study was undertaken to evaluate podoplanin as compared with EMA as a marker of ependymoma. A total of 16 ependymomas (WHO Grade (G) II, 9 cases; GIII, 4; myxopapillary, 2; GIII clear cell, 1) were immunohistochemically studied using antibodies against podoplanin (clones D2-40 and NZ-1) as well as an antibody against EMA (clone E29). In all cases, D2-40 and NZ-1 excellently labeled linear signals along the luminal surface of ependymal canals/rosettes, dot-like structures, and/or ring-like structures, as did E29. These structures were generally more abundant in GII ependymomas than in GIII ependymomas. A semiquantitative analysis between the immunopositive structures of D2-40 or NZ-1 and E29 was conducted with a focus on the dot-like structures and the ring-like structures in the cases of GII and GIII ependymoma. The result showed that there was no statistical difference between D2-40 or NZ-1 and E29. Our study suggests that podoplanin is a potential marker for the diagnosis of ependymoma that corresponds to EMA. Anti-podoplanin antibodies and anti-EMA antibodies could cooperate with each other for the diagnostic immunohistochemistry of ependymoma.Correspondence to:
K. Ishizawa, MD
Department of Pathology
Saitama Medical University
Morohongo 38, Moroyama-town
Irumagun, Saitama, 350-0495, Japan
Email: ishizawa@saitama-med.ac.jp
Tumor
Unusual case of intraventricular gliosarcoma
A. Govindan, D.I. Bhat, A. Mahadevan, S. Chakraborti, S. Sampath, B.A. Chandramouli and S.K. Shankar
Abstract
A. Govindan1, D.I. Bhat2, A. Mahadevan1, S. Chakraborti1, S. Sampath2, B.A. Chandramouli2 and S.K. Shankar1
Departments of 1Neuropathology and 2Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India
Gliosarcoma is an uncommon variant of glioblastoma characterized by a biphasic pattern of glial and mesenchymal differentiation in the tumor. These tumors occur mostly in the cerebral hemispheres. Intraventricular location is extremely rare. Extensive review of literature revealed only two cases of intraventricular gliosarcoma. The first case arose by malignant transformation of a preexisting ependymoma. The second case was a gliosarcoma involving the frontal lobe with extension into the lateral ventricle. We report a case of an exclusively lateral ventricular tumor probably arising from the interventricular septum and blocking the CSF pathway. To the best of our knowledge, this is the first reported case of an exclusively intraventricular gliosarcoma.Correspondence to:
Dr. A. Mahadevan
Assistant Professor
Department of Neuropathology
National Institute of Mental Health and Neurosciences
Bangalore – 560 029, India
Email: amahadevan@nimhans.kar.nic.in
Tumor
Schwannosis induced medullary compression in VACTERL syndrome
A. Treacy, M. Redmond, B. Lynch, S. Ryan, M. Farrell and D. Devaney
Abstract
A. Treacy1, M. Redmond1, B. Lynch2, S. Ryan3, M. Farrell4 and D. Devaney1
Departments of 1Histopathology, 2Neurology, 3Radiology and 4Neuropathology, Children’s University Hospital, Temple Street, Dublin, Ireland
A 7-year-old boy with a history of VACTERL syndrome was found collapsed in bed. MRI had shown basilar invagination of the skull base and narrowing of the foramen magnum. Angulation, swelling and abnormal high signal at the cervicomedullary junction were felt to be secondary to compression of the medulla. Neuropathologic examination showed bilateral replacement of the medullary tegmentum by an irregularly circumscribed cellular lesion which was composed of elongated GFAP/S100-positive cells with spindled nuclei and minimal atypia. The pathologic findings were interpreted as intramedullary schwannosis with mass effect. Schwannosis, is observed in traumatized spinal cords where its presence may represent attempted, albeit aberrant, repair by inwardly migrating Schwann cells of peripheral origin. In our view the compressive effect of the basilar invagination on this boy’s medulla was of sufficient magnitude to have caused tumoral medullary schwannosis with resultant intermittent respiratory compromise leading to reflex anoxic seizures.Correspondence to:
Dr. A. Treacy
Department of Histopathology
Children’s University Hospital
Temple Street, Dublin 1, Ireland
Email: anntreacy@mac.com
Tumor
Primary pineal melanoma with leptomeningeal spreading: case report and review of the literature
G. Martin-Blondel, A. Rousseau, A.L. Boch, P. Cacoub and D. Sène
Abstract
G. Martin-Blondel1, A. Rousseau2, A.L. Boch3, P. Cacoub1 and D. Sène1
1Internal Medicine Department, 2Pathology Department and 3Neurosurgery Department, Pitie-Salpetriere Hospital, Paris, France
Objective: Primary melanomas of the pineal region are exceedingly rare and may be difficult to diagnose. Clinical, radiological and pathological features as well as diagnostic procedures are discussed. Case history: We report herein on a 44-year-old man who presented with uncontrolled epileptic seizures. Magnetic resonance imaging revealed a pineal mass hyperintense on T1-weighted and isointense on T2-weighted sequences with diffuse leptomeningeal involvement and intense homogeneous contrast enhancement after gadolinium administration. A frontal leptomeningeal and cortical biopsy was performed. Histological examination showed a malignant melanocytic tumor cell proliferation expressing Melan-A, but not HMB-45 or S100 protein. Even if we have no proof that the tumor actually arose in the pineal gland, based on the radiological and histological findings, and on the unremarkable dermatologic and ophthalmologic examinations, a primary pineal melanoma with leptomeningeal dissemination was diagnosed. The patient received temozolomide-based chemotherapy followed by whole brain irradiation. The patient died 52 weeks after disease onset and 13 weeks after treatment initiation. Conclusion: A diagnosis of pineal melanoma should be considered in the presence of a pineal mass that appears hyperintense on T1-weighted images and hypo- to isointense on T2-weighted images. The diagnosis is provided by pathological examination of tumor specimens obtained at surgical resection or at leptomeningeal biopsy. However, immunochemistry using anti-Melan-A, -S100 protein and/or -HMB45 antibodies on cerebrospinal fluid and leptomeningeal samples may be helpful in diagnosing such a disease. The prognosis of primary pineal melanoma is variable but meningeal spreading carries a dismal prognosis. The best therapeutic management is yet to be defined.Correspondence to:
Dr. D. Sène
Pitie-Salpetriere Hospital
Internal Medicine Department
47-83, Boulevard de l’Hôpital
75013 Paris, France
Email: damien.sene@psl.aphp.fr
Tumor
Diffuse follicle center lymphoma of the spine: a primary epidural lymphoma?
.B. Mesfin, D. Drazin, S. Berry, S. Homan, T. Nazeer and J.W. German
Abstract
.B. Mesfin1, D. Drazin2, S. Berry1, S. Homan3, T. Nazeer3 and J.W. German2
1The Neurosciences Institute, Division of Neurosurgery, Albany Medical Center, New York, 2Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA and 3Department of Pathology, Albany Medical Center, New York, NY, USA
A 72-year-old right-handed woman presented with a 6-month history of right thoracic wall discomfort. An MRI of the thoracic spine showed a small dumbbell-shaped mass centered within the right T7-8 foramen. The patient was asked to return to clinic for reevaluation to include a new MRI of the thoracic spine in 6 months. She did not comply with this recommendation and 1 year later, she presented with increasing difficulty ambulating and spastic paraparesis. A follow-up MRI of the thoracic spine now demonstrated significant interval growth of the mass with an extra-foraminal component extending into the thoracic cavity. She was taken to the operating room for resection of the epidural tumor. The pathology was consistent with diffuse follicle center lymphoma as cells were immunohistologically positive for CD20, CD10, BCL-2 and BCL-6. Primary spinal follicle center lymphomas of the spine are rare with the current case being the first diffuse follicle center type reported in the literature.Correspondence to:
F.B. Mesfin, MD, PhD
Division of Neurosurgery
Albany Medical Center
47 New Scotland Avenue
Albany, NY 12208, USA
Email: mesfinfb@mail.amc.edu
Abstracts
The Spanish Club of Neuropathology: Meeting, Barcelona, Spain, November 28 – 29, 2008
Euro-CNS News
Society News of the European Confederation of Neuropathological Societies
