Showing papers by "Herbert Budka published in 2013"

Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series

Abstract: Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77–87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.

Globular glial tauopathies (GGT): consensus recommendations

Abstract: Recent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunoreactive globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. Extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

Abstract: G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al-Sarraj, C. Troakes, I. Bodi, A. King, T. Hortobagyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar and H. Budka (2013) Neuropathology and Applied Neurobiology39, 166–178 Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49–96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aβ IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

JC virus granule cell neuronopathy and GCN–IRIS under natalizumab treatment

Abstract: Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

Intensity of human prion disease surveillance predicts observed disease incidence

Abstract: Background Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt–Jakob disease (CJD) and whether such measures correlate with disease incidence. Method From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17 610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28 780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. Results Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. Conclusions Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

Abstract: Background: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. Results: In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2–12 months; age at death: 55–81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrP res ) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrP res by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrP Sc ) in these cases, when the results were compared with appropriate negative control groups.

The Spectrum of Tau Pathology in Human Prion Disease

Abstract: Intracellular deposition of hyperphosphorylated tau characterizes tauopathies: there is a spectrum from neuron-predominant through mixed neuronal and glial, to glia-predominant forms. However, tau pathology appears in practically all forms of human prion disease. In addition to the rare cooccurrence of a primary tauopathy with prion disease, tau pathology may associate with prion diseases in distinct patterns: (1) small neuritic profiles correlating with tissue lesioning can be observed in all prion diseases; (2) larger dystrophic neurites may be observed around PrP amyloid plaques; and (3) neurofibrillary degeneration may follow the distribution described by Braak and Braak as Alzheimer-related pathology but might show atypical locations. It may be associated with prominent neuropil threads in subcortical regions in certain mutations with Creutzfeldt–Jakob disease (i.e., E200K mutation). Furthermore, widespread neurofibrillary degeneration in several subcortical, allocortical, and neocortical regions is consistently associated with certain PRNP mutations in Gerstmann–Straussler–Scheinker disease or PrP cerebral amyloid angiopathy. Other types of tau pathologies include the rare presence of glial tau immunoreactivity. In summary, widespread application of phospho-tau immunostaining has revealed a previously underrecognized spectrum of tau pathologies in human prion diseases. The relation between tau pathology and PrP deposition, and factors influencing its appearance in prion diseases merit further studies.

Foodborne viruses and prions and their significance for public health

Abstract: Thiemo Albert graduated in veterinary medicine at the University of Leipzig, Germany, in 2000 and then started an advanced training in food hygiene at the Federal Centre of Meat Research, Kulmbach, Germany. In 2003, he obtained a doctoral degree in veterinary medicine (DVM.) from the Ludwig Maximiliań s University of Munich, Germany, for his work on the growth potential and inactivation kinetics of Listeria monocytogenes in spreadable raw sausage. Since 2006, Thiemo Albert is affiliated with the Institute of Food Hygiene at the University of Leipzig as an assistant professor. In his current position he combines teaching veterinary public health in undergraduate and postgraduate courses with research on foodborne viruses, particularly focussing on the survival time and inactivation kinetics of viral pathogens during food processing.

External granular cell layer bobbling: a distinct histomorphological feature of the developing human cerebellum.

Abstract: Introduction: The external granular layer (EGL) of the developing human cerebellum is detectable until an age of ~ 1 year. It has been described as a thin, evenly calibrated layer of germinal cells. We have repeatedly observed a distinct discontinuous bobbled configuration of the EGL (external granular layer bobbling = EGLB) in human infantile autopsy brains. Aim, materials and methods: We investigated 106 human fetal and infantile postmortem brains (range of gestational week at birth: 14 - term; range of postpartal age: 0 - 500 days) for presence of EGLB and correlated it with gestational/postpartal age, gender, developmental stage of cerebellar cortex, medical history and neuropathological findings. Results: EGLB was detectable in 38/106 (35.8%) cases. EGLB presents as focal series of uniform knob-like protrusions of the EGL. In the notches between individual knobs, capillaries penetrate from the primitive leptomeningeal vascular plexus into the molecular layer. We found EGLB predominantly in depths of fissures of cerebellar hemispheres, vermis and/or tonsils. Presence of EGLB was statistically significantly more common in liveborn cases who died after gestational week 25 and cases with higher maturity grade of the cerebellar cortex, respectively. There was no gender difference. EGLB was not associated with medical history or neuropathological findings. Conclusions: EGLB is a distinct histomorphological feature of the developing cerebellum, which is predominantly found in infants. Our data indicate that EGLB is a physiological phenomenon occuring during cerebellar development at a certain gestational age, although we cannot exclude that it represents an artifact related to tissue fixation. In any case, recognition of this recurring feature is relevant for the practicing neuropathologist and should not be interpreted as a cerebellar migration disorder.

Foodborne viruses: an introduction

Abstract: During the last ten years viruses have been increasingly recognised as causative agents in foodborne disease outbreaks. Thus, in the EU, viral agents are identified as the second most common causative agent group in foodborne outbreaks, after Salmonella. Reasons for this include the improved diagnostic methods that have enhanced detection of some virus groups and the increased marketing of fresh and frozen foods that have led to a worldwide availability of high risk food.

Risk management for foodborne prions

Abstract: The European Community has introduced a comprehensive set of stringent measures targeting all animal and public health risks resulting from all animal transmissible spongiform encephalopathies (TSEs), and governing the entire chain of production and placing on the market of live animals and products of animal origin. In addition, comprehensive rules for monitoring of TSEs in bovine, ovine and caprine animals were introduced. The three key measures for the prevention, control and eradication of TSEs are the feed ban, the removal of specified risk materials and surveillance programmes. All Community measures on TSEs are based on sound, independent and transparent scientific advice and opinions from leading experts. Until May 2003, the scientific opinions were provided by the Scientific Steering Committee. Since May 2003, the scientific opinions are provided by the European Food Safety Authority (EFSA). The EU has made great strides in its battle against bovine spongiform encephalopathy (BSE), and the consistent fall in the number of BSE cases is testament to the efficacy of the stringent comprehensive EU measures put in place to tackle this disease. Even more, surveillance has shown that most cases were in cattle born and contaminated before the EU measures were introduced. This cross-over between human and animal health as shown by the case of BSE demonstrates the need for an approach that unifies veterinary and human medicine: animals + humans = one health.