Herbert Budka

University Hospital Zürich, Zürich, Zurich, Switzerland

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Publications (451)2307.25 Total impact

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    ABSTRACT: Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrP(Sc), a misfolded and aggregated form of the cellular prion protein (PrP(C)). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.
    Science translational medicine 08/2015; 7(299):299ra123-299ra123. DOI:10.1126/scitranslmed.aab1923 · 15.84 Impact Factor
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    ABSTRACT: We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62×10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66×10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00×10-8) and rs6951643 (p-value=3.91×10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.
    PLoS ONE 04/2015; 10(4):e0123654. DOI:10.1371/journal.pone.0123654 · 3.23 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Journal of Neuropathology and Experimental Neurology 02/2015; 74(3). DOI:10.1097/NEN.0000000000000173 · 3.80 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 01/2015; 86(7). DOI:10.1136/jnnp-2014-309871 · 6.81 Impact Factor
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    ABSTRACT: Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.
    PLoS Pathogens 12/2014; 10(12):e1004531. DOI:10.1371/journal.ppat.1004531 · 7.56 Impact Factor
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    ABSTRACT: Objective To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study.Methods Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs.ResultsFourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortality rates in the normal MRIs, WML-MRI and ML-MRI were 4%, 9.1%, and 22.2%, respectively, and follow-up MRIs were available for 80%, 82%, and 61% of the participants, respectively. In the BD-MRI, however, five patients were deceased, and only five follow-up individual MRIs were available (33.3%). Autopsies were performed on six of eight BD-MRI brains, and these brains fulfilled the pathological criteria for BD independent of Alzheimer disease pathology. All these six individuals also showed systemic atherosclerosis and renal arterio-arteriolosclerosis.InterpretationThe BD-MRI participants had poor prognoses and showed pure BD pathology with advanced systemic vascular disease. BD-MRI appears to be a predictor of vascular neurocognitive impairment.
    10/2014; 1(10). DOI:10.1002/acn3.123

  • European geriatric medicine 09/2014; 5:S104. DOI:10.1016/S1878-7649(14)70244-X · 0.73 Impact Factor
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    ABSTRACT: Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of β-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular–structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for β-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.
    Neurobiology of Disease 09/2014; 69:76–92. DOI:10.1016/j.nbd.2014.05.020 · 5.08 Impact Factor

  • European geriatric medicine 09/2014; 5:S171. DOI:10.1016/S1878-7649(14)70447-4 · 0.73 Impact Factor
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    ABSTRACT: Objective We sought to identify the prevalence of MRI features of disproportionately enlarged subarachnoid space hydrocephalus in possible idiopathic normal pressure hydrocephalus (DESH-iNPH) and to describe the clinico-radiological features and outcomes of a community-based investigation (The Vienna Trans-Danube Aging study).Methods Of the 697 inhabitants (all 75 years old), 503 completed extensive neurological examinations at baseline and were followed up every 30 months thereafter with MRIs, mini-mental state examination (MMSE), and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). The DESH-iNPH participant data were compared with the data from participants with Evans index ratios >0.3 (ex vacuo hydrocephalus), cerebral small-vessel diseases, and normal MRIs. The widening of perivascular space was also evaluated by MRI in these groups.ResultsEight participants with DESH-iNPH (1.6%) and 76 with ex vacuo hydrocephalus (16.1%) at baseline were identified. The mean MMSE in DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs was 26.4, 27.9, and 28.3, respectively, and the mean UPDRSM was 9.75, 2.96, and 1.87, respectively. After a 90-month follow-up, the mortality rates for DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs were 25.0%, 21.3%, and 10.9%, respectively. The perivascular-space widening scores were significantly smaller in the DESH-iNPH cases, particularly at the centrum semiovale, compared to cerebral small-vessel disease and ex vacuo hydrocephalus cases.InterpretationThe prevalence of DESH-iNPH was 1.6% for participants aged 75 years and revealed significantly lower MMSE and higher UPDRSM scores compared to the ex vacuo hydrocephalus and controls. Moreover, it is suggested that perivascular-space narrowing is a morphological and pathophysiological marker of DESH-iNPH.
    08/2014; 1(8). DOI:10.1002/acn3.87
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    ABSTRACT: Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naïve patient. Based on recent data from genomic studies, we propose that a sequential evolution of molecular pathology lead to the co-occurrence of multiple myeloma and primary central nervous system B cell lymphoma in this patient, and interpret the development of the temporal lobe leukoencephalopathy as a likely paraneoplastic complication of smoldering myeloma.
    Ideggyógyászati szemle 03/2014; 67(3-4):135-9. · 0.39 Impact Factor
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    ABSTRACT: 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. 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 (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres 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 (PrPSc) in these cases, when the results were compared with appropriate negative control groups. Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases.
    11/2013; 1(1):72. DOI:10.1186/2051-5960-1-72
  • Gabor G Kovacs · Herbert Budka ·
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    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-Sträussler-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. © 2013 Springer Science+Business Media New York. All rights are reserved.

  • Journal of the Neurological Sciences 10/2013; 333:e613. DOI:10.1016/j.jns.2013.07.2137 · 2.47 Impact Factor
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    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.
    Acta Neuropathologica 08/2013; 126(4). DOI:10.1007/s00401-013-1171-0 · 10.76 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of neurology, neurosurgery, and psychiatry 08/2013; 84(12). DOI:10.1136/jnnp-2012-304820 · 6.81 Impact Factor
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    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.
    Acta Neuropathologica 07/2013; 126(3). DOI:10.1007/s00401-013-1157-y · 10.76 Impact Factor

Publication Stats

14k Citations
2,307.25 Total Impact Points


  • 2013-2015
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
    • University of Melbourne
      • Department of Pathology
      Melbourne, Victoria, Australia
  • 2004-2015
    • Medical University of Vienna
      • Clinical Department of Virology
      Wien, Vienna, Austria
  • 2013-2014
    • University of Zurich
      • Institut für Neuropathologie
      Zürich, Zurich, Switzerland
  • 2010-2014
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
  • 2009
    • Boston University
      Boston, Massachusetts, United States
  • 1979-2009
    • University of Vienna
      • • Institute of Neurophysiology
      • • Institute of Clinical Neurobiology
      Vienna, Vienna, Austria
  • 2007
    • Friedrich Loeffler Institute
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2006
    • University College London
      • Institute of Neurology
      Londinium, England, United Kingdom
  • 2004-2006
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 2005
    • University of Lodz
      Łódź, Łódź Voivodeship, Poland
  • 1995-2004
    • Institute of Neurology
      Moskva, Moscow, Russia
    • Austrian Academy of Sciences
      Wien, Vienna, Austria
    • National Institutes of Health
      • Unit on Behavioral Neurogenetics
      베서스다, Maryland, United States
  • 2002
    • Kyoto University
      • Department of Neurology
      Kioto, Kyōto, Japan
    • Krankenhaus der Barmherzige Schwestern
      Linz, Upper Austria, Austria
  • 1999
    • Robert Koch Institut
      Berlín, Berlin, Germany
  • 1997
    • University of Veterinary Medicine in Vienna
      • Institute of Pathology and Forensic Veterinary Medicine
      Wien, Vienna, Austria
  • 1994
    • Markusovszky University Teaching Hospital, Szombathely
      Olad, Vas, Hungary
  • 1993
    • National Hospital Organization Minami Kyoto Hospital
      Kioto, Kyōto, Japan
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 1990
    • University of Milan
      Milano, Lombardy, Italy
  • 1985
    • TNO
      Delft, South Holland, Netherlands