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From: TSS ()
Subject: Neuropathological and molecular comparison between clinical and asymptomatic bovine spongiform encephalopathy cases
Date: October 14, 2007 at 11:01 am PST

Neuropathological and molecular comparison between clinical and asymptomatic bovine spongiform encephalopathy cases

Silvia Sisó1, 2, Marcus G. Doherr1, Catherine Botteron1, Rosemarie Fatzer1, Andreas Zurbriggen1, Marc Vandevelde1 and Torsten Seuberlich1

(1) NeuroCentre, Reference Laboratory for Transmissible Spongiform Encephalopathies in Animals, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Berne, Bremgartenstrasse 109A, 3001 Berne, Switzerland
(2) Present address: VLA-Lasswade, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, EH26 0PZ, UK

Torsten Seuberlich

Received: 7 June 2007 Revised: 9 August 2007 Accepted: 12 August 2007 Published online: 1 September 2007

Abstract Interest in the proper neuropathological and molecular characterization of bovine spongiform encephalopathy (BSE) has increased since asymptomatic and atypical cases were detected in the cattle population by active disease surveillance. In this respect we investigated a total of 95 confirmed BSE cases originating from different active and passive surveillance categories (clinical suspects, emergency-slaughter, fallen stock and routinely slaughter) in Switzerland for their neuropathological and molecular phenotype. We looked for measurable differences between these categories in lesion profile, severity of spongiform change, degree of astrocytosis as well as immunohistochemical and molecular patterns of the disease-associated isoform of the prion protein (PrPd) in the caudal brainstem. Our results indicate significantly higher intensities of spongiform change in clinically affected compared to asymptomatic BSE cases. Similar effects were in trend observed for the intensities of PrPd deposition and astrocytosis, whereas the frequencies of morphological PrPd types and the molecular patterns in Western immunoblot were not different. Importantly, none of the animals included in this study revealed features of atypical BSE. Taken together, this study suggests that both clinically affected as well as asymptomatic Swiss BSE cases in cattle share the neuropathological and molecular phenotype of classical BSE and that asymptomatic classical BSE cases are at a pre-clinical stage of the disease rather than representing a true sub-clinical form of BSE.


Atypical BSE is currently classified as H-type (high) or L-type (low) according to the apparent molecular mass of the unglycosylated PrPres fragment when compared to classical BSE by WB analysis using mAbs that bind to the central part of PrPres, like 6H4 [21]. Such differences are in the range of 1.4 kDa for H-type but very subtle or even absent for the L-type [6, 21]. By contrast the latter reveals a less intense band of the diglycosylated PrPres isoform (<50% of the total PrPres) whereas in classical BSE it was found to be more prominant (>50%) [21]. Additionally, in H-type cases mAbs binding to the N-terminus (e.g. P4) readily detect PrPres, which is not the case for classical and L-type BSE. Of all cases investigated in the present study by WB with mAbs 6H4 and P4 none revealed molecular features of H-type or L-type BSE and no differences in the molecular phenotype between the four categories were identified. It must be emphasized that for 24 animals appropriate frozen tissues were not available. Consequently the molecular phenotype for these animals could not be determined. For the remaining 71 cases it was clearly that of classical BSE.

Little is known about the histopathological and immunohistochemical characteristics of atypical BSE. In two Italian cases, Casalone et al. [7, 8] described the presence of PrPd positive amyloidotic plaques mainly in the RF and the nucleus of the STT of the brainstem as pathognomonic for L-type BSE, thus also termed bovine amyloidotic spongiform encephalopathy (BASE). These animals revealed a neuroanatomical PrPd distribution distinct from classical BSE and involved mainly the more rostral parts of the brain and to a lesser extent the caudal brainstem. By contrast amyloidotic plaques have not yet been described in bovine H-type BSE cases, but in the brain of mice after transmission of the H-type agent [2]. Recently we reported a miniature zebu presenting an H-type molecular PrPres pattern [28]. The type and distribution of the histopathological lesions as well as the PrPd depositions in the brain were undistinguishable from classical BSE in cattle. Whether this also applies for H-type BSE in cattle still remains to be determined. With the current knowledge and low incidence it appears difficult to discriminate H-type BSE cases on the basis of the PrP deposition types from classical BSE. However, it is possible that suitable tests based on the same principle as the epitope mapping IHC used for TSE strain discrimination in small ruminants [16, 22] could be developed in the near future. None of the animals investigated here, including the 24 cases that remained unclassified so far, revealed plaque- like PrPd depositions indicative for L-type BSE (or BASE).

In conclusion, the present retrospective study shows that the neuropathological phenotype of the Swiss BSE cases included in this study and the molecular phenotype of all cases where appropriate tissue was available is that of classical BSE and remains remarkably constant irrespective of the surveillance stream and therefore the clinical BSE status. However, significant differences in BSE related pathology exist between clinical and asymptomatic BSE cases, but are related to severity and spread of spongiform lesions in brainstem nuclei and can be explained by the progressive nature of the disease. Thus, these results suggest that asymptomatic animals with confirmed BSE were at a pre-clinical stage of the disease rather than representing a true sub-clinical form of BSE. Therefore, this study does not support the notion that classical BSE would be maintained as a clinically silent form of BSE in the cattle population. None of the BSE animals under investigation showed features of atypical BSE, but this study was limited in sample size and if atypical BSE as often speculated represents a sporadic TSE in bovine that mainly affects older animals, than its prevalence in a given population should be directly proportional to the numbers of older animals tested. Although the Swiss H-type zebu revealed clinical neurological signs indicative for BSE, we do not know whether this also applies for H- and L-type BSE cattle and consequently they may not fall into the CS surveillance category, which was highly represented, in the present study. Considering these caveats, ongoing more extended work will clarify whether and to which extend atypical BSE cases are part of the Swiss BSE epidemic.

Acknowledgements The authors acknowledge Nathalie Ligeti, Valérie Juillerat and Doris Ambühl for excellent technical assistance. We would like to thank Dr Lorenzo González and Dr Martin Jeffrey for critical reading of the manuscript and helpful discussions as well as Heinzpeter Schwermer for providing BSE surveillance data. The Swiss Federal Veterinary Office funded this study.

I find it odd to say the least that no mention of the fact that h-BASE data strongly support the link, or at least a common
ancestry, between a sCJD subtype, as stated below. why is this $ i suppose the fact that h-BASE in the USA, and the
continued increase of sporadic cjd of 'UNKNOWN STRAIN' is of no importance to anyone. pretty handy though,
out of sight, out of mind. ...TSS

BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc
C-terminal Truncated Fragments

We here show that the PrPSc pattern obtained in infected primates is identical to BASE
and sCJD MV-2 subtype. These data strongly support the link, or at least a common
ancestry, between a sCJD subtype and BASE.

This work was supported by Neuroprion (FOOD-CT-2004-506579)

Transmission of Italian BSE and BASE Isolates in Cattle Results into a
Typical BSE Phenotype and a Muscle Wasting Disease

This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease
phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated
cattle and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease.


Date: Mon, 24 Sep 2007 21:31:55 -0500

I suggest that you all read the data out about h-BASE and sporadic CJD, GSS,
blood, and some of the other abstracts from the PRION2007. ...


USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it
today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were
''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 2007
11:52 PM. ...TSS

PLEASE NOTE IN USA CJD UPDATE AS AT JUNE 2007, please note steady increase

1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 17 inconclusive and 9 pending (1 from 2006, 8
from 2007); 4 Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3
from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, *** 26 from 2007)

still disgusted in cloudy Baycliff, Texas .........flounder

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