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that TSE infection passes from the gut Heartbeat to diagnosing vCJD along the vagus nerve into an area of the Chris Pomfrett and colleagues at the ilies time to prepare for illness. There brain stem called the solitary nucleus, an University of Manchester, UK, may have have been 110 deaths to date from vCJD area that controls RSA. found the Holy Grail of prion research: a in the UK The team measured the heart-rate vari- simple, non-invasive test to diagnose pa- Designing TSE diagnostic tests has ability under laboratory conditions of tients with variant Creutzfeldt-Jakob dis- been a challenge not only because it is 150 cows that had received either single ease (vCJD) before clinical symptoms difficult to find low dose, a single show themselves. antibodies that high dose or no 1.4 Control The technique—a high-resolution elec- penetrate the 1.3 dose of BSE. 1.2 trocardiogram (ECG)—can identify a complex, folded 1.1 Pomfrett told 1.0 unique heart rate–variability signature structure of the 0.9 Nature Medicine caused by the early stages of infection. abnormal prion, that 2 animals 1.4 The test successfully predicted bovine but also because 1.3 High Dose that later died 1.2 spongiform encephalopathy (BSE) infec- prions have no ge- 1.1 from the disease 1.0 tion in cows before they showed signs of netic material to 0.9 both showed in- 0.0

disease, and will now be tested on sus- identify. The ECG Courtesy of Chris Pomfrett. creased levels of pected human vCJD patients in the UK. test, called Tachygrams show heart rate variability in BSE RSA as compared Currently, the only definitive means to Fathom, aims to animals with controls, diagnose BSE and vCJD—which are circumvent these and this ECG pat- among a group of prion-based infections problems by de- tern was detected known as transmissible spongiform en- tecting a condition called respiratory 8 months before the animals died. Also, cephalopathies (TSEs)—is by postmortem sinus arrhythmia (RSA). Fathom mea- the higher-dose animals showed a statis- examination of brain tissue. Detecting sures beat-to-beat variability in heart rate tically higher level of RSA than those vCJD before patients show clinical symp- with respect to breathing, and was origi- that had received the lower dose. “Of the toms is an urgent priority, as it could dra- nally designed to assess depth of anesthe- 700 patients that I have seen under anes- matically reduce the risk of sia during surgery. Pomfrett decided to thesia, I’ve never seen the effect to be so contaminating blood supplies and hospi- test whether RSA was affected in BSE-in- dramatic,” said Pomfrett. tal equipment and give patients and fam- fected animals, on the basis of the idea BSE appears to be the only brain-stem disease that increases sinus arrhythmia— other neurodegenerative diseases, such as TSE threat to US increases Parkinson’s disease, reduce it—making The US Department of Agriculture last month Fathom a potentially invaluable diagnos- © http://medicine.nature.com Group 2002 Nature Publishing confirmed that two sheep taken from a farm in tic tool. “One possible reason for this Vermont were infected with a form of transmissi- [may be] that once the dorsal vagal motor ble spongiform encephalopathy (TSE). Further nucleus, which is involved in blood pres- tests are being carried out to determine whether sure control, is knocked out by TSE infec- the disease is bovine spongiform encephalopathy tion, the brain stem becomes unstable (BSE) or scrapie. The sheep were imported from and the autonomic nervous system com- the Netherlands (Nature Med. 6, 1301; 2000). pensates by inducing sinus arrhythmia to Analysis will take at least two years, and if the try and maintain the blood pressure con- Aguzzi warns of CWD danger prion is that which causes BSE, this would be the trol,” suggests Pomfrett. first case of disease in the US. For human trials, a 5-minute ECG The TSE family of diseases also includes chronic wasting disease (CWD) in deer, a recording and breathing information will condition that has spread in the US in recent years (Nature 416, 569; 2002). Speaking be taken from the 7 people currently sus- at the Days of Molecular Medicine conference in La Jolla in March, prion expert Adriano pected of having vCJD in the UK, who Aguzzi issued a strong warning against underestimating this form of TSE. “For more will be monitored to see if the worsening than a decade, the US has by-and-large considered mad cows to be an exquisitely of symptoms can be predicted. European problem. The perceived need to protect US citizens from this alien threat The study is one of 22 being funded has even prompted the deferral of blood donors from Europe,” he said. “Yet the through a £7 million ($10 million) grant threat-from-within posed by CWD needs careful consideration, since the evidence from the UK Public Funders of TSEs that CWD is less dangerous to humans than BSE is less-than-complete. Research and Development group. Five Aguzzi went on to point out that CWD is arguably the most mysterious of all prion other projects will try to identify whether diseases. “Its horizontal spread among the wild population is exceedingly efficient, ‘surrogate markers’, such as levels of and appears to have reached a prevalence unprecedented even by BSE in the UK at its manganese and tau protein in cere- peak. The pathogenesis of CWD, therefore, deserves a vigorous research effort. brospinal fluid, are linked to TSEs. Other Europeans also need to think about this problem, and it would be timely and appro- studies will look more closely at infectiv- priate to increase CWD surveillance in Europe too.” Aguzzi has secured funding from ity, at how possible transmission risk can the National Institutes of Health to investigate CWD, and the effort will be lead by be assessed and at methods to assess the Christina Sigurdson in his department at the University of Zurich. effectiveness of decontamination proce- KAREN BIRMINGHAM, LONDON dures for surgical instruments. Simon Frantz, London

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