First, a brief summary of how human disease, vCJD (Variant Creutzfeldt-Jakob disease), is acquired from BSE (Bovine Spongiform Encephalopathy) (see figure below from).
Answer’s not straightforward for five main reasons.
One, vCJD (Variant Creutzfeldt-Jakob disease) Diagnosis Is Clinical. No Lab Test Exists.
One, there is as yet no diagnostic lab blood test to diagnose sCJD (sporadic CJD) and vCJD (variant CJD), i.e., disease from consuming BSE-infected food though one blood test is in development (2). Rather, they’re diagnosed based on clinical features. Only certain hereditary forms of human prion disease can be diagnosed by sequencing prion protein gene (PRNP) to identify disease-associated mutations. Lastly, iCJD (iatrogenic CJD)’s diagnosed through history of specific causal exposures such as human growth hormone treatment, surgical grafts such as human dura mater graft or even surgical instruments contaminated with tissue from undiagnosed and unidentified human sCJD cases ().
In essence, this question’s really about how many sCJD and iCJD are really vCJD and how many such cases are routinely being missed from being diagnosed.
Answer to that is relatively more straightforward because, indirect clinical diagnosis notwithstanding, vCJD features are compellingly stereotypical. First, an initial ~6 month period of increasing psychiatric symptoms that include depression, delusions and anxiety (4). Next, rapidly developing neurological symptoms such as confusion, ataxia (5), and involuntary movements. Onset to death is usually ~14 months (6), unlike ~4 months with classical CJD.
Now, it’s a different question entirely if humans are consuming or began to recently consume sources of prion-contaminated food other than BSE, food that could be vehicles for other types of transmissible prion diseases. At the moment that’s essentially unknown. However, intensive industrialization of agriculture with its inherent, myopic focus on efficiency and cost-cutting makes such a possibility an ever-present danger. This brings us directly to the 2nd reason.
Two, BSE Source: Cross-contamination From Pig And Poultry Meat and Bone Meal (MBM) Feed
Two, other as yet-unidentified prion sources and routes of exposure. vCJD, the human disease acquired through consumption of BSE-infected food came to light in 1996. Investigations quickly honed in on the possible source of disease, namely, cows fed cow(MBM), the presumed source of the original prion contamination. With bans on MBM in place, the number of vCJD cases have been declining year on year (see figure below from ).
These trends in human vCJD cases track the declining trends in BSE cases as well (see figure below from).
However, therein lies a man-made conundrum. Cows got prions from contaminated food and passed it onto humans who ate their meat. That contaminated food turned out to be MBM from other cows, and maybe some of that MBM was also contaminated with sheep scrapie. Protective measures in place for cows have been extended to sheep and goats but not to pigs and poultry who continue to be fed MBM. For e.g., in the UK the ban on feeding ruminant-derived MBM went into effect in July 1988. Instead of risk elimination, story turned out to be more convoluted. Why? Studies show cross-contamination of cattle feed with pig and poultry feed has sustained BSE risk in the UK (8, 9, 10), France (, ), Germany (13), Ireland ( ), Spain (15), Switzerland (16, 17). Additional studies provide compelling and significant statistical correlation that cows could indeed get BSE from such sources (18, , ). No surprise then that such cross-contamination of cattle feed (where MBM is banned) with pig and poultry feed (where MBM is not banned) serves to keep BSE risk alive. Segues us back to how we got here in the 1st place, namely, cows, natural herbivores, fed MBM, an utter perversion of nature itself. The inherently unsustainable structure of industrialized agriculture makes such perversions more not less likely, hence possibility of newer forms of transmissible prion diseases remain an ever-present danger. Could they produce forms of dementia different from vCJD? Theoretically possible.
Three, Experimental Studies Suggest Transmissible Prion Diseases Like vCJD Could Have Longer Incubation Periods Than Previously Suspected
Three, transmissible prion diseases could have extended silent incubation periods, much longer than previously anticipated. Macaques are currently the preferred animal model for human prion diseases. In one recent report, a group of cynomolgus macaques () were intracerebrally injected with animal prions. Most developed disease within 2 to 8 years in a dose-dependent manner, lower the injected dose, longer the disease-free survival. However, one injected with an intermediate dose of classical sheep brain scrapie developed symptoms only >9 years post-injection, i.e., ~40 to 45% of the way through its expected lifespan ( ), much longer than previously anticipated. This brings us directly to the fourth risk factor, namely, dose. This particular monkey was intra-cerebrally injected once with 25mg of scrapie-infected sheep brain. How to translate this to human risk factor? What dose and frequency of eating potentially BSE-contaminated food yields comparable vCJD risk? Currently not possible to accurately estimate.
Four, Possible Link Between Exposure Dose And Risk of BSE
At present, it’s more or less unknown what level of exposure it takes to develop vCJD. Some clues may come from risk assessments in cows. For e.g., studies found a higher incidence in autumn-born cows compared to spring-born ones (22, 23, 24, 25). Confirmed outside UK by one French study (26), this lends credence to a dosage link since spring-born calves would more likely graze on pasture, i.e., less reliance on processed food. OTOH, autumn-born calves would more likely be fed processed concentrates, the likely source of the disease. How does this relate to human risk for vCJD? Again, currently not possible to accurately estimate.
Five: Possible Genetic Susceptibility to vCJD
Apart from dose, another issue is genetic predisposition. Widespread exposure of the UK population in the 1980s and early 1990s to BSE prions from contaminated meat products resulted in vCJD. From then until 2014, a total of 177 cases of vCJD were definitively identified. There is a distinct genetic predisposition to vCJD, linked to a polymorphism in the prion protein gene (PRNP). This is the codon 129 polymorphism. Based on the polymorphism, three genotypes are possible, methionine (M)-methionine (M), i.e., 129MM or M-valine (V), i.e., 129MV, or 129VV. In one study of 300 blood donors in the UK, the distribution of these 3 genotypes was 42% 129MM, 47% 129MV and 11% 129VV (). OTOH, all the vCJD cases that have been genotyped turned out to be 129MM, i.e., methionine homozygous at the 129 codon of the PRNP gene ( , ).
Problem is that experimental mouse model studies suggest that all three 129 genotypes could get vCJD. It’s just that 129MM genotypes tend to develop it fastest while the other two, 129MV and 129VV, could have long asymptomatic incubation periods (30).
Thus, variable and possibly long incubation periods, and uncertainty about the dose and frequency of exposure to BSE-infected food necessary to manifest vCJD disease makes a clear-cut answer impossible.
1. Cristiana, Maurella, et al. “Bovine spongiform encephalopathy: history and diagnosis of a decreasing epidemic.”
2. Edgeworth, Julie Ann, et al. “Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay.” The Lancet 377.9764 (2011): 487-493.
3. Brown, Paul, et al. “Iatrogenic Creutzfeldt-Jakob disease, final assessment.” Emerg Infect Dis 18.6 (2012): 901-907.
4. Zeidler, M. R. C. P., et al. “New variant Creutzfeldt-Jakob disease: psychiatric features.” The Lancet 350.9082 (1997): 908-910.
5. Zeidler, M., et al. “New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests.” The Lancet 350.9082 (1997): 903-907.
6. Heath, C. A., et al. “Diagnosing variant Creutzfeldt–Jakob disease: a retrospective analysis of the first 150 cases in the UK.” Journal of Neurology, Neurosurgery & Psychiatry (2010): jnnp-2010.
7. Budka, Herbert, and Robert G. Will. “The end of the BSE saga: do we still need surveillance for human prion diseases?.” Swiss medical weekly 145 (2014): w14212-w14212.
8. Denny, G. O., and W. D. Hueston. “Epidemiology of bovine spongiform encephalopathy in Northern Ireland 1988 to 1995.” The Veterinary Record 140.12 (1997): 302-306.
9. Wilesmith, J. W. “Preliminary epidemiological analyses of the first 16 cases of BSE born after iuly 31, 1996, in Great Britain.” Veterinary record 151.15 (2002): 451-452.
10. Stevenson, M. A., et al. “Area-level risks for BSE in British cattle before and after the July 1988 meat and bone meal feed ban.” Preventive veterinary medicine 69.1 (2005): 129-144.
11. Ducrot, Christian, et al. “A spatio-temporal analysis of BSE cases born before and after the reinforced feed ban in France.” Veterinary research 36.5-6 (2005): 839-853.
12. Abrial, David, et al. “Poultry, pig and the risk of BSE following the feed ban in France–a spatial analysis.” Veterinary research 36.4 (2005): 615-628..
13. Kamphues, J., et al. “Risk assessment for animal derived feedstuffs as vectors for bovine spongiform encephalopathy (BSE) in Germany. Part I: Comparative risk assessment for animal derived feedstuffs.” Deutsche Tierarztliche Wochenschrift 108.7 (2001): 283-290.
14. Sheridan, Hazel A., et al. “A temporal-spatial analysis of bovine spongiform encephalopathy in Irish cattle herds, from 1996 to 2000.” Canadian Journal of Veterinary Research 69.1 (2005): 19.
15. Allepuz, A., et al. “Spatial analysis of bovine spongiform encephalopathy in Galicia, Spain (2000–2005).” Preventive veterinary medicine 79.2 (2007): 174-185.
16. Doherr, M. G., et al. “Geographical clustering of cases of bovine spongiform encephalopathy (BSE) born in Switzerland after the feed ban.” The Veterinary Record 151.16 (2002): 467-472.
17. Schwermer, H., and D. Heim. “Cases of bovine spongiform encephalopathy born in Switzerland before and after the ban on the use of bovine specified risk material in feed.” The Veterinary Record 160.3 (2007): 73-77.
18. Stevenson, M. A., et al. “Area-level risks for BSE in British cattle before and after the July 1988 meat and bone meal feed ban.” Preventive veterinary medicine 69.1 (2005): 129-144.
19. Jarrige, Nathalie, et al. “Case-control study on feed risk factors for BSE cases born after the feed ban in France.” Veterinary research 38.3 (2007): 505-516.
20. Paul, Mathilde, et al. “Bovine spongiform encephalopathy and spatial analysis of the feed industry.” Emerging Infectious Diseases 13.6 (2007): 867.
21. Comoy, Emmanuel E., et al. “Transmission of scrapie prions to primate after an extended silent incubation period.” Scientific reports 5 (2015).
22. Wells, Gerald A., et al. “A novel progressive spongiform encephalopathy in cattle.” The Veterinary Record 121 (1987): 419-20.
23. Wilesmith, J. W., J. B. M. Ryan, and W. D. Hueston. “Bovine spongiform encephalopathy: case-control studies of calf feeding practices and meat and bonemeal inclusion in proprietary concentrates.” Research in veterinary science 52.3 (1992): 325-331.
24. Hoinville, L. J., J. W. Wilesmith, and M. S. Richards. “An investigation of risk factors for cases of bovine spongiform encephalopathy born after the introduction of the’feed ban’.” The Veterinary Record 136.13 (1995): 312-318.
25. Braun, U., E. Schicker, and B. Hörnlimann. “Diagnostic reliability of clinical signs in cows with suspected bovine spongiform encephalopathy.” The Veterinary Record 143.4 (1998): 101-105.
26. Braun, U., et al. “[Clinical examination upon suspicion of bovine spongiform encephalopathy (BSE)].” Schweizer Archiv fur Tierheilkunde 139.1 (1996): 35-41.
27. Nurmi, M. H., et al. “The normal population distribution of PRNP codon 129 polymorphism.” Acta neurologica scandinavica 108.5 (2003): 374-378.
28. Diack, Abigail B., et al. “Constant transmission properties of variant Creutzfeldt-Jakob disease in 5 countries.” Emerging infectious diseases 18.10 (2012): 1574.
29. Diack, Abigail B., et al. “Variant CJD: 18 years of research and surveillance.” Prion 8.4 (2014): 286-295.
30. Bishop, M. T., et al. “Predicting susceptibility and incubation time of human-to-human transmission of vCJD.” The Lancet Neurology 5.5 (2006): 393-398.