Introduction (1)
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare
degenerative prion disease that is inevitably fatal (Chen & Dong, 2016).
Though rare, sCJD is the most common form of prion disease with a worldwide
incidence ratio of approximately one per million (Sitammagari & Masood,
2022). The randomness and rarity with which sCJD strikes make etiological
inquiry especially difficult. No clear cause has been identified, and
researchers have cast a wide net to identify possible risk factors. Though
incredibly useful, identifying potential risk factors is only one side of the
coin, and identifying potentially protective factors may yield additional
benefits. In this paper, I review currently postulated risk factors for sCJD
and draw on sCJD’s similarities with Alzheimer’s Disease (AD) to provide a
theoretical basis for including potential protective factors in case-controlled
sCJD studies. Finally, I conduct a multi-country longitudinal regression that
suggests at least some AD protective factors might protect against sCJD risk as
well.
Current literature indicates that an abnormal
protein designated PrPSc is the infectious pathogen responsible for human prion
diseases, but the mechanism by which this sporadic disease manifests is not yet
understood (Safar, 2012). One theory advocates a spontaneous somatic mutation
in the PRNP gene (Prusiner, 2001). A second theory holds that PrPSc-like
isoforms may be present and bound to heat shock proteins even in normal brains,
but that this protective measure fails with aging (Safar et al., 2005; Yuan et
al., 2006). It has also been posited that low-level exposure to a common
external factor can be to blame for at least some cases of sCJD (Linsell et
al., 2004).
Although the specific trigger or activation factor
for sCJD is not known, onset typically occurs at a median age of 68 with a
standard deviation of approximately 9 years (Feng et al., 2021; Tam et al.,
2022) making age a well-known risk factor (CDC, 2022). Likewise,
numerous studies have shown an over-representation of 129M/M
homozygotes (Kobayashi et al., 2015; Mitrová et al., 2005) in sCJD cases compared to controls, and genetic
susceptibility has been known for decades (Deslys et al., 1994).
Though the disease is sporadic, the well-documented
risk factors of age and 129M/M homozygosity make it clear that each
individual's risk of being affected is not uniformly random and that there are
at least some factors that make the initiation of this sporadic process more or
less likely. Though elusive, uncovering additional risk factors could help
develop a more thorough understanding of sCJD and provide a basis for
risk-modifying behaviors.
Potential sCJD Risks (1.1)
To uncover potential risk factors, researchers have investigated the link between sCJD and surgery (Hamaguchi
et al., 2009; van Duijn et al., 1998; Ward et al., 2002, 2008), ocular tonometry (Davanipour et al., 2014b), profession (Hermann et al., n.d.), physical injuries (Kondo & Kuroiwa, 1982), living with pets (Harries-Jones et al., 1988), and dementia in relatives (Harries-Jones et al.,
1988). While factors such as needing surgery or
dental work are scarcely modifiable, several interesting studies have examined
a possible link between sCJD and highly modifiable dietary factors.
Even before the vCJD epidemic of the late 80s to
90s, Davanipour et al. (1985) found that increased consumption of roast pork,
ham, hot dogs, roast lamb, pork chops, smoked pork, scrapple, rare meat, and
raw oysters/clams, liver, and organs was greater among sCJD patients than case
controls. The relationship between diet and sCJD was further described by the
UK’s National CJD Surveillance Unit report that found patients were more likely
than controls to have ever eaten lamb or beef, venison, veal, sweetbreads
(organ meat), or brains (1996). In a confirmatory case-control study using
primarily data from pre-vCJD publicity, Davanipour et al. (2014a) found that
consumption of hot dogs, sausage, pepperoni, kielbasa, “other” canned meat,
poultry liver, any stomach/intestine, beef stomach/intestine, any organ tissue,
and beef organ tissue was individually associated with increased sCJD risk.
The clear distinction that the aforementioned
studies make, both in terms of timing as well as diagnostic criteria, between
vCJD and sCJD is vital because it implies that certain foods, particularly
meats, not only act as transmission vehicles for the variant form of CJD but
that dietary factors may impact the susceptibility to the non-infectious,
sporadic form of the disease as well. Though these studies demonstrated dietary
risk factors, an exciting corollary is the possibility of yet unknown
protective dietary factors.
Similarities with Alzheimer's (1.2)
Asuni (2015) stated that the common theme in the
pathogenesis between AD and prion disorders indicates that analogous
degenerative processes are likely at play. Extending this statement implies
that research into other forms of dementia might not only present a potential
rationale for an association between diet and sCJD but a possible short list of
dietary factors worthy of inclusion in sCJD questionnaires. A brief overview of
the similarities between sCJD and AD, in which 90% of cases also occur
sporadically, (Bekris et al., 2010) is provided to support this theory.
Debatin et all, (2008) note that Alzheimer’s disease (AD) and prion
diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common
features concerning their molecular pathogenesis and neuropathological
presentation. This observation is strengthened when considering that AD and
sCJD “have many common features impinging on
the metabolism of neuronal membrane proteins” (Aguzzi & Haass, 2003) and that Alzheimer's disease is a consequence of protein
misfolding, aggregation, and spread (Carlson & Prusiner, 2021).
Given that Alzheimer’s exhibits at least some of
the misfolded prion protein properties,(Jaunmuktane & Brandner,
2020) it is plausible that factors that increase or decrease AD risk might play
a role in sCJD risk as well.
Assuming that the disease pathogenesis between AD
and sCJD is comparable enough that there is at least some crossover between
risk factors, sCJD researchers might benefit from including AD protective
factors in future sCJD studies. While many lifestyle factors such as physical
activity (Iso-Markku et al., 2022) and social/cognitive leisure activities (Su
et al., 2022) have been found to protect against AD, the finding of a dietary
risk for AD (Duplantier & Gardner, 2021) presents the ideal vehicle for
exploring possible empirical support of a theoretical carryover of AD
protective factors to sCJD research as dietary data is freely available from
reputable sources at no cost and requires no clinical intervention. If a
dietary carryover is identified, then other AD protective factors which require
more detailed investigative methods could be studied in the future.
Materials and Methods (2)
To support the theory that AD-protective foods may
also protect against sCJD, I present a fixed-effects panel data regression
analysis that compares the AD-protective foods identified by Duplantier &
Gardner, (2021) against population-level sCJD rates.
To ensure the validity of sCJD incidence data and
minimize the effect of differential reporting, all data regarding sCJD cases
were collected from the Creutzfeldt-Jakob Disease International Surveillance
Network. Dietary data were collected from the United Nations FAOSTAT database (FAOSTAT,
n.d.), and the median age was gathered from the United Nations (World
Population Prospects - Population Division - United Nations, n.d.)
database. Python’s Pandas library was used to merge data from all sources into
a consolidated panel which was subsequently analyzed using the gretl 2022C
econometrics package.
Results (3)
As expected from the literature review, a higher
median age demonstrated a significant (p~.004) positive association with sCJD
incidence. The neuroprotective effects of nuts (p~.002) demonstrated in other
dementia research were reflected in this study alongside the borderline
(p~.094) protective effect of bean consumption. Fish showed no significant
effect.
Table I.
Key Regression Values.
Table I.
Key Regression Values.
|
Coefficient |
Std. Error |
t-ratio |
p-value |
|
Constant |
−4.088 |
2.1328 |
−1.917 |
0.0668 |
* |
Fish |
0.001 |
0.0203 |
0.0556 |
0.9561 |
|
Age |
0.175 |
0.0576 |
3.0290 |
0.0056 |
*** |
Nuts |
−0.224 |
0.0554 |
−4.043 |
0.0004 |
*** |
Beans |
−0.433 |
0.2490 |
−1.740 |
0.0941 |
* |
Calories |
−0.0002 |
0.0007 |
−0.2430 |
0.8100 |
|
It should be noted that the fixed effects model used in this analysis treats each country in the study as its own control to minimize the impact that omitted time-invariant factors have on the analysis. In other words, the model can yield valid results even if a country under/over reports its sCJD rate compared to other countries, so long as this deviation in reporting is chronic and consistent within that country. Sudden spikes in reporting, however, would pose a problem and are discussed later. Likewise, the fixed effects model accounts for genetic heterogeneity among countries so long as there is no major genetic drift during the study. Given the short duration of the study, intergenerational genetic drift is unlikely and genetic equilibrium is assumed.
Discussion (4)
The similarity between AD and sCJD, combined with the finding that two factors that protect against AD also appear to protect against sCJD risk, highlights the similarity between these two sporadic diseases and offers a rational justification for including potential protective factors in future sCJD case-controlled studies.
The thesis of this paper is not that sCJD is a dietary disease or that diet can prevent sCJD, but rather that there is sufficient similarity between sCJD and AD that possible protective factors should be included in sCJD studies as they are in almost all other forms of dementia research. If researchers hypothesize that certain factors such as living with pets, getting surgery, or consuming certain foods increase the risk of sCJD, a logical corollary is that some yet unknown factors may likewise decrease risk. Factors found to be protective in other fields of dementia research are natural candidates for initial consideration.
The significant amount of time needed to identify sCJD cases and appropriate controls also presents an economic argument for including protective factors in sCJD questionaries. Davanipour et al., (2014a) required approximately 30 hours of work for each control included in the study. With so much time being spent on identifying sCJD cases and controls, maximizing the information gleaned from each study is paramount. Compared to the massive time required to identify participants, the inclusion of a few questions regarding potential protective factors contributes little to the cost or time burden of the study but may provide additional insight.
The protective questions should prove no more invasive or difficult to answer for the patient's family than the long-established practice of asking about surgical history or meat consumption. While each sCJD researcher is encouraged to draw on their expertise to decide what potentially protective factors to include in their questionaries, this study suggests that dietary factors which protect against AD might be a good starting point. If initial research indicates that AD-protective foods also show a potentially preventative effect on sCJD, then subsequent inquiry can further develop this relationship by making a more detailed inquiry of food groups as well as other AD-protective habits such as exercise and social engagement that might influence sCJD risk.
Limitations (4.1)
In common with all population-based, non-intervention studies, this research should not be intended to imply a causal relationship between any variables. Given that sCJD cases have historically been under-reported, the potential for differential reporting to influence results is a possible limitation. The panel data fixed effects regression used in this study can accommodate under or over-reporting so long as this over/under-reporting does not suddenly change through increased/decreased surveillance efforts.
Though massive shifts in surveillance are possible, it is unlikely given that all the data in this study was specifically gathered after Europe-wide TSE reporting was instituted in 1999 (EuroCJD, n.d.) and after the vCJD epidemic had already increased surveillance efforts.
The inclusion of countries with relatively small populations also presented a limitation in terms of outliers in the regression analysis. Though the average incidence among small countries regresses to the mean across a multi-year time frame, the sporadic distribution of sCJD cases in small countries means that there are years in which not a single case is reported and in other years, it appears that there is a sudden spike in cases as a compensatory higher rate of cases are reported. In this case, the random nature of the disease may cause a country with a very small population to show a doubling or halving of disease incidence from one year to the next even when explanatory variables show little change.
It should be noted that such “small countries” constituted a relatively minor portion of the total cases and that preserving the unaltered quality of the data was judged to be more important than dropping countries to produce a more pristine model. To confirm the limited impact of such “small countries” a follow-up regression was conducted in which any country that reported zero sCJD cases at any point during the study period was removed from the model altogether. The secondary model with 22 countries instead of 26 substantiated the direction and magnitude of relationships among variables in the first study, but the p-value for bean consumption (.136) in the follow-up study was greater than the p-value of (.094) in the primary analysis making it non-significant at any commonly accepted cutoff.
Lastly, data aggregation at the FAOSTAT level made testing all of the AD-protective foods in Duplantier & Gardner’s (2021)’s meta-analysis impossible as FAOSTAT doesn't report a “whole grain” category. Simply aggregating other grain categories is insufficient because they may or may not be consumed whole. For this reason, the category of whole grains was dropped from the study leaving nut, fish, and bean consumption as the three dietary explanatory variables.
Conclusion (5)
Sporadic Creutzfeldt-Jakob disease is a rapidly progressive, invariably fatal neurodegenerative disease with a worldwide incidence of approximately one per million. The rarity of this disease makes etiological inquiry difficult, and few risk factors have yet to be identified.
In this study, I present a multi-country, ecological analysis that indicates that the neuroprotective effect of nut and bean consumption against AD also appears to be protective against population-level sCJD rates. As with all non-interventional, population-based studies, this study should not be construed as “proving” that certain foods protect against sCJD risk. Rather, these findings suggest that some factors which reduce the risk of AD might also reduce sCJD risk. Studies that solely focus on hypothesized risk-increasing factors leave half the equation off the table, and including a few questions regarding potentially protective factors may yield great additional insight with little additional cost or time commitment to the study. Though there are potentially innumerable factors that could decrease/increase sCJD risk, this literature review, and the findings of the multi-country analysis, suggest that including factors that have been demonstrated to reduce AD risk would be a logical starting point for inclusion in sCJD research.
References
- Aguzzi, A., & Haass, C. (2003). Games Played by Rogue Proteins in Prion Disorders and Alzheimer’s Disease. Science, 302(5646), 814–818. [CrossRef]
- Asuni, Ayodeji. A., Guridi, M., Sanchez, S., & Sadowski, M. J. (2015). Antioxidant Peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo. Neurochemistry International, 90, 152–165. [CrossRef]
- Baissa, D. K., & Rainey, C. (2020). When BLUE is not best: Non-normal errors and the linear model. Political Science Research and Methods, 8(1), 136–148. [CrossRef]
- Bekris, L. M., Yu, C.-E., Bird, T. D., & Tsuang, D. W. (2010). Genetics of Alzheimer Disease. Journal of Geriatric Psychiatry and Neurology, 23(4), 213–227. [CrossRef]
- Carlson, G. A., & Prusiner, S. B. (2021). How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders. International Journal of Molecular Sciences, 22(9), 4861. [CrossRef]
- Chen, C., & Dong, X.-P. (2016). Epidemiological characteristics of human prion diseases. Infectious Diseases of Poverty, 5(1), 47. [CrossRef]
- Cottrell, A., & Lucchetti, J. (2022). Gretl User’s Guide. 235.
- Davanipour, Z., Alter, M., Sobel, E., Asher, D. M., & Gajdusek, D. C. (1985). A case-control study of Creutzfeldt-Jakob disease. Dietary risk factors. American Journal of Epidemiology, 122(3), 443–451. [CrossRef]
- Davanipour, Z., Sobel, E., Ziogas, A., Smoak, C., Bohr, T., Doram, K., & Liwnicz, B. (2014a). Dietary Risk Factors for Sporadic Creutzfeldt-Jakob Disease: A Confirmatory Case-Control Study. British Journal of Medicine and Medical Research, 4(12), 2388–2417. [CrossRef]
- Davanipour, Z., Sobel, E., Ziogas, A., Smoak, C., Bohr, T., Doram, K., & Liwnicz, B. (2014b). Ocular Tonometry and Sporadic Creutzfeldt - Jakob Disease (sCJD): A Confirmatory Case-Control Study. British Journal of Medicine and Medical Research, 4(12), 2322–2333. [CrossRef]
- Debatin, L., Streffer, J., Geissen, M., Matschke, J., Aguzzi, A., & Glatzel, M. (2008). Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease. Neurodegenerative Diseases, 5(6), 347–354. [CrossRef]
- Deslys, J.-P., Marcé, D., & Dormont, D. 1994. (1994). Similar genetic susceptibility in iatrogenic and sporadic Creutzfeldt-Jakob disease. Journal of General Virology, 75(1), 23–27. [CrossRef]
- Duplantier, S. C., & Gardner, C. D. (2021). A Critical Review of the Study of Neuroprotective Diets to Reduce Cognitive Decline. Nutrients, 13(7), 2264. [CrossRef]
-
European Creutzfeldt-Jakob Disease Surveillance Network (EuroCJD). (n.d.). European Centre for Disease Prevention and Control. Retrieved December 25, 2022, from https://www.ecdc.europa.eu/en/about-us/who-we-work/disease-and-laboratory-networks/european-creutzfeldt-jakob-disease.
-
FAOSTAT. (n.d.). Retrieved November 28, 2022, from https://www.fao.org/faostat/en/#home.
- Feng, S., Zhao, X., Zhou, X., Ye, X., Yu, X., Jiang, W., Deng, Y., Zhou, S., Ma, L., Shan, P., & Zhou, G. (2021). Epidemiological and Clinical Characteristics of Sporadic Creutzfeldt–Jakob Disease: A Retrospective Study in Eastern China. Frontiers in Neurology, 12. https://www.frontiersin.org/articles/10.3389/fneur.2021.700485.
- Hamaguchi, T., Noguchi-Shinohara, M., Nozaki, I., Nakamura, Y., Sato, T., Kitamoto, T., Mizusawa, H., & Yamada, M. (2009). Medical procedures and risk for sporadic Creutzfeldt-Jakob disease, Japan, 1999-2008. Emerging Infectious Diseases, 15(2), 265–271. [CrossRef]
- Harries-Jones, R., Knight, R., Will, R. G., Cousens, S., Smith, P. G., & Matthews, W. B. (1988). Creutzfeldt-Jakob disease in England and Wales, 1980-1984: A case-control study of potential risk factors. Journal of Neurology, Neurosurgery & Psychiatry, 51(9), 1113–1119. [CrossRef]
- Hermann, P., Treig, J., Unkel, S., Goebel, S., Bunck, T., Jünemann, M., Friede, T., & Zerr, I. (n.d.). Sporadic Creutzfeldt-Jakob Disease among Physicians, Germany, 1993–2018—Volume 26, Number 8—August 2020—Emerging Infectious Diseases journal—CDC. [CrossRef]
- Iso-Markku, P., Kujala, U. M., Knittle, K., Polet, J., Vuoksimaa, E., & Waller, K. (2022). Physical activity as a protective factor for dementia and Alzheimer’s disease: Systematic review, meta-analysis and quality assessment of cohort and case–control studies. British Journal of Sports Medicine, 56(12), 701–709. [CrossRef]
- Jaunmuktane, Z., & Brandner, S. (2020). Invited Review: The role of prion-like mechanisms in neurodegenerative diseases. Neuropathology and Applied Neurobiology, 46(6), 522–545. [CrossRef]
- Kobayashi, A., Teruya, K., Matsuura, Y., Shirai, T., Nakamura, Y., Yamada, M., Mizusawa, H., Mohri, S., & Kitamoto, T. (2015). The influence of PRNP polymorphisms on human prion disease susceptibility: An update. Acta Neuropathologica, 130(2), 159–170. [CrossRef]
- Kondo, K., & Kuroiwa, Y. (1982). A case control study of Creutzfeldt-Jakob disease: Association with physical injuries. Annals of Neurology, 11(4), 377–381. [CrossRef]
- Linsell, L., Cousens, S. N., Smith, P. G., Knight, R. S. G., Zeidler, M., Stewart, G., de Silva, R., Esmonde, T. F. G., Ward, H. J. T., & Will, R. G. (2004). A case-control study of sporadic Creutzfeldt-Jakob disease in the United Kingdom: Analysis of clustering. Neurology, 63(11), 2077–2083. [CrossRef]
- Mitrová, E., Mayer, V., Jovankovičová, V., Slivarichová, D., & Wsólová, L. (2005). Creutzfeldt–Jakob disease risk and PRNP codon 129 polymorphism: Necessity to revalue current data. European Journal of Neurology, 12(12), 998–1001. [CrossRef]
-
Occurrence and Transmission | Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease | CDC. (2022, November 14). https://www.cdc.gov/prions/cjd/occurrence-transmission.html.
- Prusiner, S. B. (2001). Neurodegenerative Diseases and Prions. New England Journal of Medicine, 344(20), 1516–1526. [CrossRef]
- Safar, J. G. (2012). Molecular pathogenesis of sporadic prion diseases in man. Prion, 6(2), 108–115. [CrossRef]
- Safar, J. G., DeArmond, S. J., Kociuba, K., Deering, C., Didorenko, S., Bouzamondo-Bernstein, E., Prusiner, S. B., & Tremblay, P. (2005). Prion clearance in bigenic mice. The Journal of General Virology, 86(Pt 10), 2913–2923. [CrossRef]
- Sitammagari, K. K., & Masood, W. (2022). Creutzfeldt Jakob Disease. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK507860/.
- Su, S., Shi, L., Zheng, Y., Sun, Y., Huang, X., Zhang, A., Que, J., Sun, X., Shi, J., Bao, Y., Deng, J., & Lu, L. (2022). Leisure Activities and the Risk of Dementia: A Systematic Review and Meta-analysis. Neurology, 99(15), e1651–e1663. [CrossRef]
- Tam, J., Centola, J., Kurudzhu, H., Watson, N., MacKenzie, J., Leitch, M., Hughes, T., Green, A., Summers, D., Barria, M., Smith, C., & Pal, S. (2022). Sporadic Creutzfeldt–Jakob Disease in the young (50 and below): 10-year review of United Kingdom surveillance. Journal of Neurology. [CrossRef]
- van Duijn, C. M., Delasnerie-Lauprêtre, N., Masullo, C., Zerr, I., de Silva, R., Wientjens, D. P., Brandel, J. P., Weber, T., Bonavita, V., Zeidler, M., Alpérovitch, A., Poser, S., Granieri, E., Hofman, A., & Will, R. G. (1998). Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease (CJD). Lancet (London, England), 351(9109), 1081–1085. [CrossRef]
- Ward, H. J. T., Everington, D., Cousens, S. N., Smith-Bathgate, B., Gillies, M., Murray, K., Knight, R. S. G., Smith, P. G., & Will, R. G. (2008). Risk factors for sporadic Creutzfeldt-Jakob disease. Annals of Neurology, 63(3), 347–354. [CrossRef]
- Ward, H. J. T., Everington, D., Croes, E. A., Alperovitch, A., Delasnerie-Lauprêtre, N., Zerr, I., Poser, S., & van Duijn, C. M. (2002). Sporadic Creutzfeldt-Jakob disease and surgery: A case-control study using community controls. Neurology, 59(4), 543–548. [CrossRef]
-
World Population Prospects—Population Division—United Nations. (n.d.). Retrieved December 25, 2022, from https://population.un.org/wpp/Download/Standard/MostUsed/.
- Yuan, J., Xiao, X., McGeehan, J., Dong, Z., Cali, I., Fujioka, H., Kong, Q., Kneale, G., Gambetti, P., & Zou, W.-Q. (2006). Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains. The Journal of Biological Chemistry, 281(46), 34848–34858. [CrossRef]
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