Hopeful interpretation: better diagnosis. Scary interpretation: a new exposure

In 1986, in Britain, cattle started dying.

The condition, quickly nicknamed “mad cow disease” was clearly infectious, but the particular pathogen was difficult to identify. By 1993, 120,000 cattle in Britain were identified as being infected. As yet, no human cases had occurred and the UK government insisted that cattle were a dead end host for the pathogen. By the mid-90’s, however, multiple human cases – attributable to ingestion of meat and organs from infected cattle, were discovered. In humans, variant Creutzfeld-Jakob Disease was a media sensation – a nearly uniformly fatal, untreatable condition with a rapid onset of dementia, mobility issues characterized by jerky movements, and autopsy reports finding the brain itself had been turned into a spongy mess.

The US banned UK beef imports in 1996 and only lifted the ban in 2020.

The disease was made all the more mysterious because the pathogen involved was not a bacteria, parasite, or virus, but a protein – or a proteinaceous infectious particle – shortened to “prion”.

Prions are misfolded proteins that aggregate in cells – in this case in nerve cells. But what makes prions different than other misfolded proteins is that the misfolded protein catalyzes the conversion of its non-misfolded counterpart into the misfolded configuration. It creates a chain reaction – leading to rapid accumulation of misfolded proteins and cell death.

And, like a time bomb, we all have prion protein inside us. In its normally folded state, the function of prion protein remains unclear – knockout mice do ok without it – but it is also highly conserved across mammalian species – so it probably does something worthwhile, perhaps protecting nerve fibers.

Far more common than humans contracting mad cow disease is the condition known as sporadic Creutzfeldt-Jakob disease, responsible for 85% of all cases of prion-induced brain disease. The cause of sporadic CJD is unknown.

But one thing is known. The cases are increasing.

I don’t want you to freak out – we are not in the midst of a CJD epidemic. But it’s been a while since I’ve seen people discussing the condition – which remains as horrible as it was in the 90s – and a new research letter appearing in JAMA Neurology brought it back to the top of my mind.

Researchers led by Matthew Crane at Hopkins used the CDC’s “WONDER” cause of death database, which pulls diagnoses from death certificates. Normally, I’m not a fan of using death certificates for cause of death analyses, but in this case, I’ll give it a pass – assuming the diagnosis of CJD is made, it would be really unlikely for it NOT to appear on a death certificate.

The main findings are seen here – since 1990, there has been a steady uptick in the number of deaths due to CJD in this country, as well as an increase in overall incidence.

Note that we can’t tell whether these are sporadic CJD cases, or variant CJD cases, or even familial CJD cases, though unless there has been a dramatic change in epidemiology the vast majority of these will be sporadic.

The question is – why are there more cases?

And, whenever this type of question comes up – with any disease - there are basically three possibilities.

First – there may be an increase in the susceptible, or at-risk population. In this case, we know that older people are at higher risk of developing sporadic CJD and, over time, the population has aged. To be fair, the authors adjusted for this and still saw an increase, though it was attenuated.

Second – we might be better at diagnosing the condition. A lot has happened since the mid-90s, when the diagnosis was based more or less on symptoms. The advent of more sophisticated MRI protocols as well as a new diagnostic test called “real-time quaking-induced conversion testing” may mean we are just better at detecting people with this disease.

And third – and most concerning – a new exposure. What that exposure might be, where it might come from, is anyone’s guess. It’s hard to do broad scale epidemiology on very rare diseases.

But given these findings, it seems that a bit more surveillance for this rare, but devastating condition, is well merited.

A version of this commentary first appeared on Medscape.com.

Methods Man Blog

The Strange Increase in Prion Diseases

Hopeful interpretation: better diagnosis. Scary interpretation: a new exposure

The Methods Man