CJD – A downward spiral of depression into dementia and death

Post prepared by Dr Mariam Kemal, PGY-3 (Internal medicine), Monmouth Medical Center

Case History:

This 66 year old female had been living alone independently.  However, her neighbors became concerned when she had seemed more withdrawn than usual for about a month, and then stopped going out of the house and paying her utility bills.  Ultimately, one of them  noticed a dead cat in the house, and immediately called patient’s son who lived out-of- state, and he requested that she be admitted hospital.  At the time of her initial evaluation, she was depressed and had a urinary tract infection.  She was treated for the infection, and when she expressed suicidal ideation she was transferred to the psychiatric unit. While she was on the psychiatric unit she developed slurred speech, right arm clumsiness and and unsteady gait.   She was transferred back to the medical service and underwent a diagnostic evaluation.   Her brain MRI showed diffusion restriction in left putamen and caudate nucleus. Her EEG was also abnormal.  Her spinal fluid was ultimately positive for presence of Protein 14-3-3, indicating Creutzfeldt –Jacob disease.  She has progressed to a very debilitated state in just two week – Her speech was limited to a few intermittent slurred words, she was not able to walk and had diffuse myoclonic jerks. She was transferred to hospice.  Her brain was sent for autopsy to The National Prion Disease Pathology Surveillance Center which confirmed the presence of abnormal protease resistant prion protein (PrPSc), commonly identified as PrP 27-30, confirming the diagnosis of sporadic Creutzfeldt-Jacob disease.
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What is Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease (“CJD”) is a rare brain disorder that causes rapidly progressive dementia with muscle twitching, leading to death within several months.

CJD usually affects older adults.


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It is caused by abnormal proteins called “prions” that infect the brain.

“Classic” CJD has been transmitted by infected organs during transplant surgery.

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“Variant” CJD (“mad cow disease”) has been transmitted by infected beef.

In addition to dementia and myoclonus, many CJD patients also exhibit behavioral change (including depression), balance problems, and sleep disturbance.

It is the presence of these unusual clinical features, and the rapid rate of clinical deterioration, that distinguish CJD from other dementias like Alzheimer’s disease.

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How is Creutzfeldt-Jakob disease diagnosed?

MRI imaging of the brain can show characteristic findings:

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The electroencephalogram (EEG) can show periodic complexes:

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The spinal fluid can show the 14-3-3 protein.

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However, a brain biopsy demonstrating spongiform change is still necessary to confirm the diagnosis in many cases:

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How is Creutzfeldt-Jakob disease treated?

Sadly, there are no treatments that can stop or cure the disease, and all affected patients die within several months.

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Kuru (You get it from eating brains!)

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Posted by Dr Abhimanyu Kaura, PGYIII (Medicine), Monmouth Medical Center

Kuru disease is one of the five human spongioform encephalopathies caused by prions.  This group also includes Creutzfeldt-Jakob disease (CJD), variant CJD, Gerstmann-Straussler Scheinker syndrome and fatal familial insomnia.

Bovine spongiform encephalopathy also known as “mad cow disease”, is another prion disease that affects cattle, and was responsible for bringing more attention to all of these disorders in the 1990s.

Kuru is confined the Fore tribes of Papua, New Guinea.

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In the 1950s there were 2100 cases of Kuru in these tribes leading to about 1000 deaths per year.

As per the culture of the Fore tribe, if a person in a family dies his meat is eaten by his family members, especially the wife and children,  as a mark of respect to him.  90% of people affected by the disease were women and children.

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Between 1996 to 2004 only 11 new cases of Kuru were identified in the region. Currently with the ban of cannibalism in the Farah tribes the disease had become virtually non existent.

Kuru first presents with tremors, then unsteady gait and progresses to leg weakness, ataxia, incoherent speech, sporadic laughter finally.  In later stages, affected patients become demented, bed bound and unable to swallow.

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Death occurs most commonly from respiratory distress and pneumonia or infection of pressure sores. The disease is fatal within 1-2  years of the onset of symptoms and had no known cure.

Here’s a video introduction

Watch the full story here:

The causative organism is a prion, a mutated protein which replicates itself like a virus, and is spread by eating the neuronal tissue of infected people.

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The precise incubation period of the disease is unknown, but can be up to fifty years.

The pathological hallmark is the presence spongioform encephalopathy with of Prion reactive plaques mostly in the cerebellum:
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The detailed studies of theses cases of Kuru has helped us understand other prion diseases such as variant CJD, sporadic CJD whose clinical features and course is similar to this condition.

And maybe another link between Zombies and neurology?

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Prions: Could these zombie-like proteins be responsible for causing the most common form of Dementia?

Post courtesy of Dr Michael Chan, PGY2 Medicine Resident, Monmouth Medical Center.

ImageAs far as infectious diseases go, prions are a relatively new discovery. While humanity has known about parasites since ancient times, bacteria since the 1660s, and viruses since 1898, the first prion protein was only isolated in 1984. Since then, we’ve gotten to know a little more about these proteins, and we’ve found that its novelty is by no means the most interesting thing about it.
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So what are prions?

Prions are basically the misfolded version of a normal protein, PRP or Protease resistant protein. In the vast majority of instances, the body has mechanisms that adequately deal with misshapen proteins. These get tagged for destruction by antibodies or intracellularly by specific molecular signals and lysosomes. However, prions are not your run of the mill abnormal protein. They are resistant to degradation and exhibit the unique characteristic of causing other normal PRP proteins to misfold, which in turn causes even more misfolding. In this sense, prions behave like protein zombies.

And like zombies, they don’t begin their existence as malevolent molecules either. Indeed this is one of the characteristics which differentiate prions from most other infectious agents such as bacteria or viruses, majority of which are inherently disease causing. Studies have shown that normal PRP has functions in sleep, memory, neural development, and possibly the maintenance of the myelin sheath that surrounds neurons. Indeed, a mutation of PRP causes a very rare disease (only 8 cases have been diagnosed as of 2005) called Familial Fatal Insomnia which leads to progressively worse insomnia leading to dementia, hallucinations, and eventually death.

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Yes, complete inability to sleep kills.


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The connection to Alzheimer’s

Until recently, the most notable examples of prion diseases in humans are Creutzfeldt-Jakob disease and Kuru. Although spontaneous CJD does rarely occur, both these diseases are usually caused by ingestion of infected material, ie, eating infected meat (beef) for CJD and cannibalism for Kuru. Both exhibit progressive dementia, memory problems, gait and movement disturbances, and other unusual symptoms like uncontrolled laughter, hallucinations, and personality changes. Pathologically, the disease causes patients’ brains to develop tiny holes, much like a sponge. Thus the name for the disease in cows, Bovine Spongiform Encephalopathy, literally translates “cow spongy brain disease”.

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Brain of a CJD patient with multiple “holes”

However, over the past 5 years, research has shown that at least one major protein known to accumulate in Alzheimers disease, amyloid beta, behaves much like prions. Research conducted at UCSF showed that when mice brains are seeded with amyloid beta, after 300 days, the amyloid plaque is found all over the brain, not just the area seeded. A Yale university study in 2009 also showed that prion proteins of CJD interact with amyloid beta in some way to cause the dysfunction in neurons which lead to Alzheimer’s. Although there is no evidence that AD is contagious, it may open up new therapeutic avenues to think of its pathology as like that of prion diseases.

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Amyloid plaques and Neurofibrillary tangles in Alzheimer’s disease

How Alzheimer’s spreads in the brain.

Indeed, last year, a British team accidentally stumbled on a discovery that antibodies designed to treat CJD were found to block Alzheimer’s disease. These antibodies, ICSM-35 and ICSM-18, blocked the interaction between the PRP prion and amyloid beta in mice brains, resulting in decreased hippocampal nerve cell disruption. ICSM-18 and ICSM-35 are presently undergoing human trials for the treatment of CJD. With this finding, it’s likely they will be tested for Alzheimer’s as well, and we, for the first time, might have an effective and specific treatment for this disease which affects roughly 20 million people worldwide.

To see just how significant any form of treatment might be, check out the facts and figures provided by http://www.alz.org below:

References:

Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. 2011:70, 532–540.

Prusiner SB: A unifying role for prions in neurodegenerative diseases. 2012:336, 1511–1513.

Freir DB, Nicoll AJ, Klyubin I et alInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sitesNature Communications, June 7 2011