Know Your Brain: Fatal Insomnia

In 1991, Michel A. Corke was enjoying the summer break from his position as a music teacher in a Chicago high school when he started to develop sleeping problems. He had recently turned 40, and seemed to be in good health, but it was soon very obvious that he was suffering from more than just your run-of-the-mill insomnia. It wasn't just taking him longer to fall asleep than normal. Nor was he suffering from the common problem of waking up frequently over the course of the night. He wasn't sleeping at all.

Within a few months, Corke's lack of sleep was causing obvious physical and mental deterioration. He developed problems with balance and had trouble walking. He began to display signs of dementia and there were times when he appeared to lose touch with reality. Sometimes these episodes involved hallucinations.

After Christmas, he was admitted to the hospital. At that point, Corke was unable to communicate. He had become completely dependent on his family to help him perform even the simplest tasks like showering and getting dressed. His decline had been rapid and pervasive.

At first, doctors could not figure out was wrong with Corke. They diagnosed him with multiple sclerosis, despite the fact that he didn't really have the symptom profile of someone with the disease.

But doctors soon recognized that something was very unusual about Corke's "sleep." Even though Corke would often close his eyes and appear to be sleeping, measurements of his brain activity found that his brain never did actually fall asleep. This helped doctors to realize that he was suffering from a disease that had only been recognized within the previous decade, called fatal familial insomnia (now often called fatal insomnia because not all cases seem to be hereditary).

In the disease, sleep becomes progressively disrupted until patients exhibit little to no sleep. Eventually, death is inevitable.

Michel Corke's case was no exception. By the time he had been admitted to the hospital, about 130 days had passed with minimal sleep. When he died, he had essentially been awake for 6 months.

What are the symptoms of fatal insomnia?

Fatal insomnia is a rare disease that usually develops in middle age or later (the average age of onset is 51 years), and begins with complaints of trouble sleeping or excessive fatigue during the day. At first, due to this extreme daytime sleepiness, the assumption might be that the patient is plagued by a condition that is making him too sleepy.

Sometimes there are other abnormal signs early on, like double vision, impotence, hypertension, and increased perspiration, lacrimation (i.e. tear production), and/or salivation.

As the disease progresses, patients lose their ability to sleep altogether. A variety of movement problems appear, including difficulties with balance and coordination and abnormalities in gait. Patients also will sometimes become delusional and display unusual behavior that resembles dream-enactment, which involves unconsciously making movements related to what's going on in a dream.

Later in the disease, after a patient has been deprived of sleep for some time, he begins to spend more and more time in a stupor from which it's difficult to rouse him. He may experience sudden, spasmodic movements, but voluntary movement like standing and walking often become difficult to impossible. He may lose the ability to speak, have trouble swallowing, and fall into a vegetative state.

Death can occur at any time throughout these phases of the disease, but if the patient survives long enough often he will fall into a coma, which will lead to death. The duration of the disease ranges from 8 to 72 months, with an average disease course lasting just over 18 months.

What happens in the brain in fatal insomnia?

Brain activity during "sleep"

One way to verify the sleep disturbances occurring in fatal insomnia is to measure sleep activity over the course of a night using a technique known as polysomnography. Polysomnography measures the electrical activity in the brain (using an electroencephalogram, or EEG) along with a number of other physiological changes that occur during sleep like eye movement, muscle activity, and the electrical activity of the heart.

Polysomnography is often used to verify a case of fatal insomnia because patients may appear to spend periods of the night sleeping, as they have their eyes closed and aren't moving. Polysomnography reveals, however, that their brain activity doesn't resemble a pattern of normal sleep.

In a healthy person, during sleep the brain cycles from relatively light sleep into a period of deep sleep into a period a rapid eye movement (REM) sleep. A full cycle takes about 90-120 minutes and is repeated 4-6 times per night. These different stages of sleep have characteristic electrical activity that can be measured with an EEG.

Patients with fatal insomnia will, of course, display drastically reduced total sleep time. But even at times when it appears as if they are asleep, the EEG still won't show these characteristics of healthy sleep. Instead, their brain activity generally indicates wakefulness for most of the night, with very brief periods of light sleep (i.e. stage 1 or stage 2 sleep) and occasional sudden episodes of REM sleep that only last seconds or minutes. Deep sleep mostly disappears, and as the disease progresses all traces of REM sleep may disappear as well.

The thalami are the orange, oval-shaped structures in the image. They are the site of the most significant neurodegeneration in fatal insomnia.

Neurodegeneration

Fatal insomnia is associated with severe neurodegeneration of the thalamus, which is thought to be a critically important structure in sleep regulation. The thalamus is believed to play an especially important role in the generation of a type of deep sleep known as slow-wave sleep. Over the course of the disease, up to 80% of neurons are lost in certain nuclei of the thalamus.

The inferior olivary nucleus, a structure in the brainstem that is densely interconnected with the cerebellum, also suffers significant neurodegeneration in the disease, losing more than 50% of its neurons. The role of the inferior olivary nuclei in the symptoms of fatal insomnia is still unclear. It may be involved in generating movement-related symptoms like tremor and spasmodic muscle contractions, but some evidence suggests the olivary nuclei and cerebellum are involved with sleep as well.

The disease is also sometimes associated with the formation of large abnormal compartments, or vacuoles, within neurons. These "holes" in the brain can give the brain a sponge-like appearance. In fatal insomnia, this occurs primarily in the cerebral cortex.

Accumulation of prion protein

Fatal insomnia is considered a prion disease, and thus also involves the accumulation of abnormally-folded forms of prion protein in the brain. These misfolded proteins have a tendency to accumulate into clusters that are resistant to being broken down by brain enzymes. The implications of these protein clusters forming in the brain is unclear, although they are often linked to pathological changes in the brain. (For a short primer on prion diseases, read this article.)

Prion proteins also are capable of passing their misfolded state on to other healthy proteins. Thus, they can spread within the brain of an infected patient, gradually increasing the number of misfolded prion proteins. Interestingly, their "infectious" quality also allows prions to cause disease if transmitted from one host to another. While it isn't thought that fatal insomnia is spread among people in this way, the disease has been transmitted to mice by injecting them with a liquefied piece of brain tissue from a human patient who had the disease.

In fatal insomnia, however, there are relatively few clusters of prion protein in the brain as compared to other prion diseases. And, while deposits in some areas of the brain increase in number as the disease progresses, this isn't true for the areas that experience the most neurodegeneration---like the thalamus. Thus, it's still unclear what exactly causes the neurodegeneration that produces the symptoms of fatal insomnia.

What causes fatal insomnia?

Most of the cases of fatal insomnia identified to date are considered genetic diseases, attributable to a genetic mutation in the PRNP, or PRionN Protein, gene---a gene that's implicated in other prion diseases as well. The mutation is an autosomal dominant mutation, which means that if someone with the mutation has a child, the child has a 50% chance of ending up with the same mutation. When fatal insomnia is inherited, it is generally referred to as fatal familial insomnia.

To date, just over 200 individuals worldwide are known to carry the mutation associated with fatal familial insomnia. Due to the global distribution of the disease, some researchers have suggested it is caused by a recurrent mutation that has happened independently in a number of families.

In 1999, the first cases of what seems to be non-hereditary fatal insomnia appeared. Non-hereditary fatal insomnia is commonly referred to as sporadic fatal insomnia, and to date 32 cases have been identified. These patients display most of the same symptoms and pathology as fatal familial insomnia patients, but they have no family history of the disease and do not have the mutation of the PRNP gene seen in fatal familial insomnia patients.

What is the treatment for fatal insomnia?

We are severely limited in our ability to treat fatal insomnia patients. Even the strongest sedatives (e.g. barbiturates, benzodiazepines) do not cause patients of the disorder to sleep. Thus, treatment focuses on relieving the symptoms of the disorder as much as possible (which alone is a challenge).

References (in addition to linked text above):

Cracco L, Appleby BS, Gambetti P. Fatal familial insomnia and sporadic fatal insomnia. Handb Clin Neurol. 2018;153:271-299. doi: 10.1016/B978-0-444-63945-5.00015-5.

Montagna P. Fatal familial insomnia and the role of the thalamus in sleep regulation. Handb Clin Neurol. 2011;99:981-96. doi: 10.1016/B978-0-444-52007-4.00018-7.

Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol. 2003 Mar;2(3):167-76. (in

Know Your Brain: Prion diseases

Background

A healthy prion protein (not in a misfolded state). Credit: Emw from Wikimedia Commons.

The story of prion diseases really begins in the 1700s with an affliction that was spreading through sheep and goats in Europe. The disease at first caused abnormal behavior in the animals and then progressed to a more serious condition involving severe weight loss, lethargy, and eventually death. The animals also displayed signs of severe itching; they would rub up against trees, rocks, or fences so much to quell the itching that they would develop bare patches and sores. Because of this, the disease was called scrapie.

Now fast forward to the twentieth century. In the late 1950s, researchers were investigating another strange disease in a remote region of Papua, New Guinea. This disease was rampant among a group of indigenous peoples called the Fore. They called it kuru, a derivation of the Fore word for to tremble, because severe tremors are one of the most recognizable symptoms of the condition.

Kuru often begins with those tremors, movement difficulties, and trouble enunciating words. As it progresses, patients lose the ability to walk on their own, begin to have trouble swallowing, become severely malnourished and unresponsive, and eventually succumb to one of a number of immediate causes of death precipitated by their weakened state. 

In searching for the cause of kuru, scientists began to look closely at one uncommon practice of the Fore people: cannibalism. Specifically, the Fore people engaged in funerary cannibalism, where they ate the dead as part of a ritualistic practice. Men, however, did not participate in the act. And kuru rarely occurred in men, much more frequently affecting women and children.

This led some researchers to hypothesize that cannibalism was central to transmitting the disease. Carleton Gajdusek, who won the Nobel Prize in 1976 for his work on kuru, provided strong support for this hypothesis by showing he could transmit kuru to chimpanzees by injecting them with brain tissue from infected humans. Gajdusek's research supported the idea that kuru is a transmissible disease.

Now enter Stanley Prusiner, a neurologist who had become interested in both kuru and scrapie after meeting a patient who suffered from a similar disease called Creutzfeldt-Jakob disease (CJD). CJD is also an invariably fatal disease that is associated with abnormal behavior, a loss of coordination, dementia, and an overall deterioration of faculties. And at that point, like kuru and scrapie, CJD had been found to be transmissible by injecting infected brain tissue into a healthy brain.

In studying the infectious agent for scrapie, Prusiner was able to confirm a previous finding that the agent lacked DNA. Instead, his research suggested it was made up entirely of protein. With this observation, Prusiner had discovered something completely new---and totally unexpected: the agent of infection for scrapie (and potentially for other similar diseases) was not a virus, but an infectious protein. Never before had proteins been found to play such a role, and never had an infectious agent been discovered that didn't have nucleic acids and a genome. Prusiner called the infectious agent a prion, a portmanteau of the words infectious and protein. Prusiner won the Nobel Prize for his work on prions in 1997.

What are prion diseases?

It took some time for Prusiner's hypothesis to be accepted, but today prions are thought to be involved in the pathology of a group of diseases known either as prion diseases or transmissible spongiform encephalopathies (TSEs). So what exactly are prions?

The first key characteristic of prions is that they are folded in an abnormal way, or misfolded. All proteins undergo a folding process as part of their synthesis---the folding helps to determine the protein's function. In prion diseases, a protein that has appropriately been called prion protein, or PrP, is misfolded. How these misfolded proteins contribute to disease is still not completely clear, but their appearance in the brain is associated with the progression of prion diseases.

Misfolded PrP, unlike normal protein, is resistant to being broken down by enzymes, and in some cases it accumulates in clusters in and around neurons. Many of these clusters are amyloid plaques, a type of misfolded protein deposit well-known for its appearance in other neurodegenerative diseases like Alzheimer's disease

It's uncertain if PrP or the deposits of it that form are directly toxic to neurons, or if they are associated with some other mechanism that is toxic, but neuronal loss and degeneration is also often seen in prion diseases. As PrP increases in the brain, other pathological signs start to appear as well. Large abnormal compartments, or vacuoles, form within neurons and some glial cells. This can give the brain a sponge-like appearance under the microscope.

So although the role of misfolded prions in these issues is still not fully understood, the presence of prions in the brain is linked to a number of other pathological changes. And prions seem to have an amazing ability to spread their misfolded state on to other healthy proteins---a characteristic that gives them the infectious quality from which they get their name. Prions can induce misfolding when introduced into a healthy brain, and they can also propagate within the brain of an infected individual, gradually increasing the number of misfolded prion proteins while other pathological changes accumulate. With many prion diseases, this process takes a long time; it can be months to decades before clinical symptoms begin to appear.

The symptoms vary depending on the disease, but often involve dementia, problems with muscle coordination, insomnia, loss of motor function, and abnormal behavior. Eventually, all prion diseases lead to death; there are no cures and there isn't even a treatment to slow the progression of the disease.

One other unique feature of prion diseases is that they seem to be able to occur in three different ways: by being spread like an infectious disease, as the result of a heritable genetic mutation, or sporadically, which means they appear without any obvious preceding risk factor like infection or family history.

For example, variant Creutzfeldt-Jakob disease (vCJD) is a type of prion disease that is transmissible when people eat beef from cows that were infected with another prion disease, bovine spongiform encephalopathy (often called mad cow's disease). The disease is spread when prions from the beef (which are capable of withstanding the high temperatures of cooking) enter the body of a person who consumes it.

Fatal familial insomnia, on the other hand, is typically a genetically-inherited disorder where a mutation to the PrP gene leads to the production of misfolded PrP. Patients who suffer from it develop increasingly worsening insomnia until they completely lose the ability to sleep and eventually die.

In some cases, however, there is no family history of fatal familial insomnia, and the patient has no clear risk factors for how he or she may have developed the disease. When this is the case with a disease, it is said to arise sporadically. Some prion diseases, like CJD (which is distinct from the variant CJD mentioned above), are primarily sporadic.

Future research

Researchers are still attempting to fully understand prion diseases and how they work. As research has progressed, scientists have noted some surprising similarities between prion diseases and other neurodegenerative diseases. Conditions like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and others have all been associated with abnormal deposits of misfolded proteins, and research suggests these misfolded proteins may be able to spread throughout the brain just like prions. Early studies have even found that diseases like Alzheimer's disease might be transmissible by exposing someone to the brain matter of an infected patient.

This line of research has some, including prion pioneer Stanley Prusiner, arguing that prions are at the heart of many neurodegenerative diseases, not just the transmissible spongiform encephalopathies. If true, this might open up a new realm of possibilities for treatment and diagnosis. A much better understanding of prions in general will likely be necessary, however, before viable treatments emerge.

Want to know more about prions and their possible involvement in diseases like Alzheimer's and Parkinson's disease? Read this: The unsolved mysteries of protein misfolding in common neurodegenerative diseases

The unsolved mysteries of protein misfolding in common neurodegenerative diseases

Throughout the 1970s, biochemist Stanley Prusiner was obsessed with trying to find the causative agent for a mysterious group of diseases. The diseases, which included kuru and Creutzfeldt–Jakob disease in humans and scrapie in sheep, were characterized by slowly-developing symptoms and neurodegeneration so severe it eventually caused the brain to take on the appearance of a sponge (due to myriad little holes that developed where grey matter was lost). By the time Prusiner began studying these diseases, they had all been experimentally transmitted to chimpanzees or other animals by injecting the animals with biological material from an infected host. So, the diseases seemed to be spread in an infectious manner, but scientists were still trying to identify the agents (e.g. viruses, bacteria, etc.) responsible for their transmission.

Prusiner focused on trying to classify the agent involved in the transmission of scrapie. He expected the agent to be a virus, but was confused when his tests repeatedly suggested it was composed of protein rather than the nucleic acids that would make up viral DNA. For, although there were others before Prusiner who had proposed ways proteins might be involved in the transmission of infectious diseases, these ideas had not been widely embraced by the scientific community. If Prusiner were to accept what his tests were indicating it would mean challenging the conventional understanding of the nature of infectious agents--which were thought to at least possess DNA or RNA--as well as the fundamental characteristics of proteins, which were not previously known to have infectious capabilities.

In 1982, Prusiner published a manuscript outlining a hypothesis that scrapie was caused by a protein that had infectious qualities. He termed this protein a prion, for "proteinaceous infectious particle." Prusiner's ideas were considered somewhat heretical to virologists and others studying these diseases, and Prusiner was faced with criticism from scientists and non-scientists alike. But eventually Prusiner isolated the prion responsible for the transmission of scrapie, confirming his suspicions and silencing the naysayers. In 1997, he was awarded the Nobel Prize in Medicine for his discovery.

Now it is well established that prions are agents of disease, in that they can spread from host to host just like typical pathogens. Once inside their host, however, they also have a unique capability of "infecting" other proteins. This results in the spreading of pathology through different regions of the brain, eventually leading to widespread neurodegeneration. But the story of infectious proteins does not end with the rare group of diseases studied by Prusiner. What we are coming to learn now is that this prion-like transmission of pathology between proteins may be a characteristic of other--much more common--diseases that involve neurodegeneration. While these diseases are very different from prion diseases in that they are not spread between individuals, the evidence suggests that the pathophysiology of neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) may involve proteins that behave like prions in their ability to infect other proteins within the brain of an affected individual.

Alzheimer's, Parkinson's, and protein misfolding

There are a number of diseases that are characterized by neurodegeneration, but AD and PD are the two neurodegenerative diseases that have the greatest impact on our society today in terms of mortality, disability, and economic burden. While both diseases involve neurodegeneration, however, they differ in the areas of the brain most affected (which plays a large role in determining their different symptomatic profiles). In AD, neurodegeneration becomes extensive in several areas of the brain, including areas of the cortex and hippocampus. These are areas that are especially important to cognition and memory, which helps to explain some of the deficits seen in the disease. In PD, neurons in structures that are part of the basal ganglia--a group of nuclei that play an important role in facilitating movement--are severely affected. The substantia nigra is particularly impacted, with somewhere between 50% and 70% of the neurons in this area being lost by the time of death. While the mechanisms underlying the large-scale neurodegeneration that occurs in AD and PD are not yet fully understood, in both diseases the neurodegeneration is associated with the accumulation of misfolded proteins in or around neurons.

Proteins are essential to an extensive list of biological functions, including many vital processes like cellular metabolism, DNA replication, and cell signaling. When a protein is formed from a chain of amino acids, one of the final steps in its synthesis is to undergo a process of folding. The chain of amino acids (known as a polypeptide) that came together to create the protein is folded into a three-dimensional structure, and it is this three-dimensional structure--known as the tertiary structure--that decides the protein's eventual function. In other words, the folding--not simply the amino acid chain that makes up the protein--is what determines the role the protein will play in the body.

Thus, protein folding is essential to synthesizing functional proteins. In AD and PD, however, proteins seem to fold incorrectly. This creates proteins composed of filaments that are pathologically twisted together instead of folded into a typical three-dimensional structure. These proteins are said to be in an amyloid state, because when this abnormal configuration was first noticed by renowned scientist Rudolf Virchow, he mistakenly identified them as starch (amyloid means starch-like). Once they have formed, these amyloid proteins have a tendency to aggregate into insoluble clumps.

AD is characterized by aggregations of two types of proteins, called amyloid beta and tau, respectively. Amyloid beta is always present in the brain in the extracellular space around neurons, although its function has yet to be elucidated. In AD, however, it accumulates into clusters called amyloid plaques (aka senile plaques) that aggregate outside and around neurons. These amyloid plaques often begin to form in the cortex in the earlier stages of the disease, but propagate and eventually spread to the brainstem in the later stages. Tau is found within neurons, and is normally involved in maintaining the structure of the neuron through the stabilization of microtubules. When tau becomes misfolded, it can accumulate inside neurons into bundles called neurofibrillary tangles. In AD, these tangles generally begin to form in the brainstem, then spread to the temporal lobes and cortex.

PD is characterized by the aggregation of a protein called alpha-synuclein. Alpha-synuclein is found within neurons, and may play various roles in regulating neurotransmitter release. In PD, it clumps into clusters called Lewy bodies (named for Frederic Lewy, who discovered them in 1912), which form inside the neuron. There is no consistent site of origin for Lewy bodies in the brain, but often they are first seen in the brainstem or olfactory bulb.

Just like prions, misfolded proteins in neurodegenerative diseases like AD and PD seem to be able to influence previously healthy proteins to also undergo a process of misfolding, causing them to be transformed into an amyloid state. In one of the earliest studies to provide experimental evidence of this, amyloid plaque formation was induced in the brains of monkeys after brain tissue from human AD patients was injected into the monkeys' brains. This process of the spread of pathological misfolding from one protein to the next is referred to as seeded aggregation.

Misfolding, however, is not only spread from protein to protein, but also from neuron to neuron. The way this happens is also still not very clear, but it is suspected that misfolded proteins may be taken up from the extracellular space into neurons, where they begin to infect susceptible proteins and further spread pathological misfolding. Whatever the mechanism, this neuron-to-neuron transmission of protein misfolding allows disease to spread from relatively confined sites of origin to widespread areas of the brain.

What damage does protein misfolding cause?

Although misfolded proteins are characteristic of neurodegenerative diseases, how exactly they contribute to the pathology of these diseases is still unknown. In other words, while AD and PD patients have clumps of these proteins throughout their brains, we don't actually know what role the aggregates play in causing neuronal death--or if they cause cell death at all.

According to one perspective, amyloid proteins and the aggregates they form are themselves neurotoxic and can lead to the death of neurons. Additionally, it has been hypothesized that aggregates can disrupt neuronal function by affecting the integrity of neuronal structure and impairing communication within neurons in the process (also leading to neurodegeneration). However, neuronal death is often not well correlated with the degree of aggregate formation, and the most extensive areas of cell death may occur at some distance from sites of aggregation. These findings have led to the hypothesis that it is not the amyloid proteins found in aggregates that are most harmful, but rather smaller soluble forms of amyloid (called amyloid oligomers and protofibrils) that are more detrimental to neurons. These smaller amyloid species are not easily detectable when testing the brain for the presence of amyloid, and can be found in areas where aggregation isn't apparent, potentially explaining the poor correlation between amyloid aggregates and neurodegeneration.

Some have also suggested that amyloid aggregates are formed by the brain as a means of controlling the spread of potentially damaging misfolded proteins. According to this perspective, molecular chaperones--proteins that facilitate the folding process of other proteins--recognize when a protein has become folded incorrectly. The chaperones can then sequester these misfolded proteins into benign aggregates, which keeps them from having toxic effects on neurons. It may be, however, that the smaller amyloid species mentioned above escape sequestration and are still able to cause damage.

Questions still to be answered

We are still in the dark about many of the details of protein misfolding diseases. We know the misfolding occurs as part of the pathophysiology of these diseases, and that it is correlated with neurodegeneration in some way. But we don't know what prompts misfolding, how it seems to spread from protein to protein and neuron to neuron, or in what way it is related to the death of neurons. When the answers to some of these questions become clearer, it may open the way for more effective treatments for these diseases. If, for example, we can identify how neurodegenerative disease proteins are spread between neurons, we can try to develop ways to block such a mechanism (e.g. blocking a receptor they are utilizing to gain entry into the neuron). Until we learn more, however, we will continue to be somewhat at the mercy of these diseases that imbue proteins with a type of "infectiousness" that was unheard of less than 40 years ago.

Brettschneider, J., Tredici, K., Lee, V., & Trojanowski, J. (2015). Spreading of pathology in neurodegenerative diseases: a focus on human studies Nature Reviews Neuroscience, 16 (2), 109-120 DOI: 10.1038/nrn3887

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