Know Your Brain: Alzheimer's Disease

Background

Auguste Deter, the subject of Alois Alzheimer’s case study describing what would come to be known as Alzheimer’s disease.

In 1906, at a meeting of psychiatrists in Germany, Alois Alzheimer gave a lecture in which he detailed the unusual case of Auguste Deter. Alzheimer had encountered Deter about five years prior, when he was working as an assistant physician at a psychiatric institution in Frankfurt am Main in Germany. Deter had made an impression on Alzheimer because she was relatively young, but was suffering from a unique constellation of severe, dementia-like symptoms.

Deter was 51 years old when Alzheimer met her. Her most noticeable symptoms had begun in the previous year, when her behavior became alarmingly erratic. First, she began displaying uncharacteristic jealousy of her husband. Then, her memory started to deteriorate rapidly. She would easily become disoriented, and often lose touch with reality, consumed with paranoid delusions. As Alzheimer described it:

“…sometimes she thought somebody was trying to kill her and started to cry loudly… Sometimes she greets the attending physician like company…sometimes she protests loudly that he intends to cut her…Then again she is completely delirious, drags around her bedding, calls her husband and daughter and seems to suffer from auditory hallucinations. Often she screamed for many hours.”

Alzheimer was intrigued by the case. Deter seemed to be afflicted with a form of senile psychosis, which was probably a symptom of dementia. But it was rare to see dementia this severe in someone so young.

In addition to being a physician, Alzheimer was also an industrious researcher. He was intensely interested in pathological changes in the nervous system that accompanied psychiatric and neurological illnesses. Thus, when Deter died at the age of 55, Alzheimer requested her brain be sent to him for study. Upon examination, Alzheimer found the brain had suffered widespread neuronal loss and was riddled with abnormal structures (later learned to be the protein deposits discussed below).

Deter’s age, symptom profile, and neural deterioration convinced Alzheimer that she was a unique case. The psychiatrists present at his lecture on the topic didn’t seem to feel the same way, however, as there were no questions, comments, or other indications of interest following his presentation (the attendees seemed much more intrigued by the next presentation on compulsive masturbation). But little did Alzheimer know that his lecture would mark a historic moment, as only a few years later the renowned psychiatrist (and Alzheimer’s colleague) Emil Kraepelin introduced the term Alzheimer’s disease (AD) to describe an early-onset form of senile dementia.

It wasn’t until the late 1970s that researchers began to recognize that most cases of AD are not early-onset, and occur in patients over the age of 65. Today, AD is one of the greatest health concerns for people in this age group, and due to the fact that this population continues to increase in number (which is, ironically, a result of our improved ability to keep people alive longer), it is a rapidly growing problem. Today, about 1 in every 10 people over the age of 65 suffers from AD, and the number of people with AD in the United States is expected to nearly triple by the year 2050.

What are the symptoms of Alzheimer’s disease?

AD is a type of dementia, a term used to describe a condition that involves memory loss and other cognitive difficulties. There are a number of different types of dementia, however—each with its own causes and specific symptom profile. AD is just one variation.

The best-recognized sign of mental decline in AD is problems with memory. In the early stages of the disease, this often manifests as difficulties creating new memories, and problems are especially noticeable with declarative memories, or memories about information and events (as opposed to memories for how to do routine things like tie your shoes or eat with utensils, which are known as non-declarative memories). Early on, patients are typically able to maintain older memories and non-declarative memories. Over time, however, all memory can be affected, and even the most enduring memories may deteriorate.

But memory deficits are just one aspect of AD symptomatology. Patients can also experience problems with communication, and the ability to read and write may be impaired. Unpredictable mood disturbances, ranging from apathy and depression to angry outbursts, can occur. Thinking often becomes delusional, and a substantial subset of patients (up to 20%) even experience visual hallucinations.

It’s not just cognition that’s affected, though. Movement is hindered, causing patients to begin to lose mobility and have trouble performing even the simplest acts of self-care. Basic motor functions like chewing and swallowing become faulty, and incontinence eventually occurs.

In the end (if a patient survives this long), there aren’t many brain functions that haven’t been affected in some way, and patients become completely dependent on caregivers to help with even the most basic daily activities like eating and going to the bathroom. The disease is always fatal.

What happens in the brain in Alzheimer’s disease?

When Alois Alzheimer examined the brain of Auguste Deter, he noted a few distinct pathological changes. The first was that the brain had undergone significant atrophy. It appeared somewhat shrunken compared to a healthy brain.

This atrophying of the AD brain is due to the death of brain cells that occurs in the disease. AD is what is known as a neurodegenerative disease, which is a classification used to refer to diseases that cause the degeneration and death of neurons. A number of diseases fall into this category (e.g. Parkinson’s disease, amyotrophic lateral sclerosis), but AD is the most common of the group.

Alzheimer also noted unusual formations both within and surrounding neurons. He remarked that “distributed all over the cortex…there are…foci which are caused by the deposition of a special substance,” and he also mentioned “many fibrils located next to each other…they appear one by one at the surface of the cell.” Alzheimer was describing what today are the two hallmark neurological signs of AD: amyloid plaques and neurofibrillary tangles.

The first of these structures, amyloid plaques, consist of collections of small peptides (essentially a smaller version of a protein) known as amyloid beta, or Aβ, that form large clusters outside of neurons. Normally, enzymes called proteases can help to get rid of unwanted peptides and proteins in the brain. But amyloid plaques are especially resistant to degradation by proteases. Thus, they build up in the brain as the disease progresses; their presence is a defining feature of an AD brain.

Watch this 2-Minute Neuroscience video for a summary of the way Alzheimer’s disease affects the brain.

The other structure observed by Alzheimer, neurofibrillary tangles, also consist of abnormal deposits of proteins. In this case, the protein culprit is called tau. Tau normally plays an important role in helping to transport materials throughout the cell, but in AD it loses its normal function and clusters together in the tangles Alzheimer described. Like amyloid plaques, normal mechanisms the brain uses to remove unwanted protein deposits fail to effectively clear away neurofibrillary tangles. In fact, even after an affected neuron dies, the tangles found within it remain like a reminder of the neuron that was.

As the disease progresses, amyloid plaques and neurofibrillary tangles accumulate more and more in the brain. Thus, the appearance of these abnormal structures is correlated with the severity of the symptoms of AD. At the same time, exactly what role these structures play in the development of the disease remains unclear. For example, researchers are still unsure if amyloid plaques themselves are damaging to neurons, or if they represent an effort by the brain to sequester toxic Aβ peptides to protect neurons from their detrimental effects. There are similar questions about neurofibrillary tangles. Their appearance seems to be disruptive to neuronal function, and their spread throughout the brain correlates even better with neurodegeneration and symptoms than the proliferation of amyloid plaques. Nevertheless, their specific contribution to the progression of AD remains uncertain.

Causes and treatments

Thus, there are a lot of questions still surrounding the disease process of AD. Similarly, uncertainty surrounds why the disease affects some people but not others. In a small fraction of AD cases, the disease can be linked to mutations in a handful of identified genes whose protein products are involved in the production of the Aβ peptides mentioned above. But for most patients, there is no clear genetic or environmental cause of the disease.

There are, however, some known risk factors. For example, a variant of a gene called Apolipoprotein E, or ApoE, is known to increase the risk of AD by 10 to 20 times. ApoE encodes for a protein that is involved with the transport of cholesterol and other lipids in the blood, but it’s not yet clear why it might be involved with AD risk. High lipid and cholesterol levels, however, have also been identified as possible risk factors for the disease.

There are a number of other potential risk factors, like smoking, repetitive head injuries, poor cardiovascular health, and diabetes. Researchers are still unsure, however, just how these factors might increase the chances of developing AD. And by far the greatest risk factor remains one that we can’t avoid: old age.

Thus, the causes of AD remain somewhat obscure, which perhaps makes it unsurprising that our treatments are similarly unsatisfying. The most common treatment for the disease involves drugs that raise levels of the neurotransmitter acetylcholine in the brain. Acetylcholine is thought to play important roles in learning and memory, and large repositories of acetylcholine neurons (e.g. the nucleus basalis) are decimated during AD—likely contributing to memory loss.

Drugs called acetylcholinesterase inhibitors (AChEIs) suppress the activity of an enzyme called acetylcholinesterase, whose normal function is to remove acetylcholine from the synapse—in effect reducing the effect the neurotransmitter can have at that synapse. By inhibiting acetylcholinesterase activity, AChEIs cause acetylcholine levels to increase. In the process, these drugs can lead to modest improvements in memory. Because the effects are modest, however, AChEIs are often not very useful in the later stages of the disease. In fact, clear improvement in cognitive symptoms is only seen in less than 10% of patients taking the drugs. Additionally, AChEIs can only treat the symptoms of AD—they don’t do anything to stop the disease from progressing.

There are a handful of other treatments, and many others being explored, but at this point we don’t have any means of halting the neurodegeneration that underlies the symptoms of AD. Thus, we remain somewhat limited in our ability to treat the disease. Hopefully, continued neuroscience research allows us to one day develop better methods of addressing the pathological changes that occur in the AD brain.

References (in addition to linked text above):

Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8(6):429-31.

Cipriani G, Dolciotti C, Picchi L, Bonuccelli U. Alzheimer and his disease: a brief history. Neurol Sci. 2011 Apr;32(2):275-9. doi: 10.1007/s10072-010-0454-7.

Sanes JR, Jessell TM. The Aging Brain. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science, 5th ed. New York: McGraw-Hill.

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

2-Minute Neuroscience: Huntington's Disease

Huntington's disease is an incurable and fatal neurodegenerative disorder characterized by movement problems and a variety of other symptoms. It is a rare example of a neurological disorder that can be traced back to a mutation in a single gene. In this video, I discuss the symptoms and pathology of Huntington's disease.