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: Parkinson's disease

Background

In 1817, James Parkinson published an essay titled An Essay on the Shaking Palsy. In it, Parkinson described 6 patients who suffered from tremors, abnormalities in gait, balance problems, and a number of other symptoms. Parkinson, a physician in a village outside of London, hypothesized that these symptoms were characteristic of one overarching disease. His meticulously detailed account of these cases provided a clearer picture of the disorder than anyone before him had been able to produce.

Parkinson's precise descriptions and insightful conclusions led his essay to become recognized as an important step forward in understanding this collection of symptoms. Later in the 19th century, the influential neurologist Martin Charcot suggested the disorder that Parkinson had described should be called Parkinson's disease (PD).

What are the symptoms of Parkinson's disease?

The most noticeable symptoms of PD are movement-related, and the hallmark symptoms are: bradykinesia, resting tremor, and rigidity.

Bradykinesia refers to slowness of movement---especially slowness of the initiation of movement. PD patients will often have trouble getting their body to transition from a resting state to an active state. When they finally do get moving, their movement may be much slower than a healthy patient's.

Watch this 2-Minute Neuroscience video for a summary of Parkinson’s disease symptoms, neurobiology, and treatment.

Resting tremor indicates a tremor that is worse when the patient is at rest. When the patient makes a voluntary movement, the intensity of the tremor often subsides. These tremors typically start in the hands or arms and then spread to the legs as the disease progresses.

Rigidity describes a state of generally elevated muscle tone where the patient displays inflexibility and resistance to movement (try to reach for something while keeping your arm muscles contracted and you can see how this can result in rigid and difficult movement).

Although these movement-related symptoms are the most familiar signs of PD, there are a number of other common symptoms (both movement-related and non-movement-related) that occur as well. For example, later in the disease, postural instability becomes common, making falls more likely. Some of the non-motor symptoms include constipation, deficits in the sense of smell, sleep abnormalities, mood disorders like depression and anxiety, cognitive impairment, and dementia. 

What happens in the brain in Parkinson's disease?

Although there are many changes that occur in the brain during PD, there are two pathological changes that are considered hallmark signs of the disease. One is the degeneration and death of dopamine neurons in a dopamine-rich region of the brainstem called the substantia nigra. By the time a PD patient dies, she may have lost up to 70% of the dopamine neurons in this region. Neuronal loss in PD is most prominent in the substantia nigra, but as the disease progresses neurons in other areas of the brain and brainstem, like the amygdala, hypothalamus, locus coeruleus, and median raphe nucleus (among others) begin to die as well.

The basal ganglia (surrounded by red box).

How exactly the death of dopamine neurons in the substantia nigra leads to the most common symptoms of PD is still not completely clear, but current hypotheses focus on the role of dopamine neurons in the substantia nigra in facilitating movement. The substantia nigra is part of a collection of structures known as the basal ganglia, which are extremely important for movement (among other things). The basal ganglia are thought to both be involved in helping us to move when a movement is desired, and inhibiting movement when it's not wanted.

To get a better understanding of how this balance of movement and movement inhibitions works, think for a moment about what's going on in your body right now as you remain relatively still to read this text (if you are moving right now while you're reading this, then think of another time when your body was at rest). As you're reading, if you want to move your hand to the screen or mouse, the movement is initiated by your brain. But when you're not aiming to make a movement, and are trying to stay relatively motionless, your brain is also intensively involved in keeping you that way. In other words, as you're remaining still, your brain has to intentionally inhibit any undesired movements---like your head suddenly turning in a different direction, your hand involuntarily jerking up in the air, and so on.

The basal ganglia are thought to be integral to this type of inhibition, as circuits within them constantly quiet the activity of neurons that project to the motor cortex to initiate voluntary movement. Dopamine neurons in the substantia nigra play a role in the release of that inhibition. In other words, without dopamine, your basal ganglia have a difficult time stopping their inhibition of your movement. They become like a switch that can't be turned off, and in this case the switch controls a device that constantly applies force to keep another device from being turned on.

Thus, when those dopamine neurons degenerate and die, it becomes more difficult to stop your basal ganglia from inhibiting movement. Then, even desired movements can be inhibited, providing an explanation for why the initiation of movement for a PD patient requires so much effort, and why it is slow and labored even after it starts.

What causes the death of dopamine neurons in the substantia nigra, however, is still unclear. Some research suggests their death is linked to abnormal protein deposits, which are the other hallmark sign of a PD brain. These deposits consist primarily of a protein called alpha-synuclein, which in PD and several other disorders (e.g. Alzheimer's disease, dementia) can clump together in abnormal aggregates inside neurons. These protein aggregates are known as Lewy bodies, named after Fritz Lewy, who discovered them in 1910. Lewy bodies are thought to be able to interfere with cell structure and function in a number of ways, ranging from damaging DNA to the destruction of mitochondria.

Regardless, the connection between Lewy bodies and cell death is still not completely clear, and some researchers point to evidence of cell death in areas where no Lewy bodies are typically seen as proof that other factors are at play in causing neurons to die in PD.

All neurons in the brain express alpha-synuclein and rely on the same mechanisms thought to fail in neurons that die during PD pathology, so it's still unclear why PD preferentially affects the substantia nigra and a select few other areas of the brain. Some have proposed that PD is capable of spreading throughout the brain using a prion-like mechanism, and the path of spreading is dictated by the connections of neurons. Others suggest that certain neurons are simply more susceptible to the pathology that causes damage in PD, and thus they are the ones most likely to be affected. As of yet, the exact reasons for the tendency of PD pathology to preferentially affect certain areas of the brain are still unclear.

It's also uncertain what causes the disease process to begin in the first place. In most cases, it is thought to be linked to a combination of genetic and environmental factors. But exactly which genes and environmental influences are involved likely differs from case to case, and although a number of potential genes and environmental risks (e.g. pesticide exposure, repetitive head injuries) have been identified as potential contributing factors, more research needs to be done to develop a better understanding what exactly causes the initiation of the disease.

L-DOPA for Parkinson's disease

Although there are now several viable treatments for PD, the most common---and often the most effective treatment initially---is a precursor to dopamine called levodopa, or L-DOPA. When your brain produces dopamine, it starts with the amino acid tyrosine, which it can either get directly from the diet or through the conversion of another amino acid (phenylalanine). Tyrosine is then converted into L-DOPA, which can be converted into dopamine.

While it might seem that the most logical treatment for PD would be to administer dopamine to the patient to replenish depleted levels of the neurotransmitter in the basal ganglia, this would prove fruitless because dopamine cannot cross the blood-brain barrier, a structure that generally helps to keep unwanted substances circulating in the bloodstream from entering the brain. This barrier is usually beneficial, as it prevents things like pathogens from getting into the brain. Unfortunately, however, the blood-brain barrier can also thwart attempts to get potentially therapeutic substances into the brain.

L-DOPA, on the other hand, can cross the blood-brain barrier. Thus, when L-DOPA is administered to a PD patient, the brain can use the excess levels of the precursor to produce more dopamine, replenishing depleted levels of the neurotransmitter (at least this is what the role of L-DOPA typically is assumed to be---see below). This can, in less than an hour after administration, produce some astonishing improvements in motor function. Take a look at the video to the right as an example. In it, you'll see a PD patient before L-DOPA therapy displaying all of the classic signs of PD (e.g. tremor, bradykinesia, postural instability). Then, at around 1:00 into the video, you'll see that same patient after L-DOPA administration, and all of the symptoms have disappeared.

While the hypothesis that L-DOPA improves PD symptoms by acting as a precursor the brain can turn into more dopamine is taught as fact in most neuroscience courses, researchers are actually still a bit unclear on exactly how L-DOPA works. Some evidence suggests it can act as a neurotransmitter on its own, and there are also indications it can be converted into other active compounds (besides dopamine), which may be capable of influencing dopamine activity.

Regardless of how it works, when L-DOPA was first discovered it seemed like a miracle drug. But problems with L-DOPA treatment soon became apparent. One problem is that, over time, the effectiveness of L-DOPA seems to diminish. In the early days of L-DOPA treatment, the medication can sometimes completely control a patient's symptoms. Later in treatment, however, patients may experience a return of symptoms between doses, and the time they experience relief from their PD symptoms can gradually decrease with continued time on the drug.

Additionally, long-term use of L-DOPA is associated with movement-related side effects itself. These movement problems are often called L-DOPA-induced dyskinesias, and include symptoms like involuntary movements and sustained muscle contractions. It's still not fully understood why these side effects occur, but researchers have hypothesized that chronic L-DOPA therapy can lead to excessive dopamine activity in the basal ganglia, essentially creating the opposite effect (excessive movement) from what the paucity of dopamine typically causes in PD (a lack of movement). This perspective has been challenged, however, by evidence that suggests the development of dyskinesias may not be dependent on increases in dopamine levels.

Since the discovery of L-DOPA, there have been a number of other drugs discovered that can increase the effectiveness of L-DOPA or have their own effects to improve PD symptoms. New surgical methods like deep brain stimulation also offer some promise in treating cases of the disorder that have become resistant to other types of treatment. None of these approaches, however, has the ability to stop the progression of neuronal death that leads to Parkinsonian symptoms to begin with. L-DOPA, for example, may be able to replenish dopamine levels, but it can't stop dopamine neurons from dying. Thus, L-DOPA and other PD treatments are ways of managing symptoms, but they do not remedy the underlying pathology of the disease. Because of this, researchers continue to fervently look for better alternatives for treating PD.

Reference (in addition to linked text above):

Obeso JA, et al. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord. 2017 Sep;32(9):1264-1310. doi: 10.1002/mds.27115.

Want to learn more about Parkinson's disease? Try these articles:

Deep brain stimulation in Parkinson's disease: Uncovering the mechanism

The unsolved mysteries of protein misfolding in common neurodegenerative diseases

Know Your Brain: Chronic Traumatic Encephalopathy (CTE)

Background

comparison of a healthy brain and brain afflicted with CTE, from the Boston University Center for the Study of Traumatic Encephalopathy

In 1928, physician and researcher Harrison Martland published a scientific paper titled Punch DrunkIn it, he described 23 cases of boxers who had started to display neurological symptoms after experiencing the repetitive head trauma that goes hand in hand with their sport. They sometimes developed symptoms that resembled Parkinson's disease, like tremors and abnormalities in gait, as well as more general types of cognitive deterioration. About a decade later, another researcher gave a new name to Martland's punch drunk syndrome, calling it dementia pugilistica.

A year before Martland's popularization of the term punch drunk syndrome, physicians Michael Osnato and Vincent Gilberti had published a review of cases of what was known at the time as postconcussion neurosis---a neurological disorder that emerged after a concussion. Osnato and Gilberti concluded that concussions could be associated with subsequent neurodegeneration, or the degeneration and death of neurons. Because the pathology they saw in the cases they studied resembled the effects of a type of brain inflammation known as encephalitis, Osnato and Gilberti decided this disorder should be called traumatic encephalitis, which soon was modified to traumatic encephalopathy.

In 1940, researchers Bowman and Blau coined the term chronic traumatic encephalopathy when describing the case of a 28-year old professional boxer who had been unable to get commisioned to continue boxing because he was suffering from a number of symptoms including paranoia, depression, memory deficits, and impaired cognition. Bowman and Blau added the word chronic to Osnato and Gilberti's original terminology because this patient's case had not improved over the course of 18 months. They thus called the condition chronic traumatic encephalopathy, or CTE.

Although the first reports of CTE described boxers, it wasn't long before similar symptoms were reported in American football players---and players of any sport that involved the potential for multiple head injuries. It wasn't until 2005, however, that widespread attention was focused on American football as a potential cause of CTE. This attention followed the publication of a report by neuropathologist Bennet Omalu and colleagues after the examination of the brain of former NFL player Mike Webster. Webster had died of a heart attack but had suffered from memory problems and depression late in his life. Upon autopsy, it was found that Webster's brain showed signs of degeneration and the researchers concluded that Webster had suffered from CTE. Autopsies of the brains of a number of other football players have resulted in similar observations.

What is CTE?

CTE is a neurological condition thought to be the consequence of repetitive head trauma, although other risk factors must also be at play since not everyone who experiences repetitive head trauma develops CTE. Symptoms associated with CTE generally begin to appear years (sometimes decades) after trauma and may include: problems with cognition like memory and attentional deficits; behavioral abnormalities like paranoia, aggression, and impulsivity; mood disturbances like depression, anxiety, and suicidal thoughts; and movement problems like tremor and other Parkinsonian symptoms. In the majority of cases, the symptoms of CTE are progressive---meaning they get worse over time.

Despite a long list of recognized symptoms, however, there are no widely accepted diagnostic criteria that define what CTE should look like (although at least two sets of diagnostic criteria have been proposed). Sometimes CTE is defined specifically as the pathological changes that occur in the brains of patients, while the presentation of symptoms is called traumatic encephalopathy syndrome.

What causes CTE?

Typically, CTE is associated with repeated concussions and subconcussive blows (i.e. trauma that doesn't result in clinical symptoms). The evidence is not clear at this point as to how many instances of head trauma are required to cause CTE, or if it could be caused by one incident. Also, not everyone who experiences repetitive head trauma will develop CTE, which suggests that other factors must also be involved. But researchers are still working to identify those other risk factors.

Populations who are at risk for frequent head trauma are also most likely to develop CTE, as CTE has been observed in: boxers, American football players, professional hockey players, professional wrestlers, victims of physical abuse, military personnel, and so on. It's important to emphasize that, as mentioned above, head trauma does not have to result in clinical symptoms to increase the risk of CTE. Someone who takes frequent blows to the head may be at greater risk of developing CTE, even if those blows don't result in concussive symptoms.

What happens in the brain in CTE?

The pathological features of CTE in the brain are perhaps better defined than the overt symptoms of CTE. The principal feature is the accumulation of a protein called tau into insoluble clusters, also known as aggregates. This process is thought to begin when tau protein becomes hyperphosphorylated, which means that multiple chemical groups called phosphoryl groups have attached to tau to the point where no more can attach to the molecule. At this point, tau, which normally interacts with and helps to maintain the stability of microtubules in the cell, disassociates from the microtubules. Then, the hyperphosphorylated tau protein forms the aggregates mentioned above in neurons and astrocytes surrounding blood vessels in the brain. The clusters of tau are called neurofibrillary tangles when they appear in neurons and are often called astrocytic tangles when they appear in astrocytes.

The tau aggregates in CTE form in the cerebral cortex, primarily at the depth of the invaginations of the cortical surface known as the cortical sulci. These aggregates may also form in other layers of the cortex, some regions of the hippocampus, and in other subcortical nuclei.

What effect these clusters have exactly is still uncertain, as while their presence is correlated with the severity of neurodegeneration, it has not been clearly demonstrated to cause it. Still, neurofibrillary tangles are thought to be able to disrupt cellular communication, which could lead to detrimental effects on the cell. They also have the ability to pass from one affected neuron to other unaffected neurons, which seems to indicate a potential for the pathology to spread within the brain. 

Aggregates of tau are found in other neurodegenerative diseases like Alzheimer's disease as well, and some hallmarks of other neurodegenerative diseases, like the amyloid plaques commonly seen in Alzheimer's disease, also occur in CTE. But the distribution of tau in CTE, as well as the absence of defining features of another neurodegenerative disease is what allows for the diagnosis of CTE. For example, if tau-associated degeneration occurs in certain regions of the hippocampus alongside the formation of amyloid plaques, it would be indicative of Alzheimer's disease rather than CTE.

While tau deposits are the primary microscopic sign of CTE, there are also more evident signs, like reduced brain weight, atrophy of the cerebral cortex (especially in the frontal and temporal lobes), atrophy of various other regions of the brain like the hippocampus and amygdala, enlargement of the ventricles, and thinning of the corpus callosum

Prevalence of CTE

CTE has received a great deal of media attention over the past several years, and this has led to some misunderstandings about the prevalence of the disorder. For example, in 2017 a story about CTE in National Football League (NFL) players received a lot of media attention, with headlines reporting that CTE was found in 99% of brains of NFL players that had been studied. This study, however, used brains that had been donated to be studied for CTE, regardless of whether or not symptoms had emerged during the players' lives. This introduces a potential source of bias, as relatives of players may have donated the players' brains because of concern about symptoms that had arisen during the players' lives. In other words, many of the brains involved in the study may have been donated because of concerns about CTE, making it less surprising that almost all of the brains showed signs of CTE.

Due in part to the potential biases surrounding brain donation for CTE study, the actual prevalence of CTE is difficult to estimate. One study that included a larger brain bank found CTE in 31.8% of the brains of individuals with a history of repetitive head trauma, and no cases among 198 brains without such a history. Larger studies are underway now to try to get a better sense of how prevalent CTE is in the general population.

Read more about the neuroscience of traumatic brain injury.

References (in addition to linked text above):

Asken BM, Sullan MJ, DeKosky ST, Jaffee MS, Bauer RM. Research Gaps and Controversies in Chronic Traumatic Encephalopathy: A Review. JAMA Neurol. 2017 Oct 1;74(10):1255-1262. doi: 10.1001/jamaneurol.2017.2396.

Montenigro PH, Corp DT, Stein TD, Cantu RC, Stern RA. Chronic traumatic encephalopathy: historical origins and current perspective. Annu Rev Clin Psychol. 2015;11:309-30. doi: 10.1146/annurev-clinpsy-032814-112814. Epub 2015 Jan 12.

Know Your Brain: Huntington's disease

Background

George Huntington was not a prolific researcher. In fact, he only published three scientific papers in his career. The first of these, however, published in 1872 when Huntington was just 22 years old, would lead to his name being found in most neuroscience textbooks today.

In that paper, titled On chorea, Huntington discussed a disorder called chorea that had been known since the Middle Ages. The word chorea comes from the Geek word choreia, which means to dance, and it was used to describe a disorder characterized by involuntary, spasmodic movements of the limbs that bore some resemblance to an odd dance. 

There are a number of different types of chorea, each linked to a different underlying cause. George Huntington wrote the best description to that point of a particular form of chorea that began in adulthood and was inherited, inexorably progressive, and always fatal. Within a few decades, the chorea Huntington described was widely-recognized as a unique disorder, which---in appreciation for Huntington's clear and accurate depiction of the disease---was called Huntington's chorea. The name was eventually changed to Huntington's disease (HD), as it became apparent that the condition involved more than just chorea. Not all patients with HD develop chorea and even those who do experience a number of other symptoms that are not related to movement.

In the 20th century, the hereditary nature of HD became even clearer as our understanding of common patterns of inheritance improved. In the 1980s, a gene was identified that seemed to be the cause of HD. With this discovery, HD joined a short list of diseases caused by the mutation of a single gene.

What is Huntington's disease?

The symptoms of HD can appear at any age, but typically emerge in middle age (the average age of onset is 40 years). At first, patients will often experience subtle changes in personality, cognition, and movement. For example, a patient might become irritable, have trouble remembering things, or be especially restless or fidgety. These symptoms, however, are usually not enough to lead to a diagnosis. 

The early symptoms then progress into symptoms that allow for a clear diagnosis of HD. These include: conspicuous movement problems like chorea, impaired coordination and balance, abnormal eye movements, and muscle rigidity. Also, cognitive symptoms can become debilitating, and can involve difficulty focusing, a tendency to become fixated on a thought, lack of impulse control, and lack of awareness. Psychiatric symptoms like depression, insomnia, and fatigue are common as well.

huntington's disease causes significant neurodegeneration in the basal ganglia (highlighted structures here in the middle of the brain).

HD is a neurodegenerative disorder, meaning it is characterized by the degeneration and death of neurons. Thus, symptoms are accompanied by pathological changes to the brain, including neuronal loss in specific brain regions. The caudate and putamen (both part of the basal ganglia) are the two areas where cell loss is the most prominent, and damage to them is thought to be the cause of some of the movement problems HD patients experience. Other areas of the brain, however, like the substantia nigra, cerebral cortex, hippocampus, cerebellum, hypothalamus, and thalamus are also affected. The disease is invariably fatal; the average time from diagnosis to death is around 20 years

What causes Huntington's disease?

HD is a rare disorder, occurring in the western world at a rate of about 4-10 cases per every 100,000 people. As mentioned above, the disease is inherited, and can be traced back to a mutation in a single gene called huntingtin (HTT). The HTT gene contains a DNA sequence that consists of three nucleotides (cytosine, adenosine, and guanine, or CAG) in repetition---a pattern known as a trinucleotide repeat. 

Some degree of trinucleotide repetition in the HTT gene is normal and will not result in HD. When the gene is mutated, however, excess CAG repeats (above 35) can occur. The higher the number of repeats, the greater the risk of developing HD. For example, 36-39 repeats leads to an increased risk of HD, but also the possibility that the onset of the disease will be so late in life that noticeable symptoms may not appear before death due to other causes. 40 or more repeats, however, is a fully penetrant mutation, meaning that all people with the mutation will develop disease. As the number of repeats increases, the age of onset is more likely to be younger, with 70 or more repeats causing the disease to appear during youth. The largest repeat length seen so far has been 250, but it is very uncommon to see repeat lengths greater than 80.

The mutation in the HTT gene that leads to HD is known as an autosomal dominant mutation. This means that the gene variation that encodes for the mutant protein is dominant, and will be expressed if it's inherited. If one parent has HD, their child has a 50% chance of inheriting the mutated gene, and thus of developing HD.

The function of the huntingtin protein (which is produced by the HTT gene) is not fully understood, but it is thought to play important roles in embryonic development. There are also indications it is an important regulator of signaling pathways in the cell. It's expressed throughout the body, but is especially prevalent in the central nervous system.

An excess number of CAG repeats in the HTT gene leads to the production of a mutated form of huntingtin protein. The characteristics of these mutated proteins cause them to be likely to be cleaved by cellular enzymes. The cleaved fragments then have a propensity to group together, forming clusters within neurons that are not easily removed by brain enzymes. It has been hypothesized that these protein clusters (which are similar in some ways to the protein aggregates seen in Alzheimer's, Parkinson's, and other neurodegenerative diseases) may play a role in the neuronal damage seen in HD.

Watch this 2-Minute Neuroscience video to learn more about Huntington’s disease.

Additionally, mutant huntingtin seems to also be able to recruit other, normal proteins, into these clusters. In this way, huntingtin protein is thought to spread its abnormal state to healthy proteins, which might cause normal cell functions to be disrupted. Finally, some have suggested that mutated huntingtin may also have direct toxic effects on neurons.

As with other neurodegenerative diseases, however, the exact way HD leads to neurological damage is not fully understood, and the effect the protein aggregates have on the brain is still not completely clear. Some researchers, for example, have even argued that huntingtin aggregates are part of the brain's defense mechanism as it tries to cope with other pathogenic changes that are occurring. In general, though, the evidence supports the hypothesis that huntingtin aggregates are toxic and play some role in the progression of disease.

As huntingtin protein deposits accumulate in the brain of an HD patient, areas of the brain also begin to display neurodegeneration. As mentioned above, the caudate and putamen are strongly affected, but other regions like the substantia nigra, cerebral cortex, hippocampus, cerebellum, hypothalamus, and thalamus experience degeneration as well.

There is no cure for HD. There are a number of medications, however, that can be taken to treat the symptoms of the disease. These vary depending on the symptoms being targeted, and range from drugs liked tetrabenazine to treat chorea to selective serotonin reuptake inhibitors for depression. While drugs like tetrabenazine are effective in treating symptoms of HD, some also have significant side effects. This often leaves patients without great options for treatment. The sparsity of treatment options combined with the inevitably fatal nature of the disease contributes to the suicide rate being about 5 to 10 times higher in HD patients.

Reference (in addition to linked text above):

Walker FO. Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28.

Know your brain: Lyme disease

Background

There are a number of documented cases throughout history of what was probably the same disorder we now call Lyme disease. But Lyme disease didn't earn its name and become appreciated as a syndrome of its own until the 1970s, when two exasperated mothers from a town in southern Connecticut contacted the Connecticut State Department of Health and the Yale School of Medicine in search of help with an outbreak of (what seemed to be) arthritis that was primarily affecting children.

The outbreak spanned three towns in a small region of Connecticut: Old Lyme, Lyme, and East Haddam. By that point, 51 residents (including 39 children) of this region, which had a total population of only 12,000, had been diagnosed with some form of arthritis. 

Researchers from Yale and the Department of Health came to Lyme to investigate. One clue that emerged from the investigation was that 25% of the patients had noticed a skin lesion that formed several weeks before the symptoms began. Researchers began to find other similarities: most patients lived in wooded areas of town, patients often lived near one another, and the cases generally appeared in summer and early fall months. 

Based on these clues and descriptions of the rash that can occur after a tick bite, researchers began to suspect ticks were spreading the disease, which had come to be known as Lyme arthritis. The name would soon be changed to Lyme disease to reflect the fact that this was much more than just a type of arthritis.

In the 1980s it was confirmed that Lyme disease was spread by ticks when the bacterium responsible was discovered. The bacterium was named Borrelia burgdorferi in honor of Willy Burgdorfer, the scientist who discovered it (Borrelia refers to the genus of bacteria B. burgdorferi belongs to). Sometimes Lyme disease is also called Lyme borreliosis to indicate the involvement of Borrelia bacteria.

What is Lyme disease?

B. burgdorferi is spread by several species of hard-bodied ticks. In the United States, the disease is primarily spread by the blacklegged tick, or deer tick, and the western blacklegged tick. Ticks are known as hematophages, meaning they need blood to survive and move through their life cycle. Ticks generally become infected with B. burgdorferi in the first stage of their life cycle (the larval stage) when they bite infected small mammals or birds. Subsequently, when they feed on the blood of a new host, B. burgdorferi will pass from the tick to the new host. 

After their first blood meal, the tick enters its nymph stage, which is a part of the insect life cycle where the insect is not quite an adult but resembles the adult form. Nymphal ticks feed on small mammals or birds, which helps to spread B. burgdorferi among these populations. 

Nymphal ticks can also feed on humans, however, and they are the most common source of Lyme disease because they are very small at that stage (about the size of a poppy seed). Thus, they are more likely to go unnoticed while they are attached to a host, which allows them to stay attached for the amount of time it takes Lyme to be transmitted (usually at least 36 hours). Since humans aren't thought to spread B. burgdorferi among themselves or to other animals, they are considered a dead-end host for the bacteria (meaning there is no other host for the bacteria to go to after them). Adult ticks can feed on humans too, but are most commonly found on large animals in the wild, like deer.

Symptoms

The initial sign of B. burgdorferi infection in most patients is a round or oval, gradually expanding skin lesion at the location of the tick bite. At the same time, patients may experience flu-like symptoms like fatigue, headache, and fever. Over the following days or weeks, patients may develop multiple skin lesions that are widespread and generally similar in appearance to the first, but smaller.

In around 5% of patients, cardiac symptoms will occur several weeks after the first signs of disease. These symptoms can range from mild ventricular dysfunction to a fatal form of pancarditis, a term that refers to inflammation of the heart.

Several months after the initial signs of infection, about 60% of untreated patients begin to experience symptoms of arthritis like joint swelling and pain.

Neuroborreliosis

About 15% of untreated patients will also experience neurological symptoms several weeks to a few months after the infection begins, and in about 5% of untreated patients these symptoms may become chronic. The neurological effects vary but often manifest initially as meningitis, cranial neuritis, and/or radiculoneuritis. Meningitis is an inflammation of the meninges and may involve headaches, vomiting, neck stiffness, and other symptoms. Cranial neuritis involves inflammation of the cranial nerves and may cause symptoms like facial palsy/weakness, abnormalities in facial sensation, visual disturbances, tinnitus, vertigo, hearing loss, or other symptoms depending on the cranial nerve most affected. Radiculoneuritis involves an inflammation of the nerve roots; symptoms often include pain, numbness, and/or tingling sensations. 

Chronic neurological symptoms are diverse as well. Chronic effects may include a brain disorder that is linked to cognitive problems like difficulties with memory, verbal fluency, and processing of information. Encephalomyelitis, which is an inflammation of the brain and spinal cord, may also occur and lead to symptoms like confusion, psychiatric problems, a variety of movement difficulties, and seizures. Other psychiatric symptoms may appear too, including irritability, anxiety, depression, mood swings, sleep disturbances, sensory hyperarousal (i.e. extreme sensitivity to sensory stimuli like light or sound), and, in rare cases, hallucinations.

What causes the symptoms of Lyme disease?

While the symptoms of Lyme disease can be severe if untreated, they are not thought to be caused by any toxins or detrimental substances produced by B. burgdorferi, as is the case with some other particularly harmful bacteria. Unfortunately, what does cause the symptoms is still not completely clear. It is thought, however, that most of the problems likely are due to side effects of the immune system response to the presence of the bacterium. The primary immune response thought to be at play is inflammation, a general reaction your immune system has to any potentially harmful or foreign substance.

Inflammation involves the accumulation of immune system cells at a site of infection or damage, and the goal of the response is to repair damage and remove potentially dangerous foreign invaders. Inflammation, however, can also lead to secondary symptoms; a well-known example of this is when you experience redness, pain, and swelling around the area of an injury. Secondary effects of this sort are thought to contribute to the symptoms of Lyme disease ranging from the initial skin rash to joint problems.

The inflammation that occurs after B. burgdorferi infection seems to be disproportionate to the threat of the bacterium. In other words, the inflammatory response is stronger than it needs to be. Often, it even continues after the immune system has eliminated B. burgdorferi from the body. The reasons for this exaggerated response are unclear.

In the nervous system, the inflammatory response to B. burgdorferi may lead to secondary damage to neurons and glial cells. Additionally, there is evidence B. burgdorferi may adhere directly to brain capillaries, neurons, and glial cells, in the process causing changes in the permeability of blood vessels as well as damage (e.g. demyelination, or the deterioration of the myelin sheath of neurons) to cells. There is also some indication B. burgdorferi may be able to invade neurons and glial cells to cause additional damage. These direct effects, of course, may compound the damage caused by inflammation. In truth, however, these mechanisms for B. burgdorferi's pathogenic effects are poorly understood at this point. 

Outcomes

The immune system is capable of removing B. burgdorferi such that the bacterial numbers eventually fall even without treatment, and symptoms in most patients are mitigated over time. In untreated patients, however, the bacterium has the capability of remaining in the system at low levels for years, which can cause chronic symptoms.

Treatment primarily consists of antibiotics, and if begun early enough, the treatment is often completely effective. A small percentage of patients, however, may experience lingering effects, even after treatment. These patients are sometimes said to be suffering from post-treatment Lyme disease syndrome, or PTLDS. There is some controversy about these chronic symptoms, however, and how much we can say they are attributable to the infection with B. burgdorferi versus immune system abnormalities occurring post-infection or other factors altogether.

Reference (in addition to linked text above):

Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, Li X, Mead PS. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090. doi: 10.1038/nrdp.2016.90.