Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
26
2010

Huntington’s Disease Comparisons

The following chapter aims to compare Huntington’s disease to other neurological diseases such as Alzheimer’s disease and Parkinson’s disease.

Risk Factors^

HD is caused by a mutation in the Huntington gene, which lies on chromosome 4. A certain sequence of DNA (C-A-G) of the Huntington gene is repeated multiple times. Generally, if a person has 35 or fewer copies of CAG on a particular segment of the Huntington gene, the person will not get HD. However, if he or she has 40 or more copies, he or she will get the disease. The greater the number of repeats, the more likely it is that the person will develop symptoms and the greater the chance that these symptoms will occur at a younger age. Every child of a parent with HD has a 50% chance of inheriting the disease, and the disease may occur earlier and more severely in each succeeding affected generation because the number of repeats canincrease. For more info on inheritance, click here.

gene altered neurons base ganglia control nucleus

Like Huntington’s disease, family genetics present a significant risk factor for inheriting Alzheimer’s disease. A study performed by Erasmus University Medical School in The Netherlands found that the risk of developing Alzheimer’s disease for those with at least one affected immediate relative was 3.5 times greater than those with no affected relatives. The study also showed a significant association between Alzheimer’s disease and family history of Down’s Syndrome, as well as an increased risk in with a family history of Parkinson’s disease. Perhaps the most significant risk factor of Alzheimer’s disease is age. Although there is variability in the age ofHD symptom onset, the incidence of Alzheimer’s increases with age, doubling every five years from 1% at 60 years to as many as 50% for those over 85 years of age. This is because normal aging is associated with altered protein metabolism, a process that often leads to the degradation of brain cells and the formation of abnormal clumps of protein in the brain over time. Other risk factors for Alzheimer’s disease include Down’s syndrome, untreated chronic hypertension, high cholesterol, and sustained head injuries.

Age is also the main risk factor for developing Parkinson’s disease. A subtype of Parkinson’s disease called young-onset Parkinson’s disease affects those younger than 40; however, most of those affected do not experience symptoms until after age 55. Although controversial, researchers now think genetics may play a rolein the development of the disease. The recent discovery of an abnormal protein called a-synuclein in an Italian family with many Parkinson’ssufferers has contributed to the understanding of Parkinson’s disease. As of early 2002, there were nine genetic abnormalities that had beenassociated with Parkinson’s disease. New studies show that having one close relative with Parkinson’s may increase the chances of developing Parkinson’s three or four-fold, and having two or more relatives may increase the chances ten-fold. However, most often a definite family history is not present for most patients. In these sporadic cases, agenetic predisposition may still play a role by increasing the chance of getting the disease when patients are exposed to possible environmental risk factors such as certain pesticides and herbicides. Other risk factors that may contribute to Parkinson’s disease include reduced estrogen levels and low folate levels (see section onnutrition).

Neurobiology: Neuromotor Comparisons^

As addressed in the HD Neurobiology chapter, the part of the brain most affected by HD is a group of nerve cells (neurons) at the base of the brain known collectively as the basal ganglia. The basal ganglia is responsible for the muscle-driven, motor movements of the body. As the cells in this area die, a person with HD experiences uncontrollable muscular movements likened to fidgetiness or nervous restlessness.

Similarly, Parkinson’s disease patients experience uncontrollable movements due to the disease’s effects on a specific area of the basal ganglia called the substantia nigra. The substantia nigra produces a chemical called dopamine, which is a neurotransmitter. Neurotransmitters are special chemicals that help neurons communicatewith each other. Dopamine and another neurotransmitter, acetycholine help to control our movements. In Parkinson’s disease, the neurons inthe substantia nigra gradually die off, which causes less dopamine to be made. With less dopamine than normal, there is an imbalance between dopamine and acetylcholine (see figure). This imbalance causes the nerve cells to fire out of control, leaving patients unable to direct their movement in a normal manner.

In Alzheimer’s disease, neurons in the brain and the spaces between them become clogged with protein deposits called beta amyloid plaques and neurofibrillary tangles. Even in people who don’t have AD, plaques and tanglesdevelop as part of the normal aging process. However, in people with Alzheimer’s disease, there are many more plaques and tangles. Plaques are dense, mostly insoluble (cannot be dissolved) deposits of protein and cellular material outside and around the neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. When neurons are clogged with tangles, and the spaces between neurons are clogged with plaques, the transmission of nerve impulses from one neuron to the next does not happen properly. As a result, the brain cannot perform mental functions such as remembering and thinking. There are other senile dementias (like Multi-infarct Dementia) that present like Alzheimer’s disease but have very different causes and are not comparable to HD. Though they many share certain neurobiological properties, these are distinctive conditions.

Though Huntington’s, Parkinson’s, and Alzheimer’s disease are caused by unique cellular processes, all three diseases are facilitated by the inability of neurons to communicate with each other. Gradual neuron death in people with HD hinders the ability of neurons to communicate. For people with PD, neurons die, causing an imbalance of dopamine and acetylcholine and the uncontrolled firing of nerve cells. Finally, in people with AD, plaques and tangles inhibit neurons’ ability to communicate.

Neurobiology: Emotional/Cognitive Comparisons^

Disclaimer: Despite many similarities, these cognitive and emotional signs present at different stages of the disease in different people. A person with HD may very well maintain healthy cognitive functioning throughout the remainder of his/her life.

The symptoms of Huntington’s disease are both behavioral and cognitive. Symptoms are the direct result of neurological changes in the brain. Apathy is one of the most common behavioral symptoms of HD due the death of nerve cells controlling “emotions” in the brain. Deterioration of a certain area of the brain called the caudate nucleus causes HD sufferers to be unable to control intensities of emotion, and makes them more likely to experience frustration, irritability, and aggression. For more on behavioral symptoms associated with HD go here.

In addition to behavior symptoms associated with HD, many cognitive changes also arise with the onset of Huntington’s disease due to neuronal damage. A patient’s ability to initiate a conversation and to communicate is altered due to degeneration in the brain. Furthermore, an individual suffering from the cognitive symptoms of HD may have memory, problem solving, and judgment difficulties. Tasks that were once simple are difficult for an HD patient to perform efficiently. An HD patient also experiences difficulty with visual spatial impairment, awareness, and organization. For more on the cognitive symptoms associated with HD, go here.

Similarly, patients of Alzheimer’s disease may experience both behavioral and cognitive changes at different stages of their disease process, many which are similar to HD. Difficulty with the acquisition of new information is generally the most salient symptom to emerge in patients with AD. Whereas learning new information for HD patients is disorganized and slow, Alzheimer’s patients experience rapid forgetfulness and an inability to store information. Several studies have demonstrated that people with AD lose more information over a brief delay than other patients with disorders that involve amnesia or dementia. Though at first their symptoms may be mild, people in the later stages of AD may forget how to perform simple tasks, like brushing their teeth or combing their hair. They neglect to bathe, or wear the same clothes over and over again while insisting that they have taken a bath or that their clothes are still clean. They can become lost on their own street, forget where they are and how they got there, and not know how to get back home. Eventually, patients need total care because they are unable to think clearly and perform tasks for daily living.

Another similarity to HD is that Alzheimer’s patients lose their initiative to perform normal activities or to engage in activities they used to enjoy. They often become very passive, sitting in front of the television for hours and sleeping more than usual. Furthermore, Alzheimer’s patients can experience rapid mood swings for no apparent reason, and their personality can vary from becoming extremely confused and suspicious to being fearful or dependent on a family member. They also may see, hear, smell, or taste things that are not there. Finally, like those with HD, Alzheimer’s patients sometimes exhibit poor judgment, which creates safety issues when left alone. They may wander and risk exposure, accidental poisoning, falls, self-neglect, or exploitation.

For patients with Parkinson’s disease, the most prominent symptom is tremor. Tremor often starts in one extremity and worsens with precipitating factors such as stress, fatigue, and cold weather. The tremor associated with PD occurs predominantly at rest, and results in the slowness of a patient’s movement (also known as Bradykinesia) A delay in initiating movements develops due to the brain’s inability to transmit necessary instructions to the body at a normal rate. Parkinson’s patients often report difficulties in performing activities of daily life, such as dressing, walking, and doing household chores. Symptoms that appear later in the progression of the disease include poor balance and the inability to swallow. Upon walking, a Parkinson sufferer has a decreased or non-existent arm swing, short shuffling, and difficulty negotiating turns. Another major symptom is rigidity, characterized by increased tone and stiffness in the muscles; rigidity is responsible for a Parkinson patient’s sometimes mask-like facial expressions and stooped posture.

As with HD and AD, depression is commonly seen in the early stages of Parkinson’s disease. It is estimated that about half of people with Parkinson’s may suffer from depression. This is thought to be not only a reaction to the diagnosis, but rather an intrinsic part of the disease process. Also, as with HD, Parkinson’s disease causes anxiety and can cause panic attacks. Symptoms of anxiety include breathlessness, sweating, chest discomfort, choking, and dizziness. In severe cases, patients may have feelings such as the fear of dying or the fear of going insane. Also, about 15-25% of individuals with Parkinson’s disease will suffer from memory and cognitive deficits similar to those of Huntington’s disease patients. Mild cognitive deficits are common in Parkinson’s and are characterized by a lack of flexibility in thought, difficulty in learning new information, and impaired visual-spatial skills. Short-term memory deficits are common and may progress to more severe memory deficits. Language skills are relatively spared although some studies have found a mild impairment in naming. Higher executive function (abstract thinking, planning abilities, judgment, and initiative) is often affected in patients with Parkinson’s disease as well.

Treatments^

Currently there exists no cure for any three of the neurological diseases. As with Huntington’s Disease, treatments for Alzheimer and Parkinson’s can be split into two distinct categories: treatments that target the specific mechanism of the disease, and palliative treatments (eg those that lessen symptoms but do not cure). For HD, mechanisms which are targeted include protein aggregation, inflammation, and free radical damage (See treatments section).

As of this writing (Jan 04), there are five FDA-approved drugs that can control symptoms and slow the progression of Alzheimer’s disease. Four of these drugs, Cognex, Aricept, Exelon, and Reminyl belong to a class of drugs known as cholinesterase inhibitors. Each drug acts in a different way to slow the metabolic breakdown of acetylcholine, an important brain chemical involved in nerve cell communication, and to make more available for communication between cells. Those suffering from AD have low levels of acetylcholine, and the medication helps to slow the progression of cognitive impairment and is most effective for patients in the early to middle stages of AD. The fifth drug, Namenda (memantine), is the first drug approved for the treatment of moderate to severe AD. Namenda shields brain cells from overexposure to another brain chemical called glutamate, excess levels of which contribute to the death of brain cells in people with Alzheimer’s. Although all five drugs have all been shown to modestly slow the progression of cognitive symptoms and reduce problematic behaviors in some people, at least half of the people who take these drugs do not respond to them. While the overall treatment effect of these medications is modest, studies show that, when they do work, they can make a significant difference in a person’s quality in life and day-to-day functioning.

Research is now focused upon prevention trials which try to stop the disease process from happening in the first place, and a number of studies are underway to test the effectiveness of various therapies in people without symptoms or who have only slight memory problems. Some of these studies are examining estrogen and various classes of anti-inflammatory and antioxidant chemicals. Research has shown that vitamin E and other antioxidants may slow the progression of AD in some people, although the overall impact is minimal. Research also suggests that ginkgo biloba, an extract made from the leaves of the ginkgo tree, may be of some help in treating AD symptoms. However, there is no evidence that ginkgo will cure or prevent AD. (For more on ginkgo biloba, click here.)

Palliative medications that can control depression, anxiety, agitated behavior (including aggression, hyperactivity and combativeness) and psychotic symptoms can help patients in the middle stages of AD. The medications prescribed for these symptoms are not specifically designated for AD, but they may be considered as part of the treatment plan by the supervising physician. Generally, medications for these symptoms are considered when non-medicated alternatives have failed and/or these symptoms put the AD patients, or others, in danger.

The purpose of all medicines for Parkinson’s disease is to help control tremor, movement, and balance to maintain daily activities. One of the mechanisms targeted by Parkinson’s medications includes the interactions of dopamine, a neurotransmitter (chemical messenger) that affects brain processes by allowing nerve cells to communicate with one another in the brain. Scientists have determined that people with late PD have lost more than 80 percent of dopamine-producing cells in the substantia nigra, an area deep within the brain. Normally, these cells communicate with other brain cells in the nearby striatum via dopamine. Thus, without dopamine, the striatum can’t send out certain messages and the symptoms of Parkinson’s ensue. Levodopa, also called L-dopa, was the earliest treatment discovered for Parkinson’s disease. L-dopa is a method of dopamine replacement therapy; it is turned into dopamine in the brain to supplement the cells that are producing less.

Another group of medications fit into the category of dopamine antagonists, drugs that bind but don’t stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors; they help improve control of various body movements, which begin to slow or become irregular in early Parkinson’s disease. Dopamine antagonists work by copying the effect of the neurotransmitter dopamine, proving effective in people with Parkinson’s disease who are losing their dopamine-producing cells. By doing this, dopamine antagonists can help people maintain their daily activities. Furthermore, anticholinergic drugs can be used to treat mild symptoms of Parkinson’s disease. Anticholinergic drugs block a neurotransmitter that affects dopamine so that more dopamine is available in the brain. Other pharmacological medications exist to treat Parkinson’s, and they too usually involve the mimicking or replacement of dopamine.

Prognosis^

As discussed elsewhere in this website, HD is a progressively debilitating disease with no known cure. The person with Huntington’s disease may be able to maintain a job for several years after diagnosis, despite the increase in disability. Loss of cognitive functions and increase in motor and behavioral symptoms eventually prevent the person with HD from continuing employment. Ultimately, severe motor symptoms prevent mobility. HD is usually fatal within15 to 20 years. Progressive weakness of respiratory and swallowing muscles leads to increased respiratory infection and choking, the most common causes of death. (For more information about the complications of HD, click here.) However, not all patients with Huntington’s disease progress at the same pace and are equally affected. The number of repeats may determine severity. There are people with a low number of repeats that have mild abnormal movements later in life and progression is slow whereas others with a large repeat length who are severely affected at a young age.

Although different in many ways, Alzheimer’s disease is also an incurable and progressively debilitating disease that can vary widely in its progression. Some people have a very precipitous course and go downhill rapidly, while others remain stable for a long time. For some, the disease only for the last 5 years of life; others may have it for as many as 20 years. A study of the prognosis of AD at the University of Massachusetts Medical School suggests that initial degree of severity (“how far”) rather than the variation in the rate of progression (“how fast”) best predicts prognosis in the early to intermediate stages of Alzheimer’s disease. Total disability is common in people with Alzheimers, and the most common cause of death is infection or a failure of other body systems.

Predicting disease progression for Parkinson’s disease is difficult because of the wide spectrum of disease types. Again, the course and prognosis of this disease vary according to the individual. Without treatment, PD causes severe disability or death in 25% of patients within 5 years, 65% of survivors after 10 years, and 89% of survivors after 15 years. However, with treatment, the life expectancy of people with PD without an accompanying dementia is nearly normal. The mean time from diagnosis to death in treated PD is 14 years. Death is usually due to complications of immobility, such as pulmonary embolism (blood clot in the lungs) or aspiration pneumonia (lung infection from regurgitated stomach contents).