Neurodegenerative diseases all involve a progressive destruction of nerve cells. They more often affect older people, and are likely to become more common as life expectancy rises due to improved medical care — not only in the in the U.S. but worldwide. From 2015 to 2060, the number of people 65 and older in the U.S. is expected to jump from 48 million (15 percent of the population) to 98 million (nearly 25 percent of the population). As scientists look ahead, the field of neurodegenerative disease promises to become increasingly important.
In the past two or three years, articles in Nature, Scientific American, and other major science publications have discussed the intriguing possibility that many, if not all, neurodegenerative diseases involve misfolded proteins called prions. You may have heard of prions in the context of “mad cow disease.” Scientists now wonder if prions also contribute to more familiar disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease). In the case of prions, a protein’s normal 3-D structure has somehow been altered, so that it no longer functions correctly. Worse still, the misfolding can cause proteins to collect in irregular clumps that can damage cells. Is this really the cause of neurodegenerative diseases? Many scientists are asking that question. As you read this chapter, remember that there’s still a lot to learn in this field — and each step toward understanding normal brain function aids the development of prevention or treatment for thousands of people in the future.
ALZHEIMER’S DISEASE
Alzheimer’s disease is a form of dementia that is eventually fatal. Over time, a person’s brain undergoes irreversible, progressive degeneration that impairs his or her memory and reasoning. In the late-onset form of Alzheimer’s, patients display symptoms in their mid-60s or later, with symptoms becoming more severe with age. In early-onset forms of the disease, patients can start to experience symptoms in their 30s. Fortunately, early-onset Alzheimer’s occurs in less than 10 percent of cases of the disease.
Prevalence and Impact
Alzheimer’s is the most common cause of dementia in older adults. Of the 47 million people with dementia worldwide, approximately 60 to 70 percent have Alzheimer’s. The disease affects 5 to 8 percent of all people over 65 years of age, 15 to 20 percent above 75, and 25 to 50 percent of those over 85. It’s estimated that more than 5 million people in the U.S. suffer from the disease; however, the actual number could be as high as 11 million, including many who are now asymptomatic. Conservative estimates are that Alzheimer’s will affect 13.8 million people in the U.S. by 2050.
In 2014, Alzheimer’s was the sixth leading cause of death in the U.S., accounting for 93,541 deaths. Deaths rose from 16.5 per 100,000 people in 1999 to 25.4 per 100,000 in 2014, but Alzheimer’s-related deaths are believed to be severely underreported. Some patients go undiagnosed, and others have dementia-related conditions (such as aspiration pneumonia) rather than Alzheimer’s listed as their primary cause of death. Some estimate that the number of Alzheimer’s-related deaths might be six to seven times higher than reported. If this is accurate, it would be the third leading cause of death among older Americans.
NIH.
Alzheimer’s disease damages and destroys the connections between cells, causing widespread cell death. The damage causes problems with learning, memory, and thinking, and is eventually fatal.
Symptoms of Alzheimer’s Disease
Alzheimer’s symptoms are classified by the disease’s progression. Early stage symptoms include memory problems (greater than expected in healthy people of a similar age), difficulty concentrating or finding appropriate words, problems judging and calculating, and disorientation in time or place. Most people are not diagnosed until the mild stage when symptoms include personality and behavior changes, wandering and getting lost, repeating questions, losing and placing objects in odd places, taking longer to complete daily tasks, and having trouble handling money and paying bills. In the moderate stage, some patients have trouble recognizing family and friends; inability to learn new things; problems coping with new situations; difficulty getting dressed or performing other multistep tasks; hallucinations, delusions, and paranoia; and impulsive behavior. In the severe stage, patients are completely dependent on others for care, as their body begins shutting down. Their communication is reduced to groans, moans, and grunts; sleeping increases; and they become bedridden. Other severe stage symptoms include weight loss, seizures, difficulty swallowing, skin infections, and a lack of bowel and bladder control.
Diagnosing Alzheimer’s
Alzheimer’s dementia is most commonly diagnosed by a physician asking the patient and a family member or friend about the patient’s health, medical history, ability to perform daily activities, and changes in behavior and personality. Next, the physician conducts tests on memory, problem-solving, attention, counting, and language. Even if mental deficits are found, including dementia, the condition still might not be Alzheimer’s. Similar deficits could be due to other conditions including Lewy body disease, frontotemporal dementia, Parkinson’s disease, stroke, a tumor, sleep disturbances, side effects from medication, or infection.
Researchers are searching for a defining biomarker for Alzheimer’s — a specific indicator that can physically identify a disease. Two candidate primary biomarkers are amyloid-beta (also called beta-amyloid) and tau. In Alzheimer’s, amyloid-beta forms extracellular senile plaques, also known as neuritic plaques. These malformed clumps contain a fragment of the preliminary protein. In addition, tau, a type of protein that normally stabilizes the cellular skeleton, forms neurofibrillary tangles inside neurons. Both abnormalities are found in the brains of people with Alzheimer’s but, at present, no definitive biomarker can diagnose the disease in its early stages. A diagnosis can only be confirmed by postmortem examination.
Some potential diagnostic methods for Alzheimer’s include brain imaging, genetic risk profiling, and examining cerebrospinal fluid or blood. Neuroimaging, among the most promising areas of research focused on early detection, uses a mildly radioactive chemical marker that binds to amyloid plaques and shows their location in PET scans of living people. Starting in 2012, the FDA began approving the use of molecular imaging tracers to evaluate possible Alzheimer’s disease or other causes of dementia. To date, the FDA has approved the use of three tracers — florbetapir F-18, flutemetamol F18, and florbetaben F18 — to detect amyloid-beta in the brain. However, neuritic plaques are also present in the brains of people with no dementia or Alzheimer’s, so these scans are not used for routine evaluation.
Jensfloran.
Amyloid plaques, seen here as dark spots against pink brain tissue, are a hallmark of Alzheimer’s disease. Scientists are still investigating whether plaques cause the disease or are merely a symptom of it.
Causes and Pathology
The causes and mechanisms underlying Alzheimer’s disease are not fully understood. Most forms are likely caused by a combination of heredity, environment, and habits. Evidence has been building that head trauma is one contributing factor, based on a condition known as chronic traumatic encephalopathy (CTE) seen in football players and other athletes who play contact sports. Those with CTE typically show a buildup of tau protein in brain cells; some also have amyloid-beta deposits, but this is less common.
It appears that patients experience the first cellular changes associated with Alzheimer’s a decade or more before becoming symptomatic. The neuronal transport system shows damage early in Alzheimer’s. Patients produce fewer neurotransmitters — chemical molecules that are released from an axon terminal, travel across gaps called synapses, and transmit signals to another neuron, organ, or other tissue type. In Alzheimer’s disease, axons and synapses are damaged and ultimately destroyed. Damage to neuronal transport impairs attention, memory, learning, and higher cognitive abilities. While the cause is unknown, neuritic plaques and neurofibrillary tangles are the two prime suspects. Plaques consist of amyloid-beta, which is formed from malformed clumps of a fragment of amyloid precursor protein (APP), a fibrous protein often found at neuronal synapses. In its soluble form, amyloid-beta can bind strongly to neural receptors, which initiates the erosion of synapses. Evidence indicates that this soluble form is highly synaptotoxic, while the insoluble form (which has low toxicity) tends to aggregate, and is found in much higher concentrations than the soluble form. Some research suggests that the highly toxic, soluble form would be a better target for effective therapies.
The amyloid hypothesis is currently the dominant theory of how beta amyloid and tau protein interact to cause Alzheimer’s. This hypothesis asserts that amyloid-beta starts a sequence of events that ultimately lead to Alzheimer’s disease. Amyloid-beta accumulations first appear in the neocortex. Its neurotoxicity might be due to the fact that it exacerbates oxidative stress and damages the mitochondria, the cell’s primary energy supply unit, initiating a cascade of neuronal dysfunction and cell death. The formation of neuritic plaques induces tau proteins to become defective and tangle into neurotoxic neurofibrillary tangles (hyperphosphorylated tau protein) within neuron cell bodies. (In contrast, normal tau protein stabilizes microtubules, which are crucial to axonal transport). Neurofibrillary tangles are generally first seen in the entorhinal cortex and the hippocampus, regions responsible for short-term memory and for transferring those memories to longer-term memory.
Although amyloid-beta and tau accumulations are found in people with Alzheimer’s, there is no definite proof that they cause Alzheimer’s. We do have evidence that tau and amyloid-beta might interact before clumping into their recognized disease forms. Even before it aggregates, malfunctioning tau can damage cellular transportation by blocking the microtubule tracks. Also, high tau levels can impair the function of amyloid-beta.
It’s possible that inflammation and the presence of obesity can trigger these protein changes, increasing Alzheimer’s incidence and severity. Plaques and tangles are known to negatively interact with microglia, non-neural brain cells that act as immune cells for the central nervous system, and astroglia, which offer physiological regulation and structural support in the brain.
Genetics of Alzheimer’s
Early-onset Alzheimer’s is a rare, dominantly inherited form of the disease. Dominant mutations in three genes — APP, PSEN1, and PSEN2 — cause early-onset familial Alzheimer’s disease that starts when people are in their 40s and 50s. In late-onset Alzheimer’s, the ApoE4 variant of the Apolipoprotein E (APOE) gene is a major genetic risk factor but not a determining one. The normal protein, ApoE, is mainly produced by astroglia or damaged neurons and helps clear soluble amyloid-beta from the brain.
In most people, Alzheimer’s results from a combination of genetic and environmental causes. Several genetic associations have been noted. A mutant C9ORF72 gene has been found in people with both early- and late-onset forms of the disease. This gene codes for a protein that regulates transportation in the intracellular matrix. The mutation was already known to play a major role in ALS and frontotemporal dementia, but recent studies show that it also disrupts a key mechanism for DNA repair.
The TOMM40 gene, which codes for a protein responsible for moving proteins into mitochondria, has a complex relationship with Alzheimer’s. People with a longer version of the gene were shown to be either predisposed or resistant to Alzheimer’s — depending on whether a parent had the disease. Among those with an afflicted parent, people with the longer version of the gene were more apt to develop dementia than those with the shorter allele; but among those with no afflicted parent, people with a longer allele displayed better memory than those with a shorter gene allele.
With the TREM2 gene, loss-of-function mutations cause a sequence of physiological events associated with Alzheimer’s disease. This suggests a possible genetic link between early- and adult-onset variants — the homozygous loss-of-function mutation is associated with early-onset and the heterozygous variant with adult-onset. Normally, TREM-2 protein helps regulate removal of cell debris, clearing amyloid proteins, and suppressing inflammation in microglia.
Two large programs are currently studying early-onset Alzheimer’s. The Dominantly Inherited Alzheimer Network project is funded by the U.S. National Institute on Aging with 10 research centers in Australia, the United Kingdom, and the United States; and the Alzheimer’s Prevention Initiative is studying an extended family of 5,000 with the disorder in Antioquia, Colombia.
Treatments for Alzheimer’s
The FDA has now approved five prescription drugs for treating Alzheimer’s. While they relieve some symptoms, they do not cure or halt the disease. Three of these drugs are cholinesterase inhibitors: donepezil, galantamine, and rivastigmine. Cholinesterase inhibitors stop the action of acetylcholinesterase, an enzyme that breaks down the neurotransmitter acetylcholine. This increases the available amount of acetylcholine (involved in learning and memory), which counteracts the damaging effect of the disease on production of this neurotransmitter.
The fourth drug, memantine, is an NMDA receptor antagonist. Normally, NMDA receptors bind the neurotransmitter glutamate, allowing calcium to enter the neuron. In Alzheimer’s, the damaged cells become overwhelmed with calcium, further damaging the neurons — a condition called neuronal excitotoxicity. Memantine blocks the flow of calcium through NMDA-receptor channels.
The fifth approved medication combines donepezil and memantine. Donepezil can be used in all stages of the disease, galantamine for mild to moderate stages, memantine for moderate to severe stages, and rivastigmine in all stages. The donepezil/memantine cocktail is used to treat moderate to severe Alzheimer’s.
Several clinical trials are now underway to find new and better treatments for Alzheimer’s. The Alzheimer’s Forum currently lists 14 treatments that are in the later stages of clinical trials. Overall, however, there is a high failure rate for drugs on the road to approval. Between 2002 and 2012, just 0.4 percent (1 in 245) of Alzheimer’s drugs were approved. Potential drugs have often proved ineffectual because they don’t target Alzheimer’s early pathology. Online registries may improve the situation by hastening participant recruitment for clinical trials and looking for people at ever-earlier stages of disease progression. Trials are also broadening their pool of participants to include people likely to develop Alzheimer’s but currently asymptomatic, as well as other participants at the pre-dementia stage.
Another treatment strategy, based on the amyloid hypothesis, uses the body’s immune response to attack and clear amyloid plaques. Trials for active immunization (which trains the immune system to build a person’s antibodies) and passive immunization (which transfers already active defensive antibodies without bolstering the person’s own immune system) have both been explored. So far, however, these types of therapies have been inadequate for people with moderate to severe symptoms.
PARKINSON’S DISEASE
Parkinson’s disease is the second most common neurodegenerative disorder in humans. Like Alzheimer’s, its incidence increases with age, with the average onset around age 60. About 5 million people in the world’s 10 most populous countries have Parkinson’s, and its frequency is expected to double by 2030. With 50,000 to 60,000 cases diagnosed annually in the U.S., the actual figures may be much higher — especially since early symptoms can be mistaken for normal aging and thus are not reported.
From 2000 to 2013, the age-adjusted death rates for those with Parkinson’s disease increased in the U.S. from 8.8 to 11.0 per 100,000 for males and from 3.9 to 4.8 per 100,000 for females. For reasons not yet understood, the disease is more prevalent in men than in women. Five to 10 percent of cases are “early-onset,” occurring before age 50. Rarer still, patients with “juvenile Parkinsonism” may develop symptoms before age 20.
Estimates of the prevalence, or overall number, of Parkinson’s patients vary widely, so incidence — the occurrence of new cases within a given time period (for example, per year) — is a better index for this disease. There is a higher incidence of Parkinson’s in developed countries but the reason is unknown, although increased risk of the disease has also been reported in rural areas with increased pesticide use.
Symptoms
At first, Parkinson’s is characterized by motor problems: slow movement; muscular rigidity; poor coordination and instability; and shaking in hands, arms, legs, jaw, and face while at rest. As the disease progresses, the shaking, known as resting tremor, may worsen and interfere with walking, talking, and other simple tasks. Cognitive decline often occurs at later stages. Some people develop depression and other emotional changes, difficulty swallowing and chewing, skin problems, constipation or urinary problems, and sleeping problems. However, the rate and intensity of Parkinson’s progression vary. Some people become severely disabled, while others have only minor motor disruptions.
Pathology and Causes
Parkinson’s is a motor system disorder caused by the loss of dopamine-producing cells neurons in the substantia nigra — a midbrain structure that is considered part of the basal ganglia. This brain region affects movement, reward, and addiction. At the cellular level, the death of neurons likely arises as a result of damage to mitochondrial respiration.
National Institute on Aging, NIH.
Alzheimer’s disease is associated with high levels of the beta-amyloid protein. This protein clumps together and forms plaques, which are pictured in brown. These plaques can build up between neurons and interrupt their activities. Tau proteins also accumulate and form tangles — seen in blue — within neurons, disrupting communications.
Some early-onset cases are linked to mutations in the PARK2 (or PRKN) gene, which codes for the protein “parkin.” Most types of Parkinson’s are caused by a combination of genetics and environment, but an estimated 15 to 25 percent of people with adult-onset Parkinson’s have a known relative with the disease. Genes like alpha-synuclein (SNCA), repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) also point to the importance of genetics as a causal factor. While Parkinson’s and Lewy body dementia are sometimes considered different disorders, Lewy bodies, accumulations of proteins in neuron bodies, have been implicated in both diseases. Lewy bodies are mainly composed of the protein alpha-synuclein entangled with other proteins, including neurofilament, ubiquitin, alpha B crystallin, and probably tau protein in neurofibrillary tangles. The Lewy body protein, alpha-synuclein, is involved in dopamine transport in the nervous system.
There is no definitive test for Parkinson’s so, without accepted biomarkers, diagnosis is based on medical history and neurological tests that can include brain scans. Accurate diagnosis can be difficult, because some non-Parkinson’s conditions display similar symptoms. In the future, mitochondrial molecules could be a potential source of a Parkinson’s biomarker.
Research
Scientists can treat mice with the chemical MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to create an animal model that can provide further insight into Parkinson’s. In the body, MPTP metabolizes into the neurotoxin MPP+ (1-methyl-4-phenylpyridinium), which causes a Parkinson’s-like loss of cells in the substantia nigra and cognitive deficits. However, MPTP does not perfectly mimic the symptoms of human Parkinson’s disease, including the motor deficits.
Research on using stem cells to replace damaged dopamine neurons in Parkinson’s patients has shown promise. There are two types of stem cells: the more flexible (and controversial) fetal tissue and induced pluripotent stem (iPS) cells, which are specialized adult (often blood or skin) cells that have been repurposed into a generalized embryonic state. There have been successful lab studies using iPS cells, and positive to mixed results in clinical studies with the fetal stem cells. A Kyoto University study, published in August 2017, transferred human iPS cells into the brains of monkeys treated with MPTP. Two years after this transplantation, the treated monkeys were shown to have healthy DA neuron integration, growth, and even functioning in the striatum.
Treatments
Treatment with levodopa (L-Dopa) temporarily relieves Parkinson’s motor symptoms but does not slow disease progression. Ironically, the long-term use of L-Dopa can induce dyskinesia — abnormal and uncontrolled involuntary movements. Strategies for treating Parkinson’s include gene therapy and targeting specific cellular molecules.
A surgical procedure called deep brain stimulation (DBS) is increasingly used to treat Parkinson’s patients whose symptoms, including rigidity, tremor, slowed movement, and mobility problems, do not respond adequately to medication. The DBS technique implants a small neurostimulator device — like a pacemaker — that sends electrical impulses that interfere with and block brain signals that cause the motor symptoms of Parkinson’s. Before implanting a neurostimulator into the brain, the neurosurgeon locates where the patient’s symptoms are originating, using MRI or CT scans. Most often, the problem areas in the brain are the thalamus, the subthalamic nucleus, and a portion of the globus pallidus (part of the basal ganglia). After the imaging, microelectrode recording — which involves a small wire that monitors the activity of nerve cells in the target area — is sometimes used to further localize problem areas in the brain. This approach has proven to be highly successful with a segment of patients.
ALS is also called Lou Gehrig’s disease after the renowned New York Yankee first baseman, a famous patient with the disease.
One treatment still in the research stage is a strategy to break apart Lewy bodies. The idea is to use high hydrostatic pressure to break apart aggregated alpha-synuclein fibril plaques, like those found in Lewy bodies, and return the protein to its properly functioning form. Another novel approach to preventing Parkinson’s was suggested by epidemiological studies that found that the disease is less common among coffee drinkers and cigarette smokers. If caffeine and nicotine offer protection, this could reflect some central action that benefits the brain’s dopaminergic systems.
AMYOTROPHIC LATERAL SCLEROSIS
ALS is a group of progressive, ultimately fatal motor neuron diseases. ALS is also called Lou Gehrig’s disease after the renowned New York Yankee first baseman, who was one of the most famous victims of the disease. ALS forced Gehrig to retire at age 36. Gehrig died two years later. ALS afflicts as many as 15,000 Americans, most between the ages of 50 and 70. Although men are slightly more likely than women to develop the disorder, that difference lessens with increasing age. For unknown reasons, non-Hispanic whites are more likely than other ethnicities to develop ALS. Military veterans’ likelihood of developing the disease is as much as 1.5 to 2 times higher than the rate in the general population — possibly due to exposure to environmental toxins like lead and pesticides.
Symptoms
Unlike the previously discussed neurodegenerative disorders, generally neither cognition nor personality is affected in individuals with ALS. Early ALS symptoms include muscle weakness, twitching, and eventual paralysis in the hands and feet. These symptoms gradually spread as patients lose strength and the ability to move, speak, and eat. Most ALS patients die within three to five years after symptoms appear due to nerve damage affecting the respiratory muscles. However, 10 percent of ALS patients — like the physicist Stephen Hawking — survive 10 years or more.
Pathology and Causes
Motor neurons connect the brain to the spinal cord and to the voluntary muscles throughout the body. In ALS, the motor neurons degenerate and then die. Without this neural communication, a person’s voluntary muscles weaken, begin twitching, and finally atrophy.
Only 5 to 10 percent of ALS cases are due solely due to genetic factors — a condition called “familial ALS”; the non-familial disease is called “sporadic ALS.” While several genes have been identified that increase susceptibility to ALS, there is no clear pattern of inheritance. Among cases with a genetic component, about 25 to 40 percent are caused by a harmful mutation in the C9ORF72 gene. Some individuals with this mutation show symptoms of both motor neuron and dementia disorders, a condition known as ALS-FTD (ALS-frontotemporal dementia). Another 12 to 20 percent of hereditary cases result from mutations that prevent the SOD1 gene from coding for superoxide dismutase — an enzyme that catalyzes the breakdown of cell-damaging superoxide radicals into more benign molecular oxygen or hydrogen peroxide. These and other hereditary forms of ALS, such as those involving UBQLN2 and VEGF genes, provide valuable insights into the mechanics of the disease.
Research and Treatments
There is no cure for ALS, nor has any medication been found that can stop or reverse its progression. But the FDA has approved edaravone and riluzole for treating ALS. Edaravone, an antioxidant that inhibits the production of cell-damaging free radicals, can ameliorate disease symptoms. Riluzole decreases glutamate levels, and has been shown clinically to extend the life of ALS patients by a few months.
A therapy called NurOwn, developed by BrainStorm Cell Therapeutics, is entering a phase 3 clinical trial (to confirm drug safety and efficacy over a longer testing time) after showing promise for halting or reversing ALS progression. NurOwn uses undifferentiated stem cells from the patient’s own bone marrow, which are then modified to boost the production of neurotrophic factors that support and protect neurons destroyed by the disease.
For those with the SOD1 mutation, there is also hope for a gene silencing technique using an artificial RNA snippet. Lab tests in mouse models have preserved muscle strength and motor and respiratory functions, and delayed disease onset and death. This treatment has also safely silenced SOD1 in the lower motor neurons of nonhuman primate models.
Participation in a multidisciplinary ALS clinic, an ALS Association Certified Treatment Center of Excellence, or a Recognized Treatment Center can also improve ALS patients’ quality of life.
HUNTINGTON’S DISEASE
Huntington’s disease (HD) is a heritable disease that impairs voluntary movement and cognition. The disease afflicts 3 to 7 people of 100,000 people of European descent, but is less common among Japanese, Chinese, or African populations. The HD variant of the HTT gene is dominant; if one parent has a single copy of the HD gene variant and the other parent has normal HTT genes, a child has a 50 percent chance of inheriting the HD variant and developing the disease. The most common form of HD begins earlier than most progressive brain diseases, becoming active when people are in their 30s and 40s. Death occurs 15 to 20 years after a patient becomes symptomatic. Juvenile HD begins in childhood or adolescence, and juvenile HD patients usually die 10 to 15 years after their symptoms appear.
Symptoms
Signs of HD begin with irritability, mood swings, depression, small involuntary movements (called chorea), poor coordination, and difficulty making decisions and learning new information. As the disease progresses, the chorea becomes more pronounced and patients have increasing trouble with voluntary movements like walking, speaking, and even swallowing. Their cognitive problems also worsen. While juvenile HD displays the same symptoms as the more common form, it also includes slow movements, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance declines as thinking and reasoning abilities become impaired, and seizures occur in 30 to 50 percent of children with this condition.
Causes and Genetics
In 1993, Huntington’s disease was found to be caused by mutations in the HTT gene, which codes for the huntingtin protein, located on chromosome 4. The protein likely interacts with other proteins involved in signaling, transport, binding to proteins and other structures, and protecting the cell from self-destruction. The disease mutation involves an abnormal number of repeats of a three-part (trinucleotide or triplet) snippet of DNA in the HTT gene. This sequence of the nucleotides cytosine, adenine, and guanine (CAG) normally repeats 10 to 35 times, but occurs from 36 to 120 or more times in the mutation. The greater the number of CAG repeats, the earlier symptoms appear and the more severe they are.
The “expanded” huntingtin protein is susceptible to clumping. While aggregated huntingtin proteins don’t cause cell death directly, they disrupt the mitochondrial electron transport chain, initiating a cascade of neuronal dysfunction and death. Brain areas most often affected are the basal ganglia (voluntary movement) and the cortex (cognition, perception, and memory).
Detection and Treatments
In late 2015, Ionis Pharmaceuticals began the first human trials of a “gene silencing” or “huntingtin lowering” drug. IONIS-HTTRx is an antisense oligonucleotide — a single strand of a chemically modified DNA designed to interrupt and decrease the mutated form of the huntingtin protein produced in HD patients. The drug is now in phase 2 trials comparing it to a placebo in early-stage HD patients who are randomly assigned to treatment or control groups.
In spring 2017, the FDA approved the drug deutetrabenazine for treating chorea associated with Huntington’s disease. This is reportedly only the second product approved for treating HD. Furthermore, there is now evidence for viable HD biomarkers. Tau (which turns up regularly in neurodegenerative diseases) and neurofilament light chain, a component of the neuronal cytoskeleton, are found at elevated levels in cerebrospinal fluid of HD patients. A recent study points to the neurofilament light chain, and to a lesser extent tau, as viable HD biomarkers. Interestingly, the neurofilament light chain is also being investigated as a biomarker for ALS and other neurodegenerative diseases. In mouse studies, the amount of neurofilament light chain found in the animals’ cerebral spinal fluid and blood increased before neurological signs appeared, likely coinciding with the development of brain lesions. 