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.
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
