Biological basis of parkinson's disease

- In this video, I'm going to talk about the biological basis of Parkinson's disease. Parkinson's disease is a progressive neurological disorder, involving motor abnormalities and often mental dysfunction as well. Many motor abnormalities may occur but the most common are slowed movements, a type of tremor, a type of increased muscle tone, a type of abnormal walking, and poor balance leading to falls. So in this drawing of a person with Parkinson's disease, this is a very typical way that a person with advanced Parkinson's disease will walk. They're slow, they're kind of stooped and shuffling, and often the hands have a tremor to them, and if you ask them to relax, and you try to move their muscles around, their muscles are stiffer than normal, they feel slow and stiff, and then they often have the tremor as well. Late in the course of the disease, when motor abnormalities are severe, patients may become unable to care for themselves, and may also develop abnormalities of cognitive, emotional, or autonomic functions. The brains of patients with Parkinson's disease often have an abnormality that is visible to the naked eye. Here, if we look at this normal brain that's been cut from the top to the bottom, so this is the right half, and this is the left half. And if we look, not at the cerebrum, this part on the top, but this part on the bottom, called the brainstem, there's a small part of the brainstem right here and right here, called the substantia nigra. Let me just write that term out, substantia nigra. And this term, substantia nigra, just means black substance, because these areas are darker than the surrounding brain tissue. With Parkinson's disease, the substantia nigra is less dark, or it's not dark at all. Sometimes you can't see any dark spots here like we do in a normal brain. And if we look with a microscope, we can see that inside the substantia nigra, there has been the loss of a particular kind of neuron that's pigmented, giving it the dark color. The rest of the cells in the tissue in this area look pretty normal, suggesting that with Parkinson's disease, it's only a specific type of neuron that's lost, while sparing the rest of the brain tissue, at least early in the course of the disease. These cells are dopaminergic neurons, meaning they are neurons that release the neurotransmitter dopamine that synapses with other neurons. Let me just write dopamine, an important neurotransmitter, that lets neurons communicate with each other. There are other small collections of dopaminergic neurons scattered around the central nervous system, and it turns out these cells may also be lost with Parkinson's disease. But it appears that most of the motor abnormalities, the movement problems that occur, are from the change that happens to the substantia nigra, where these dopaminergic neurons are lost. This illustration is showing that same thing, but here we're looking up at the brain from underneath, and they've cut off the brainstem at the level of the substantia nigra, and they're showing that in a person without Parkinson's disease, we usually see this dark area very well, the substantia nigra, on both sides, but in a person with Parkinson's disease, since those pigmented dopaminergic neurons have been lost, we often see less, or none of that darkness that we normally see in the substantia nigra. The substantia nigra is one part of a collection of structures called the basal ganglia. Let me write that term out, basal ganglia. So here, on this illustration, they're showing that if we take the brain and section it from top to bottom, and then we look deep inside the cerebrum, all these areas that they've colored here, represent this collection of structures called the basal ganglia. And one part of that is the substantia nigra. And here's the same thing kind of zoomed in, and here, down here, is the substantia nigra in this illustration. The basal ganglia plays a major role in motor functions, as well as some mental functions. The wiring of the basal ganglia is complex and incompletely understood, as you can tell by how busy and complicated this diagram looks with lots of pluses and minuses, because certain areas excite other areas, and certain areas inhibit other areas. But the simplistic way I think about the basal ganglia, is that it receives information from many places in the nervous system, and importantly, from the outermost layer of the cerebrum, the cerebral cortex. The basal ganglia then performs complex processing of that information in a way we don't totally understand yet, and then the basal ganglia sends information back to areas of the cerebral cortex influencing its activity, such as the motor cortex, for motor tasks. The primary output of the substantia nigra, is to another part of the basal ganglia, called the striatum. And the loss of these dopamine neurons projecting from the substantia nigra to the striatum appears to cause most of the motor abnormalities of Parkinson's disease. When we look under the microscope, we can see diseased neurons that are degenerating in the substantia nigra. Like this neuron right here. And they often contain abnormal structures like this, which are called Lewy bodies. So let me just write that out, Lewy body. These abnormal structures we can see inside the degenerating dopaminergic neurons of the substantia nigra in Parkinson's disease. These Lewy bodies primarily contain a protein called alpha synuclein. Let me write that out, too, alpha synuclein. And this alpha synuclein is a normal protein that's present in brain cells under normal conditions, but for unclear reasons, in Parkinson's disease it appears that the alpha synuclein is not cleared normally from the neurons, and then it clumps together inside the neurons to form Lewy bodies. So how the Lewy bodies form is not entirely clear, and another thing that's not clear is if the Lewy bodies form and that kills the dopaminergic neurons in the substantia nigra, or if something else is killing the dopaminergic neurons, and these Lewy bodies are just formed as a by-product of that process. With severe Parkinson's disease, that also includes cognitive dysfunction. There is often widespread Lewy body deposition, and neuronal loss, not just in the substantia nigra, but throughout the cerebral cortex, this outermost layer of the cerebrum. And there's also a separate condition that's related but seperate, called Lewy body disease, where there is less motor abnormalities from basal ganglia dysfunction, and more cognitive dysfunction from loss of neurons throughout the cerebral cortex. A few things have been associated with the risk of developing Parkinson's disease. Several genetic mutations have been found in some families that have an inherited form of the disease, and some other studies have suggested that rural living, possibly with exposure to agricultural chemicals may be a risk factor, although it's unclear how these factors might cause or contribute to the disorder, because most of the symptoms are caused by loss of a small population of a similar kind of neuron in the substantia nigra. Parkinson's disease is a leading candidate for the possibility of treatment with stem cells, and intense research is ongoing to see if these cells can be replaced safely and effectively.