Let's talk about Parkinson's disease..

I discovered parkinson's disease (PD) approximately 5 years ago when my friend's grandmother was diagnosed after a long period of illness. Being one of the most frequent neurodegenerative diseases in the world alongside with Alzheimer, PD affects nearly 2 people out of 1000, this scary number makes it a disease worth mentioning. In 1817 an english surgeon Dr.James Parkinson described a clinical condition that he first called shaking palsy (shaking paralysis), an association of resting shaking and difficulty moving. Soon after, Dr.Jean Martin Charcot, a french anatomopathologist and neurologist helped the science community understand the disease even further and renamed the condition parkinson's disease in honor of Dr.James.

What to expect ?

First of all, we're going to discover the early symptoms of the disease, then we will discover the cause behind all of them. You see when the disease starts kicking off, the person is generally fine and have no complaints whatsoever. The first clear sign is a resting tremor, that's just a fancy word to describe a persistent trembling. It disappears when the person starts taking action/moving and reappears when he is resting, this is the most significant and reliable sign. It can be a real burden if the parkinsonian become unable to achieve the slightest task in his daily life like having a drink or changing his clothes. Meanwhile other symptoms can be seen due to a dysfunction of the autonomic nervous system (ANS), in fact many vital functions in our body like breathing, sweating, blood pressure control etc. are controlled by a network of neurons that acts independently and without active conscience, they are called the ANS. In the early stages of parkinson's disease, hypersalivation, excessive sweating, and swings in blood pressure are very common among patients, alongside with the resting tremor they can declare the beginning of the disease.
Naturally the disease tends to aggravate with time, the family members often report a decent decrease in the movements of the patient, we call that bradykinesia Brady=decrease, kinesia=movements. The frequency of the gestures are not the only problem we're facing, the initiation of an action is a huge deal for parkinsonians, they find it very hard to take a spoon and eat without missing things up, write a text to a friend or even pick up the controller and change a TV channel. Paradoxically there are other times where bradykinesia fades completely like magic and the parkinsonian moves like crazy!
The third main symptom in PD is rigidity, the muscles of the patient become so stiffed and over-contracted. In the beginning, it affects only the proximal muscle groups like the neck and the back giving the person a weird posture but spreads slowly to the distal muscles and finally the muscles of the face. When he stands, the patient tends to lean forward due to the unstable posture and when he walks he finds it difficult to make normal steps, Here's a video demonstration of how parkinsonian walks made by @mhdbelalalsabek:

Anyway, if you find this video unsatisfying, you can always look up for more examples on the internet and there's a lot of them!
In the face, the combination of rigidity and bradykinesia results in poor facial expressions often seen parkinsonians, they are not emotionless or sad, they simply have difficulties expressing their emotions. Now you have a pretty good idea about PD but what causes it in the first place? Can we explain the different symptoms? Why the tremor disappears when the person starts taking action? To answer these question we need to take a look inside own brains...

Some neuroanatomy mixed with physiology!

When we look at a normal human brain, we notice a group of central nuclei that make the grey matter, they are called basal ganglia and they communicate between each other to accomplish many functions including memory, recognition, emotions, movements etc. Scientists identified a specific pattern called the direct pathway responsible for initiating movements, it includes the collaboration of specific nuclei of the basal ganglia.

The thalamus is the centerpiece of initiating movements. When someone is resting, the thalamus is always inhibited. When I start to think about it, I want to imagine the thalamus l like a dog on a leash, in other words, if we succeed to remove the inhibition of the thalamus we can move freely! But we don't want it too loose otherwise it starts firing up excitatory signals to the motor cortex therefore random muscles contractions aka random movements, we don't want to look crazy so we don't want that to ever happen. Also, we don't want it too tight otherwise our movements will be slow and rare, we want to remove the right amount of inhibition. You may ask how we managed to move normally for so long?
The idea of making a move starts in the motor cortex, there are two types of neurons in the brain excitatory and inhibitory, they use different neurotransmitters to communicate with other neurons via synapses.
First, the neurons of the motor cortex send excitatory signals to the striatum using a neurotransmitter called glutamate, now it becomes more active and excited. Second, the striatum send inhibitory signals to the globus pallidus internal using a potent inhibitory neurotransmitter called GABA to make him less and less active, this nucleus is the one responsible for holding the thalamus on a leash, which takes us to the final step, the weakened signal from the globus pallidus internal makes the thalamus freer and able to send excitatory signals back to the cortex itself and finally to the muscles through nerves. Basically, this is the direct pathway, so if you think about it, it's like running in circles but with each lap, we manage to make more accurate and efficient movements.
But this cycle is somehow weak and can't free the thalamus alone, so we need to strengthen the signals and here comes the role of The Substantia Nigra (SN), It comes from Latin which means Substantia=matter, nigra=dark . It's a small nucleus characterized by a darker color than the rest of the brain because it contains the dark pigment melanin. It plays a huge role in movement and contributes to both the direct and indirect pathways. In the direct pathway, the SN stimulates the striatum using the neurotransmitter dopamine via D1 receptors (Nigro-striatal pathway) and helps free the thalamus a little bit more to execute movements more easily. In the opposite side, the indirect pathway is responsible for inhibiting the thalamus and prevents unwanted movements, this time the SN inhibits the striatum using the same neurotransmitter dopamine but via a different type of receptors: the D2 receptors.
To put it all together, the SN plays a crucial role in both facilitating movements and preventing unwanted ones. Parkinson's disease is caused by the excessive death of the dopaminergic neurons of the substantia nigra, on one hand, the alteration of the direct pathway explains the bradykinesia and difficulty initiating movements, on the other hand, the alteration of the indirect pathway is responsible for the resting tremor. The brain cut of a dead parkinsonian showed a decreased black coloration in comparison with a normal brain as shown in the picture below:

But how we can confirm the diagnosis? The most certain method is a brain biopsy but this operation is way too risky and can be lethal if we manage to get a sample of the substantia nigra of a patient, the decrease in dopaminergic neurons is very remarkable and confirms the diagnosis. The anatomopathological test reveals specific intracytoplasmic inclusions called the Lewy bodies which are highly suggestive of the disease. In practice, the association of the 3 clinical symptoms confirms the disease and no further tests are required.

How PD is treated ?

Parkinson's disease is a chronic disease, basically, it's a result of the lack of dopamine in the human brain, we can manage the symptoms by increasing dopamine concentrations but that's just a temporary solution and can't reduce the progression of the disease. In the treatment of the disease, we face many obstacles, first of all, we can't just give the person dopamine because in the brain there is a protective blood-brain barrier that doesn't let any substance pass easily, that makes perfect sense because the brain is a noble organ. Luckily for us, there's a thing called L-DOPA, it's a precursor of dopamine which can pass through the barrier normally.

Second, the L-DOPA can act on dopaminergic receptors like dopamine itself but not with the same strength of course which leads us to many adverse unwanted effects like hypotension, stomach aches, nausea, sleep disturbances and even cardiac problems. Finally comes the most annoying obstacle aka drug tolerance, in the nervous system each neurotransmitter can link to one or more receptors and produce a particular effect depending on the relationship between the drug and the receptor, if the concentration of the drug increases dramatically, the nervous system tries to bring things back to normal by producing more and more receptors so that the same effect requires higher dose. It's the same problem that happens with drug usage, the consumers often want higher dose to have the same feeling as before and most of the time the story ends with an overdosage and a sad tragedy, blame the tolerance, not the drug!
With L-DOPA we want to avoid this huge problem, so we have strict rules in prescribing the drug, we want to delay it as long as possible and use other dopamine agonists first, if we decide to use it then we start with small doses and increase little by little as the time passes. Despite being purely symptomatic the treatment works like magic but is there any hopes of a permanent treatment ?
To answer this question we need first to take another look at the nature of the disease, PD is a neurodegenerative disease, that means cells die in the process and as you may know, neurons don't divide or regenerate and if there are gone, they are gone for good. We cannot reverse the process (probably in the far future but at least not for now) but what we can do is try to slow its progression. Unfortunately or the moment there is no permanent treatment but many ongoing researches are dedicated to the subject, they try to deal with the mitochondrial dysfunction, the formation of the Lewy body and gene therapy (For more details take a look in the references below). We humans don't give up without a good fight so I have faith in the future of neurotherapy.
PD is a progressive disease that can take years to manifest, up to 20 years of the beginning of the cell death. Scientists believe that more than 80 % of dopaminergic neurons need to be gone until the onset of the illness. The life expectancy and the intellectual ability are normal compared to normal populations with the same age and risk factors but their social and professional lives are severely altered. As a doctor and also for many other health professionals, i believe that PD is a manageable disease compared to other fatal conditions especially in early stages, a parkinsonian lives normally 90 % of his life until his last months when the illness become uncontrollable, but still a disease is a disease and it can ruin lives.

References and further readings:

Parkinson's disease 1
Parkinson's disease 2
Different dopamine receptors
Recent advances in treating Parkinson’s disease
I also recommend visiting this site for more infos and lectures about PD.