What can symptom changes tell us about Parkinson’s Disease ?

Document under construction. It will be developed via input and discussion with other PwP.

Parkinson’s disease symptoms develop over a timescale of several years. My experience is that they appear individually or in clusters. The first is the loss of sense of smell which may occur a decade or more before diagnosis and often passes unnoticed. Some years later one may suffer from a cluster of non-motor symptoms which can include: stiffness, slowness, fatigue, apathy, brain fog, mood changes, constipation, urinary urgency, daytime sleepiness, poor sleep … 2 to 3 years later motor symptoms show up progressively; dystonia, soft voice, difficulty articulating speech, problems of balance, muscular weakness, co-ordination problems, walking (gait), stooping and tremor.

If symptoms are the consequence of the existence of a particular medical condition, then the order of their appearance/disappearance represents changes in that condition

I will start with the assumption that chronic diseases are caused by a dysfunctional process which over time creates a condition. When a particular process is not working properly or is too strong or too weak, the effects of the dysfunctional process build up over time to create a condition where an organ or some part of the body part is chronically impacted.

Let’s take a simple example that we have all experienced; sunburn. As kids, most of us will have been over-exposed to the sun at least once and felt the pain of sunburn. During that over-exposition, we did not feel the sun burning our skin. There were no symptoms, other than feeling the heat during the process when UV light was creating free radicals that were attacking our skin cells. Some hours later, long after the free radical attack had finished, the damaged skin cells launched a cytokine storm (this takes time) and created a condition of intense and painful inflammation in order to protect the skin and clean up the damage. The symptoms of sunburn; red swollen skin and severe pain, were felt as the severity of the condition became established but was hardly noticed when the damage was actually being done.

If we apply the same thinking to Parkinson’s disease symptoms, we might be able to understand what is happening or what is has already happened. My second assumption is that the process causing Parkinson’s disease is oxidative stress, i.e. excessive production or insufficient elimination of reactive oxygen species (ROS). ROS are not unlike the free radicals caused by UV light in the example above. However the actual process occurring does not really change the argument. What we do know is that the process causing PD is a slow one that takes years to build up. It is therefore natural that we don’t get symptoms during the process. It is like getting older, we start to feel symptoms when the condition that is developing over many years gets serious enough to create problems.

We have been told that at the time of diagnosis, about 70% of our dopamine-producing cells are dead. I’m not convinced that this is true, but I will acknowledge that many are either dead or not functioning well and perhaps very few are functioning at full power. This is the condition at diagnosis when we already suffer from a cluster of both non-motor and motor symptoms. Now let’s go back in time to the beginning of the process. It began maybe 15 years before diagnosis and we didn’t feel it coming on at all. I will denote each condition as a phase #.

Phase #1 occurred when we started to lose our sense of smell. This would indicate that the neurons in the olfactive bulb or the connections to these neurons were being lost. Was this due to loss of dopamine-producing neurons? Were these among the first of the 70% to be lost? We cannot answer that at this time.

Phase # 2 occurred when we started to suffer from a cluster of non-motor symptoms. So what were the physical parameters present at this time? Were they something quantitative like passing the 50% threshold of lost dopaminergic neurons? Or were they more qualitative due to years of accumulated damage which meant that some neurons were only functioning at low power? 

Phase #3 was recognised at the time of diagnosis. At that time we were suffering from serious non-motor and motor symptoms. For simplicity let’s admit we have lost 70% of dopamine production, so we have a real shortage of dopamine in the brain and this seems to coincide with the appearance of motor symptoms. Is this extra dopamine loss a necessary and sufficient parameter to distinguish phase #3 from phase #2 above?

How can we find out more about the parameters of the different phases?

One way is to look at how various external or internal parameters change the symptoms. These can be medication, diet, lifestyle, stress, exercise, sleep, even supplements. We will each have our own experiences, but some would seem to be common to many.

  • Adding synthetic dopamine or using dopamine agonists: this allows the chemical signalling to be improved between synapses of neurons and improves motor symptoms. It does not resolve many non-motor symptoms such as fatigue, apathy, urinary problems, sleepiness etc.
  • Good diet, stress free lifestyle, exercise: these are all credited with slowing the progression of the disease. They therefore affect all conditions, but are not believed to reverse them.
  • Stress, poor sleep, poor lifestyle: rapidly increases both motor and non-motor symptoms, but short-term changes can be reversed.
  • High-dose vitamin B has been shown to have a strong effect on fatigue and can improve some motor symptoms, but some people report that it makes tremor much worse.
  • Mannitol seems to be the only supplement that has any effect on sense of smell. I hope to get more information from PwP to extend this section.
  • Sulforaphane: The latest trial with broccoli seed tea containing sulforaphane produced very clear results. Sulforaphane (when used without changing dopamine medication) rapidly and substantially reduced non-motor symptoms, but left motor symptoms unchanged..

So what is this telling us?

  • Phase #1 seems to be in a class of its own. We don’t have much information.
  • Phase #2 seems to be in part reversible. Both high dose thiamin and the broccoli trial imply this, but doing so does not reverse the motor symptoms of phase #3 even with added levodopa. Since dead neurons cannot come back to life in a few weeks, this means that phase #2 is related to the health of neurons rather than simply the quantity of neurons. Loss of cellular energy due to mitochondrial damage could be a major parameter in phase #2
  • Phase # 3 motor symptoms are not affected when phase #2 is attenuated.

The behaviour of phase #2 is particularly interesting. If activating the antioxidant response of Nrf2 by sulforaphane at least partially reverses this phase, this leads to a certain number of reflections or tentative conclusions.

  • Oxidative stress and inflammation is the likely cause of phase #2. The major cause may be oxidative damage to mitochondria which drastically reduces cellular energy
  • Stopping oxidative stress, if applied early enough, may prevent reaching phase #3
  • Phase #3 is not simply phase #2 with a lower dopamine supply
  • Phase #3 may be a combination of phase #2 with additional damage elsewhere that may not be reversible or may take a long time to repair.

To be continued ….

Published by

wriga38

Research scientist with Parkinson's disease exploring transcription factor Nrf2 activation to stop PD progression. See patientresearcher.com for more details.

3 thoughts on “What can symptom changes tell us about Parkinson’s Disease ?”

  1. Hi Albert,
    I have always thought that the motor symptoms of PD are caused by loss of dopaminergic neurons and subsequent loss of dopamine in the in the SN. In theory it is the oxidative stress that is fueling this damage. You are already diminishing the excessive oxidative stress . Replacement of dopamine via C/L intake helps to replace dopamine and in turn reduce some motor symptoms. Perhaps it takes significantly more time for your reduction of oxidative stress to help damaged yet salvageable dopaminergic neurons to recover enough to start producing enough dopamine to start to have enough effect to improve motor symptoms.

    I base this idea on the fact that in a melatonin PwP study that used a total of 50 mg/day for 3 months it took that length of time to start to see a motor symptom improvement. This kind of goes with the idea that the damage being done in PD takes place over years and possibly longer than a decade in order to start to experience motor symptoms. Based on that idea, it seems like reversing this damage, if possible, is not likely to happen in a month or two??? In the melatonin study it took 3 months to barely start to see anything resembling motor deficit improvement during off times. In melatonin studies, 50 mg /day would likely be an insufficient dose to see more improvement in motor symptoms.

    Here is a link to that study:
    https://www.sciencedirect.com/science/article/pii/S0753332220306788?via%3Dihub

    In contrast, a study using just 10mg/day of melatonin started to show measureable non motor symptom improvement
    (UPDRS Part 1) in 12 weeks. Here is a link to that abstract, but you will have to access the full study to get the particulars:

    https://pubmed.ncbi.nlm.nih.gov/32417629/
    Again, the dosing in this study was likely too low to show the optimal effects of melatonin in PwP.

    Albert, I am not trying to push melatonin on you, just using these two studies to try and explain my thinking for what I said above.

    Art

    Liked by 1 person

  2. Hi Albert,
    Regarding mannitol and improved or normalized sense of smell, B1 has offered this benefit in some forum members, but has not worked for all. B1 has actually offered quite a few benefits, especially in conjunction with some form of dopamine including mucuna pruriens. Here is a list of benefits that HU forum members who are using or testing B1 have reported :

    https://healthunlocked.com/parkinsonsmovement/posts/139172119/eighty-real-reasons-to-consider-dr.-costantinis-thiamine-hdt-b-1-protocol-based-on-hu-forum-members-experiences

    Art

    Like

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