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Darwin’s notebooks and Parkinson’s Disease?

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What connection could there be between Charles Darwin’s notebooks and PD?

According to Roger Barker, writing in the Advanced Clinical Neuroscience Rehabilitation journal on Parkinson’s disease over the last 20 years – new concepts and developments, it took Cambridge University that much time to realize that it had lost two priceless original notebooks belonging to Charles Darwin, and during that time, in the field of PD much new knowledge has been gained, partly due to

  • Stem cell creation discoveries, (how to create induced pluripotent stem cells {iPSCs)),
  • Gene cell editing with CRISPR/Cas9,
  • and the ability to do single cell RNA analyses.

Much has been gained directly from observational and clinical studies, however.

First, alpha synuclein proteins were observed in tissues which had been transplanted, which led to hypotheses that

  • Alpha synuclein fibrils  can spread seed pathology in the adult Central Nervous System (CNS), which led to the hypothesis that
  • PD begins in the gut/olfactory system and then spreads along the connecting nerves to the brain, seeding the pathology as it goes until it finally reaches the STN (subthalamic nigra) dopaminergic cells.

This in turn led to

  • The concept of a prodromal stage of PD before the cardinal symptoms of tremor, bradykinesia and rigidity are evident in the motor control brain cells, and
  • The possibility of targeting pathological alpha synuclein proteins to slow down or stop the progression of PD.

In addition, PD has been hypothesized to have two different origin points

  • H1: The disease starts in the PNS and spreads centrally or
  • H2: The disease tarts within the CNS itself and then out to more peripheral sites. 
  • Recent imaging studies support this concept of PD falling into these two subtypes
  • Not either/or, but both could be true (Blog author’s note: which could be a reason why the course of PD is different for each person?)

Many different methods have been used to study the course of PD

  • The most powerful are those using community based epidemiological studies following patients over time
    • avoids possible bias in selection
    • Results:
      • younger patients tend to do better than older patients and
      • that those with more PD related symptoms and signs at diagnosis do less well

Another area of interest has been the relation between PD and the gut biome and inflammation

  • Alpha synuclein pathology starts in the gut and travels to the brain and CNS
  • People on anti-inflammatory medication seem to have lower rates for PD
  • Result is:
    • Repurposing of anti-inflammatory medications to treat PD and
    • Use of drugs specifically targeting the gut biome or alpha synuclein
  • Further advances include
    • stem cell transplants (now in clinical trials)
    • autologous cell transplants
    • As to whether these therapies will prove effective not yet known

Twenty years of research on PD has produced a great deal more knowledge than the previous 200 years since Dr. James Parkinson wrote his essay on the “Shaking Palsy.” The concept of prodromal stages and symptoms (to me) seems to be one of the most important ways to diagnose probable PD before the cardinal symptoms appear – resting tremors, bradykinesia, and rigidity – and thus provide the possibility of delaying the onset of the disease through lifestyle or nutritional changes, or both.

Dr Barker’s review can be read at:  Barker R. Adv Clin Neurosci Rehabil 2021;20(2):13-15

And that’s my slide presentation of Dr. Barker’s article. Hope I hit all the major points and didn’t miss anything.

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So.. what’s new?

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A couple of recently published reviews (for folks that want to stay on top of things) :

What do we know about PD and what can we do about it?   This one is more of a commentary piece, that is to say, it isn’t an experiment or a structured desk review of other papers. It covers PD in (almost) layman’s terms, the causes (genetic, environmental, and perhaps lifestyle choices – nicotine and caffeine seem to have a neuroprotective effect), and the signs and symptoms:

… symptoms appear in other diseases as well so that not everyone with one or more of these symptoms has
the disease. In some people, the disease evolves more quickly than in others and it is not possible to predict what course the disease will take.

According to the author, the younger the age at onset, the more likely it is to be genetically related. Later onset symptoms appear more gradually. ( my note: I had many of the prodromal symptoms beginning around age 16, including REM Sleep Behavior Disorder, depression (probably due to environmental (e.g., workplace management) factors), essential tremors,  and have the LINGO1 gene variant that has been linked to both essential tremors and Parkinson’s. A recent Michael J. Fox Foundation – 23AndMe study found another couple of dozen or more gene variants associated with a higher risk for Parkinson’s. Clearly, there is a need for earlier detection and mitigation of Parkinson’s and parkinsonism conditions).

PD dementia and dementia with Lewy bodies differ in when dementia occurs, among other things. In PD, dementia occurs after PD diagnosis, in the latter, dementia occurs before PD symptoms become apparent. 

The author continues to provide an overview. But for me the sentence that stuck out glaringly was “Scientists still do not know what causes cells that produce dopamine to die.” (I need to finish reading this one… Will have to put it on my to-do list). 

Parkinson’s patients’ needs during the pandemic   This was a survey study done in Northern Italy with PD patients. Findings included:

(i) fearing the risk of contracting coronavirus,

(ii) the reduction of physical activity,

(iii) perception of the risk of not being able to access outpatient clinics or support services, and

(iv) the suffering from the important reduction in socialization.

The authors also noted that the perception could be greater than the actual difference, especially for item iii.

Enhanced differentiation of human induced pluripotent stem cells toward the midbrain dopaminergic neuron lineage through GLYPICAN-4 downregulation    I just tossed this link in for kicks – it is way outside of my area of expertise, but might be of interest to someone who knows something about the workings of the brain.

A scoping review of the nature of physiotherapists’ role to avoid fall in people with Parkinsonism – Now, here’s something I have a little more experience with – having fallen 3 times in October 2020 while stepping backward off of boulders, or trying to step up onto a boulder, either in my yard or in a park/preserve. Fortunately, I was referred to an excellent Physical Therapist who zeroed in on the greatest source of pain and then has moved toward improving strength, balance and posture. She noted my habit of leaning back when stepping high, and suggested that this might have caused the last, and most painful fall. 

As for the review, it noted that PT can have a positive effect on many issues related to falls in Parkinsonism. But the many studies were so varied, that many more studies would have to be done to specify which therapy works best for which problem at what stage of the disease. (surprise, surprise).

And now, to sleep, perchance to dream (Shakespeare) and hopefully, not to be tossin’ and turnin’ all night (Phillip Upchurch).

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