#149

Amazing! They’re lucky to have you. Did you see this specifically with tirzepatide + rapa? Or also with other GLP-1RAs? Might be worth writing a case study and publishing it (at least here :slight_smile: ).

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#150

I need more patients who have early PD. I’ll get them as this is an area of interest to me. I’ve got cost effective access to Tirzepatide and Semaglutide as cost is always a factor for patients. Given the 2 choices - and Tirzepatide having dual action - and more potency, I go with that. I’ve seen solid improvement in 2 patients – as I just don’t have the numbers yet with this. Neither need weight loss - so just at 2.5 mg weekly. I am pushing the doses of Rapa, and monitoring levels and going on a higher dose such that they are getting ~4.5 days of levels >3, but then the cycle is going at 14 days to have ~35% time under therapeutic level and 65% under this level.
This allows a higher peak level of Rapa, which hopefully gets more in the brain during those times.
All theoretical - but seems to be having positive impacts.
Hopefully I get more patients with early PD who desire to attempt a disease modifying treatment rather than waiting for progression. It is too early to know how the next 10 patients will do, but I’m keen to get properly consented folks willing to try.

5 Likes
#151

@DrFraser How do you increase peak rapa levels for them? Dose stacking over 2-3 days or just a higher bolus dose? Matt K. suggested that based on mice studies, to ensure that it would cross the BBB, rapa needed to be administered almost continuously for a little while, almost to “push through” the largish molecule. For humans, translationally, it seemed to mean 2-3 consecutive days of dosage.

#152

If you want a high peak level - a single big dose is the plan. You however need to wait until it has distributed into tissues before measuring the level - as people will inappropriately think they know the half life by measuring 2 values very early on - the first one represents absorption and then the second that represent absorption and redistribution along with some metabolism. I heard Matt K. on his recent podcast think he had a much faster half life than he did due to this error.
I like measuring initial level in these patients around 20-24 hours, then get a repeat level in 48 hours after that level. I’m finding a half life of mid range between the published single dose metabolism (~32-35 hrs) to that of repetitive dosing which is in the 60’s. So a single big dose like 12-15 mg seems to have a half life of ~45 hrs. But I’m still gaining experience with gathering data on this - but that is my best guess right now. Nothing definitive as I plainly don’t have enough data points.
Doing several doses will not get as much of a peak, and will just prolong having lower levels as that metabolizes.
This is all theory - no evidence - but for neurocognitive decline - not general anti-aging, it would seem worth taking the strategy of a high dose to get a high peak, and then a longer interval between dosing to make sure you aren’t having too high a % of time under MTORC1/C2 inhibition.
This is how I’m doing things for the time being. I have my logic as to why - as to whether that logic is correct … not sure I’ll ever know, but its the best I’ve got today, and I’ll continue to read and participate in this board and learn.

8 Likes
#153

Causal association between long-term exposure to air pollution and incident Parkinson’s disease 2024

PM2.5 was positively associated with Parkinson’s disease across different models.
PM2.5 exposure may have a causal relationship with Parkinson’s disease.

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#154

Just published in Neurology (“The most widely read and highly cited peer-reviewed neurology journal”):

Guardians of the Brain: Exploring the Neuroprotective Potential of Immunosuppressants in Parkinson Disease

Beneficiaries taking tacrolimus (RR 0.50, CI 0.40–0.61), everolimus (RR 0.35 CI 0.23–0.53), sirolimus (RR 0.59, CI 0.37–0.95), cyclosporine (RR 0.92, CI 0.74–1.14), mycophenolate (RR 0.77, CI 0.68–0.86), lenalidomide (RR 0.68, CI 0.60–0.78), or ustekinumab (RR 0.82, CI 0.56–1.22) before PD diagnosis or control selection had a lower risk of developing PD when compared to those who did not take these mediations.
Medications from classes associated with lower risk of PD included corticosteroids, biologics, antimetabolites, and inhibitors of IMDH, JAK, MTOR, dihydrofolate reductase, and calcineurin. The medications within these classes act through mechanisms that target T cells, protein synthesis, the autophagic pathway, and their downstream effects. These medication classes might have potential as disease modifying therapies for PD.

Natural Statins as Inhibitors of Alpha-synuclein Fibril Formation

We observed partial inhibition of a-syn fibril growth by the fungal-derived statins, which structurally share a naphthalene. Of these, lovastatin (IC50 = 19 ± 5 uM) provided the greatest inhibition, with simvastatin (IC50 = 36 ± 5 uM) and mevastatin (IC50 = 32 ± 2 uM) conferring similar lower levels of inhibition. In contrast, the synthetic statins that we tested (atorvastatin, cerivastatin, fluvastatin, pravastatin, pitavastatin, and rosuvastatin) and ezetimibe did not inhibit a-syn fibril growth. In a population-based sample of 48,295 incident PD patients age 66–90 from 2009 Medicare data, lovastatin use at baseline was associated with a modest but significant reduction in mortality over 5–6 years of follow-up (adjusted hazard ratio 0.92, 95% confidence interval 0.86–0.99, p=0.03). We confirmed this potential effect was beyond any generic effect among non-cases (interaction p-value<0.001).

Modern Approaches to the Diagnosis of Patients with Parkinson’s Disease

Helicobacter pylori (HP) is a bacterium associated with gastrointestinal diseases and It was stated that HP might lead to the pathogenesis of PD by causing direct damage to the dopaminergic neurons or acting as neurotoxins via increasing the level of cholesterol glucosides.
The prevalence of HP infection among PD patients is significantly higher and is more common in patients over 60 years of age.

1 Like
Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
#155

Given that Mitochondrial Dysfunction is causative, fixing that is likely to mitigate against the disease. If statins are also mitigating then it looks like the pathway from the mitochondria via SLC25A1 through ACLY to acetyl-CoA is where at least one problem lies.

Both acetate and citrate, therefore, might be able to help. Acetate through ACCS2, but ACCS2 is in part self-inhibitory via acetylation so citrate may be useful.

#156

Ergothioneine’s relationship to PD

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#157

What’s the source? Associations between biomarkers and PD (and many other diseases) are always tricky because the abnormal levels are often a compensatory mechanism of the body to the disease as it progresses rather than a cause of the disease.

#158

I read about it at Consumer Lab, but here’s the paper.

#159

Thanks. Old paper (for the field of neurology) and tiny study so unless replicated recently I would not attribute much value to this finding.

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#160

What are some preventative strategies for Parkinson’s? I’m thinking ultra small dose nicotine (very small patch cut up weekly, reducing risk of addiction and might not even be that noticeable). Risk-reward seems favorable.

See this video in 2x speed:

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#161

I’ll start downing bell peppers, that I can do!

I’m here to follow too! My mom had it and my grandmother had ALS and my aunt has something that they can’t figure out… scary genes in my family.

#162

I don’t think it’s that dangerous to use a miniscule part of a nicotine patch, but I might be wrong.

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#163

I feel like that is also what I heard once on Huberman

… but my dad died from lung cancer so I err on side of caution… not to mention the second hand smoke I inhaled with 2 smoking parents in cars when I was little with the windows up!!! Probably the case for many in my generation!

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#164

Sorry for your loss! Nicotine patches doesn’t cause lung cancer, unless you decide to start smoking after using a relatively nonaddictive way of consuming it. Nicotine from patches reach the brain much slower so it is apparently much less addictive.

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#165

Thank you!!! :heart:

He had a heart attack at 40 and quit smoking and became super healthy (strict on no fat because that is what they said back then). But 20 years later, he got cancer.

Good to know about patch vs smoke. Ty

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#166

Nicotine: total BS, don’t do it. Trials failed. It’s something else in cigarettes that protects from PD, but we don’t know what yet (we’ve discussed it above already).

I won’t cite sources because I think I’ve already posted them all, but for PD prevention, what we know:

  • Drink coffee
  • Healthy diet (“MIND diet”)
  • No/low processed food
  • SGLT2 and/or GLP-1 RA
  • Avoid high-dose metformin
  • Telmisartan (and potentially also a dihydropyridine CCB?) and avoid beta-blockers
  • Avoid statins and prefer other lipid-lowering drugs (ezetimibe?)
  • Stress management
  • Sleep hygiene
  • Maintain social connections and an active life (a “purpose”)
  • B12 supplementation (as methylcobalamin?)
  • As much exercise as possible
  • Avoid laxative drugs
  • Prefer non-drug treatments for anxiety and depression (e.g., low-dose lithium?)
  • Avoid pollution (air, water, pesticides, etc.) (eat organic?)

Then, in terms of things that are for now only exploratory, as 1/4 of PD patients have mitochondrial impairment outside the dopaminergic substantia nigra (not the others), agents improving mitochondrial function might help: but which ones? Similarly, the immune system is affected in PD, so there are trials of immunosuppressants (rapamycin hasn’t been proven to work so far). Also, probably avoid viral infections and get vaccinated and in case of bacterial infections, use antibiotics.

9 Likes
#167

Adssx,
Thanks, this is helpful

Can you talk to me about metformin (and/or sglt2)

I’m on metformin 2x per day because, after wearing a cgm, I discovered I get much bigger spikes than the average person. My bloodwork is good, but the worry for me is contributing to existing heart disease.

I asked my doc about some other medicines you all discuss but he said easy trigger… i just started rapa and ezetimibe and he wants me to be cautious about polypharmacy

1 Like
#168

See this: Parkinson's disease - #28 by adssx

Then use the search to find posts about metformin and SGLT2.