If it succeeds, does that mean it will be available for Parkinson’s?
No because the trial is led by a charity. But new European laws we lobbied for should change this in the future: EU pharmaceutical policy: MEPs support comprehensive reform | News | European Parliament
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I’m utilizing Tirzepatide on my patients with PD as it seems to cross the BBB, is more potent of a GLP-1 Agonist, and there is also evidence in the area of neurodegeneration having the added GIP agonism seems to have an additive effect. Clearly no definitive evidence at this point - but I got anecdotes of significant improvement with Rapa + Tirzep. Given the low risk to this intervention, and having a progressive disease, I’ve been satisfied with the Risk:Benefit on this one.
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We don’t really know if tirzepatide is better than exenatide for PD as it doesn’t seem to cross the BBB and stay in the brain as well: https://x.com/foltynie/status/1735700379491307973?s=20
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Yes I saw the article and I also see another group has generated at GLP-GIP agent that does cross the BBB. The question is the mechanism of action of these agents - is it insulin sensitivity of the brain and anti-inflammatory effect such that being present in the arterial supply to the brain is sufficient - or does it require a tissue level. Our more potent GLP-1’s including semaglutide and tirzepatide seem to not get a tissue level in the brain to any extent.
It is furthermore interesting that the potent behavioral changes seen with these agents appear to occur without achieving a level in the brain. All by nerve signally - presumably from the vagus nerve.
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That is true; we don’t know the mechanism, so these graphs may not matter. Until we have proper RCTs for semaglutide, tirzepatide and retatrutide in PD, anecdotal evidence like yours is extremely valuable. Same with this: https://www.reddit.com/r/Parkinsons/comments/1azbx7c/semaglutide_and_symptom_relief/ Signal or noise? I don’t know, but exciting and promising! 
How do you consider polypharmacy in your decision-making? Meaning, what is your method to determine whether a PD patient can use Tirzepatide or Rapa, where do you check for drug-interactions and what is important?
I’ve seen the same - rigidity, markedly improved and quickly - constant and progressive - in early disease with almost complete reversal. Anecdotal - but give me another 10 of these patients in early disease to work with - and I’ll be a bit more confident in saying there is a true effect. Just don’t have enough of these folks in my practice yet - but keen to add them. Folks at risk of neurocognitive decline or with early disease seem like a group that could markedly benefit from the stuff many of us are focused on.
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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 ).
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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.
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@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.
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.
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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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Just published in Neurology (“The most widely read and highly cited peer-reviewed neurology journal”):
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.
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.