adssx
#222
It seems that carbon monoxide is indeed what protects from PD: Low-dose carbon monoxide may explain the paradoxical reduced risk of Parkinson’s disease among smokers 2024
“Building on multiple Phase I and Phase II clinical studies in both healthy people and people with a variety of clinical conditions showing safety of carbon monoxide at the low doses studied here, a clinical trial of low-dose, orally administered carbon monoxide in patients with PD is planned.”
(poke @AnUser)
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AnUser
#223
The paper: Neuroprotection of low dose carbon monoxide in Parkinson’s disease models commensurate with the reduced risk of Parkinson’s among smokers | npj Parkinson's Disease
It could be something downstream from that.
Carboxyhemoglobin seem interesting, FDA threshold is set at 14% for clinical trials according to Wikipedia for safety. There is also endogenous ways the body create it, including with heme:
The most extensively studied pathway is the metabolism of heme by heme oxygenase which occurs throughout the body with significant activity in the spleen to facilitate hemoglobin breakdown during erythrocyte recycling.
Vegetarians also have a higher PD risk, which I assume is lower in heme. There are also multiple natural genetic mutations that increase COHb levels, so why hasn’t this been picked up in Mendelian randomization studies?
adssx
#224
I’m not sure vegetarians have higher PD risk. Also: anemia is protective of PD.
2 Likes
AnUser
#225
Apparently a non-invasive hemoglobin etc tracker:
Hemoglobin
Pulse Rate Variablity
Oxygen Content
Carbon Monoxide
Methemoglobin (Met)
Pulse Rate
Perfusion Index
Oxygen Saturation
Respiration Rate
Pleth Variability Index
1 Like
adssx
#226
Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson’s Disease in Patients with Type 2 Diabetes: A Population-Based Cohort Study 2024
This study included 89,074 Medicare beneficiaries who initiated either GLP-1RA (n = 30,091) or DPP4i (n = 58,983). The crude incidence rate of PD was lower among GLP-1RA users than DPP4i users (2.85 vs. 3.92 patients per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63–0.95). Our findings were largely consistent across different subgroup analyses such as sex, race, and molecular structure of GLP-1RA.
They looked at individual GLP-1RAs and surprisingly higher the BBB crossing (dulaglutide > exenatide > liraglutide > semaglutide) the lower the PD protection!!! (poke @DrFraser)
They note:
Really convincing chart with increased protection over time:
3 Likes
This is an interesting paper - still need more data, including in mixed GLP/GIP agents. I do wonder if individuals taking GLPs are more metabolically healthy and at better weight than there comparison group of those on the DPP4 agents, which don’t have the same ability to decrease obesity, in general? However, if this was a big area of benefit, we’d expect semaglutide to have performed better.
My patients with early PD right now, I’m favoring Trulicity (Dulaglutide), but there is a cost issue. Out of Canada (requires an Rx, but they accept U.S. Rx’s) looks to be in the $400/month range, whereas in the U.S. it somewhere in the $1000 range.
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adssx
#228
Unless I misunderstood something, I think there’s a big problem in the paper: they didn’t adjust for weight. Obesity seems protective vs PD (see: Association of Body Mass Index and Parkinson Disease A Bidirectional Mendelian Randomization Study 2024) so then no wonder that GLP-1RAs that are also weight loss drugs are associated with lower PD risk vs DPP4 that are neutral on weight. It would be a massive confounder.
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Really interesting point. Now ChatGPT seems to think the relationship is complex, and Obesity increases risk of PD. Your friend’s Vera Health, which I’m signed onto seems to also concur that obesity increases risk and further more states obesity diminishes glymphatic function. Vera does a much more detailed job, incidentally, and has multiple article citations.
So I guess I’d interpret this to indicate that despite semaglutide doing much better to fix metabolic issues, it’s lack of brain penetrance might be a factor, with the main impacts of GLPs/GIPs not crossing the BBB being indirect effects via the vagus nerve (which clearly happen on functional MRI’s) and then metabolic benefits which seem on the literature to decrease rate of PD.
Your thoughts?
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adssx
#230
I think ChatGPT and Vera are wrong. The Mendelian randomization proves it. PD patients also exhibit lower body weight compared to age-matched healthy subjects. PD patients are often so frail that PD researchers I talked to were initially concerned about trying semaglutide on them.
I’m not sure I follow you here. In the paper, semaglutide offered the highest protection against PD (0.49), way better than the best BBB-crossing drugs exenatide (0.75 but not significant as the top CI is 1.39) and dulaglutide (0.88 but same issue). That’s what I find hard to explain.
3 Likes
Interesting. I looked at the initial post you had on this and thought I’d missed something as the semaglutide looked best, but then the text said “Thus, it is suggested that GLP-1RAs with greater brain penetrance, such as … may be more likely to modify the clinical course of PD.”
I thought the data above showed the opposite, but figured I’d missed something as I’ve not reviewed the study, but the text seemed to indicate otherwise.
So - if Semaglutide is better on this - I wonder if the trend continues with Tirzepatide or Retatrutide?
Clearly more data needed.
3 Likes
AnUser
#232
I’ve heard body weight SNP’s are expressed in the brain, if so, then it’s behavior that leads to lower BMI rather than BMI itself? Those SNP’s might affect neuronal function, so some pleiotropy seem possible here, unlike the SNP’s that just decrease PCSK9 or something.
1 Like
adssx
#233
@AnUser: here we have MR + association studies + the experience of practicians pointing to PD patients being quite frail rather than obese.
@DrFraser: that’s the being question. My theory is that because they did not adjust for weight or BMI (it looks like this wasn’t part of their dataset), we cannot conclude, and there might be a confounder due to weight. To add on this: in terms of BBB crossing we know that dulaglutide > exenatide > liraglutide > semaglutide. This paper gives us OR so that the best for PD protection are semaglutide (0.49) > liraglutide (0.70) > exenatide (0.75) > dulaglutide (0.88). So, the exact opposite. And for weight loss, we have semaglutide > liraglutide > dulaglutide > exenatide.
However, we also know that the exenatide phase 2 trial showed improvements in motor and non-motor symptoms. whereas the liraglutide trial only improved non-motor symptoms. That’s why they moved exenatide, but not liraglutide, to a phase 3 trial (results expected in 6 months). There’s an ongoing semaglutide PD trial in Japan. I don’t think anyone is testing dulaglutide, though. So if the phase 2 trials hold, for PD, it seems that exenatide is superior to liraglutide. Which is the opposite of what was found in the above paper.
It also entirely possible that the CI are wide and actually we cannot conclude anything and with more data over a longer period of time (and adjusted for weight) the conclusion will be entirely different.
We can at least say that GLP-1RAs seem neuroprotective, even without weight loss.
AnUser
#234
The direction could be like this I would speculate, if not controlled for weight:
Fewer PD genes → More dopamine → Wanting more food → Obesity → Ozempic → (Ozempic decrease PD the most!)
Do you have full access to the article on the GLPs vs. DPP4’s? I need to take a careful read of it.
adssx
#236
I only paid for limited access that prevents me from downloading so the best I can are these screenshots:
4 Likes
Very useful - thank you so much.
adssx
#238
A Mendelian randomization study investigating the causal role of inflammation on Parkinson’s disease 2022
In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = −2.364, 95% confidence interval (CI) = −4.789–0.060; years difference per 1 log-unit increase = −2.011, 95% CI = −3.706 to −0.317; years difference per 1 log-unit increase = −1.569, 95% CI = −2.891 to −0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson’s disease and its age at onset.
How do you lower brain IL-6? 
Tocilizumab does not cross the BBB:
IL-6 is part of SASP. Maybe the IL-6 is symptomatic of more cells issuing SASP rather than being causal.
adssx
#240
This MR seems to show that IL-6 is causal, no?
I am not sure how it can.
