#542

I went over that paper a couple of times, very interesting. A few things struck me. Compared to AD and ALS, PD is a very tough customer. You can find several drug classes that appear to be associated with lower odds of ALS and AD 5-10 years out, especially anti-diabetics, but it’s much tougher to find any for PD - Figure 2, panels a, b, c.

Looking at the forest plots for all three in the same graphic, Figure 2, panel d, the best case for PD are antihypertensives, especially renin-angiotensin modifiers, though even then confidence intervals cross zero slightly. Surprisingly, after all those dire criticizms of statins impact on PD, lipid modifying agents sit at roughly zero for PD, and the confidence intervals straddle the zero on both sides - and actually look slightly worse for ALS and AD, though the effect sizes all appear pretty tiny. I assume that is because statin use is likely lower in PD, because generally there is less hyperlipidemia in that population, Figure 3 - or maybe I’m wrong and there is some other explanation.

I find it quite dissapointing that there are no real classes of drugs (other than BP) that pan out positively for PD. This is all the more strange, because looking at associated symptoms, if anything, PD maps more closely with hypotension, not hypertension - although, you, Antoine apparently atypically have essential HTN(?), at least allows for use of possibly beneficial ARBs etc. This could be protective(?) in the same way higher lipids are protective, so if you are lucky(?!) enough to have hyperlipidemia and HBP with PD, you are better off?

1 Like
#543

I think the issue here is that they used broad categories. For instance, for antidiabetics, metformin and insulin seem to be detrimental, while SGLT2is and GLP1RAs might be protective. So, my friend is now looking to do the same paper but at the individual drug level.

PD also probably has way more heterogeneity than AD and ALS.

1 Like
#544

Ah, that would make sense. And yes, absolutely PD is far more diverse compared to AD and ALS. I wonder if your friend has enough data sets to break out his analysis for specific drugs for PD that presents at a young age, vs older. If there is something different about PD at younger ages compared to older, then there might theoretically be different associations with drugs too. That might give valuable clues. Could you ask your friend to perform that analysis?

#545

I can ask but it takes months/years to get an answer in the wonderful world of academia :sweat_smile: Also, I suspect he might not have enough people with young onset PD.

#546

Yes, I was afraid the data sets may not be there. I only ask, because he has so many anyway from all over the world, so I was hoping maybe there would be enough :cry:.

1 Like
#547
4 Likes
#548

Wow, that’s a lot of money. I know it costs a lot, but that’s a LOT.

It reminds me of when they said the TAME trial was like $75million and to me if it costs 75 million to tell whether a drug works, it doesn’t work very well.

#549

Only about 1% of the value of Sergey’s Google stock, so not a big deal. :wink:

And, regarding causal factors for PD:

So if genes don’t explain most cases, how about the environment? Several environmental factors have been linked to Parkinson’s, which has been shown to occur at higher-than-expected rates in, for instance, people who were prisoners of war in World War II. There is also a higher rate in people who live on farms or who drink well water, probably because of exposure to certain pesticides.

But the environmental connection is precisely what makes Jack and Jeff so interesting. For almost all of their 68 years, they have lived no more than half a mile apart. They have been exposed to the same air, the same well water, the same dusty farm chores, the same pesticides. They built their homes a five-minute walk from each other, on two plots of their father’s 132-acre farm in eastern Pennsylvania. And since 1971 they have worked in the same office, their desks pushed together, at a graphic design firm they co-own. All this makes their particular discordancy tougher to explain.

The existence of a pair of twins with identical DNA and nearly identical environments in which only one is sick—that’s a researcher’s bonanza. Whatever difference can be untangled in the twins’ physiology probably relates directly to the disease and its origins. The genome can be held constant; environmental toxins and other exposures can be held constant; what remains, researchers are left to think, might be an odd shift in a particular neural pathway that has a relevant function all its own.

1 Like
#550

This is very disappointing. No effect of exenatide on Parkinson’s in new phase 3 trial.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02808-3/fulltext

4 Likes
#551

Disappointing indeed. We discussed the results when they were announced in October: Parkinson's disease - #329 by adssx

John and I attended the event where the principal investigator explained the results. HbA1C didn’t change in the exenatide arm. The paper says “Future post-hoc analyses will also explore whether any subgroups defined according to biochemical assays, such as modestly elevated glycated haemoglobin A1c levels, might have differential clinical, target engagement, or biochemical responses to exenatide.”

Also, I was super excited by GLP1-RAs for PD so I tried dulaglutide and semaglutide and didn’t see improvements (actually I saw tiny ones but the sympathetic overactivity made the whole experiment a net negative). I wasn’t surprised when the results came out…

That being said, the GLP-1RA story in PD is not finished:

1 Like
#552

I think the key is when glucose goes over 8/144 Then a different pathway kicks in and you get a higher level of ROS as a result of more fructose availability. (hence more mtDNA damage)

2 Likes
#553

That’s why I’m bullish on SGLT2i for PD (+ the kidney article above).

2 Likes
#554

Actually, there’s another hypothesis regarding N-acetyl-DL-leucine (Tanganil) & N-acetyl-L-leucine (NALL)'s mode of action and you might like it @John_Hemming:

Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C 2024

Treatment with NALL was shown to normalize neuronal membrane potentials in a guinea pig model, thereby ostensibly improving cellular signaling processes and restoring and protecting neuronal circuits.6 In various animal models, treatment with NALL has led to dampening of neuroinflammation, which indicates a potential neuroprotective effect.

https://uca.hal.science/hal-01978421/file/Acetylleucine Paul VANDERKAM HAL.pdf

In France, Acetylleucine (Tanganil®) is often prescribed to treat attacks of vertigo, whether in general practice clinics or in emergency wards. Its pharmacodynamics are not fully understood. The hypothesis is that it restores the membrane potential [14-16], via an interaction with membrane phospholipids on the injured side of vestibular neurons mainly in the thalamus or parietal region of the cortex

The RBD case study also notes:

The agent enters enzyme-controlled pathways that correct metabolic dysfunction and improves energy adenosine triphosphate (ATP) production. Lysosomal and mitochondrial dysfunctions have been proposed as important factors in the pathogenesis of PD. Therefore, AL might also have a favorable impact on the prodromal stage of PD by slowing down its progression already in the stage of iRBD.

#555

Its an interesting thought. Arguably there is a merit in increasing ΔΨM by small amounts by other techniques, but there will be a point where the additional oxidative stress is counter productive.

The intensity of the electric field is really quite high, because the distance is small.

#556

I missed this paper from Dec 2024: Rapamycin Abrogates Aggregation of Human α-Synuclein Expressed in Fission Yeast via an Autophagy-Independent Mechanism

Yeast model, so not ideal.

Also, great paper from 2021: Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans. They screened dozens of compounds to find candidates. First with AI in silico, then in vitro with an alpha-syn assay, then in vivo on C. Elegans, then on neurons, and last on rodents. Top hits at the end: rapamycin, losartan, and rifabutin. A trial of telmisartan is about to start in PD. Rifabutin has been prioritized by PD charities to repurpose it but no trial has started yet. Rifabutin is part of the rifamycin family of antibiotics, together with rifampicin / rifampin (touted as a longevity drug). But no one seems to be working on rapa for PD. The failed MSA trial could be the reason. But there’s some interesting data here and there in favor of rapa in PD.

This paper also makes me reconsider rapa: Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration - #12 by adssx

2 Likes
#557

Gardenin A treatment attenuates inflammatory markers, synuclein pathology and deficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-α-syn mice

https://www.sciencedirect.com/science/article/pii/S0753332224002543?via%3Dihub

1 Like
#558

OK, this is more of an entertainment value than anything, but interesting to see pop sci getting excited over fecal transplant research. Nothing new here, but an entertaining look at FT and a few conditions (including alcohol use disorder!). The strictly PD segment starts about minute 8:00.

Poop treats Parkinson’s

#559

Brilliant. I was going to mention that my dad had ALS and was in a study of a new drug. Everybody but him died within 6 mo. He went on for several years and improved slightly toward the end. I was giving him raw goat milk kefir and that was what he credited it to. He thought his health improved starting then. He died of prostate cancer because they didn’t treat it thinking that he would die of the ALS.

My point is that I was going to mention that Parkinson’s may be from dysbiosis too. I think the poop transplant would work much faster than raw goat milk kefir, and more certainly. I would say, as I frequently do, the cost and risk are low and this would be a good move.

3 Likes
#560

Apologies if this has been posted before, but this is from June 2024, I may have missed it, if so, please ignore. Note, this is in older people, not young onset PD., so caveat.

Statin use and risk of Parkinson’s disease among older adults in Japan: a nested case–control study using the Longevity Improvement and Fair Evidence study

https://academic.oup.com/braincomms/article/6/3/fcae195/7687729

I confess to being very puzzled by these results. If high LDL is protective against PD, then why do short term statins increase PD odds vs non-statin users, while long term statin use has been found to be protective? Does anyone find the proposed resolution in the discussion section at all convincing? As a side note, pitavastatin is used more widely in Japan, and it did very well against PD, FWIW (see table 4).

“Our study revealed an association between a high cumulative dose of statins and a reduced risk of Parkinson’s disease. However, the low cumulative statin dose group demonstrated an increased risk of Parkinson’s disease compared with non-users. This 1–30 TSDD group may comprise subjects diagnosed with hypercholesterolaemia with high low-density lipoprotein cholesterol (LDL-C) and started on statins, which were quickly discontinued possibly due to poor adherence or adverse events. This group may also include patients who were diagnosed with Parkinson’s disease soon after statin therapy for hypercholesterolaemia. The association between serum cholesterol levels and Parkinson’s disease is still controversial. A previous study in Finland suggested that higher blood cholesterol levels were associated with an increased risk of Parkinson’s disease.36 However, recent two meta-analyses suggested an inverse association between serum LDL-C levels and Parkinson’s disease risk, although the conclusion regarding the association between Parkinson’s disease risk and serum levels of total cholesterol or triglycerides was inconsistent.37,38 Of note, Parkinson’s disease could dysregulate lipid metabolism and vice versa, and prodromal symptoms of Parkinson’s disease may affect serum cholesterol levels. Thus, future studies will be required to elucidate the association among hypercholesterolemia, statin usage and Parkinson’s disease. One possible reason for an increased risk of Parkinson’s disease in this low TSDD group is that this group may comprise patients at the prodromal phase of Parkinson’s disease. On the other hand, a substantial number of Parkinson’s disease patients suffer non-motor symptoms including depression prior to their diagnosis of Parkinson’s disease. This could result in discontinuation of newly prescribed drugs due to poor adherence, leading to an increased number of Parkinson’s disease cases in the low TSDD group. However, we adjusted variables including depression and psychosis in multivariable models to control for the effects of these factors in this study. Conversely, in the higher cumulative dose group, the population was continuously treated with statins and might have better control of hypercholesterolaemia. In addition, statins may exert protective effects such as anti-inflammatory effects against Parkinson’s disease.39,40 Consequently, we observed a reduced risk of Parkinson’s disease in this group. This observation reinforces the notion that continuous statin use is associated with a decreased risk of developing Parkinson’s disease.”

1 Like
#561

High Cholesterol can be indicative of high acetyl-CoA levels. If you use a statin to inhibit the conversion of acetyl-CoA to Cholesterol there is more available for acetylation of the histone.

1 Like