#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:

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#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)

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#553

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

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#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

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#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

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#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.

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#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.”

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#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.

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#562

Yes FMT looks very promising. @TomParkinson did several sessions and attributes a lot of his improvement to that.

#563

Yes, we discussed it when it was published (you can search for the title of the paper): Parkinson's disease - #182 by adssx

They didn’t control for baseline LDL and BMI and the dose-response relationship is weird and they don’t explain it. So back then I concluded the opposite. I’d love to know your thoughts!

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#564

Just published and relevant to our discussion: Association of cholesterol and glycaemic state biomarkers with phenotypic variation and Parkinson’s disease progression: the Oxford Discovery cohort 2025

HDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behaviour disorder [RBD] and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (ADL) (e.g. UPDRS-II score with 1 SD increase in HDL-C -0.74, 95%CI -1.22 to -0.26, p=0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression. Fructosamine levels were not associated with phenotypic variability or rate of disease progression.
Hypercholesterolaemia was associated with a better motor/non-motor disease subtype and daily living impairment at presentation, but did not predict longitudinal change. Future research needs to determine if these associations are causally related or secondary to disease onset by examining prodromal subjects.

Interesting bits:

  • “Fructosamine levels were not associated with phenotypic variability or rate of disease progression.” => Fructosamine is a proxy for chronic glucose levels. So glucose levels are irrelevant? Unless as stated by @John_Hemming what matters is more to stay in the “normal” range rather than the average?
  • “Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (ADL) (e.g. UPDRS-II score with 1 SD increase in HDL-C -0.74, 95%CI -1.22 to -0.26, p=0.002) and non-motor features” => Do statins worsen PD symptoms? Or is it reverse causation?
  • Positive impact on non-motor features as well: previous papers found that high cholesterol was associated with more Lewy body dementia
  • Doesn’t predict progression: so cholesterol levels might be more relevant in the prodromal phase?
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#565

I think the issue with glucose is to try to stay below 8/144.

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#566

@momgotshocked: N-acetyl-L-leucine about to get approved in Turkey, so potentially 10x cheaper there (it would still be a lot…)?

Source: x.com

#567

Thanks for the info!

I’ve gone ahead and started taking the “supplement” version after chatting up others doing the same thing, and also after finding out from a different company that it is supposed to be sour (it’s an acid, after all) and somewhat insoluble.

I’m not dead yet, anyway. It’s ridiculously cheap (I mean, relative to $13,000/mo). I’d like to think time will tell, but these benefit-type treatments happen so s-l-o-w-l-y It’s hard to notice much of anything. My symptoms aren’t bad enough, which is a good thing, I guess.

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#568

Em https://healthunlocked.com/cure-parkinsons there are a few people reporting some quick improvements in restless legs syndrome and RBD. So maybe look at the impact on your sleep?

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#569

Yes–I think that’s where all this hype started. Somehow, randomly(?) Tanganil (the OTC racemic version) was found to improve these sleep issues in people who didn’t have parkinson’s…yet?

But, though I have PD, I don’t have restless legs or RBD. I’m not complaining, but it means I have nothing to report on that front. Of course, I only started in the middle of January. “Quick results” could still be longer than that, no?

#570

If you have a watch or whatever app that measures your sleep you might still be able to see improvements in scores even if you don’t have specific sleep-related conditions. It might be interesting to track that. (I don’t track sleep myself as it makes me more anxious :sweat_smile: )