#527

I asked ChatGPT (o3-mini-high, Deep Research), some assumptions as to why high cholesterol might be protective in PD (select excerpts):

  • Marker of Underlying Biology: High LDL levels might be a proxy for other physiological factors that protect against PD. Genetically higher LDL (as seen in MR studies) could be accompanied by other gene-driven changes that benefit the brain.
  • Reduced Exposure to Cholesterol-Lowering Therapies: Some experts have suggested that the apparent benefit of high LDL might actually reflect the absence of statin exposure – i.e. avoiding statins could avoid any deleterious off-target effects those drugs have on the nervous system
  • Mevalonate Pathway Byproducts (CoQ10 and Prenylation): Cholesterol is the end-product of the mevalonate pathway, which also produces crucial metabolites for cells. High cholesterol levels indicate robust activity of this pathway, which means ample production of coenzyme Q10 (ubiquinone) and isoprenoids (farnesyl/geranylgeranyl pyrophosphates). CoQ10 is a key component of mitochondrial respiration and a potent antioxidant; it is thought to have neuroprotective properties. Higher endogenous CoQ10 could support neuronal mitochondrial function and reduce oxidative damage in PD. Conversely, interventions that lower cholesterol (like statins) also reduce CoQ10 synthesis. Huang et al. noted that “statins reduce coenzyme Q10, which helps produce energy for cells and is hypothesized to have protective qualities in nerve cells.” Similarly, isoprenoids from the mevalonate pathway are required to prenylate many cell-signaling proteins (including those involved in autophagy and synaptic function). If LDL is high, isoprenoid levels are likely sufficient, ensuring proper prenylation of neuronal proteins (like small GTPases needed for vesicle trafficking and lysosomal activity). In contrast, low cholesterol status might mean fewer isoprenoids and impaired cellular housekeeping (potentially hindering the clearance of toxic proteins such as α-synuclein).
  • Systemic Inflammation and Immune Effects: Peripheral lipoproteins can modulate inflammation. LDL particles carry not only cholesterol but also antioxidants and can bind bacterial endotoxins, potentially blunting systemic inflammation. Chronic inflammation is implicated in PD pathology (even peripherally). Higher LDL/ApoB might neutralize circulating pro-inflammatory factors or supply immune cells with cholesterol needed for effective repair, thereby indirectly protecting neurons. Conversely, very low LDL has been associated with upregulated inflammation and even higher risk of certain strokes (e.g. hemorrhagic stroke)​, suggesting that some cholesterol is necessary for vascular and immune homeostasis. A healthier peripheral immune environment might slow the propagation of PD pathology from peripheral sites (like the gut) to the brain. Indeed, some researchers speculate that Parkinson’s disease may, in part, begin outside the brain (in the gut or olfactory system) and then spread centrally
#528

Not bad from ChatGPT. Here’s the problem. NDDs existed before any of these medications were in use at all, or in wide use.

The History of Parkinson’s Disease: Early Clinical Descriptions and Neurological Therapies

Statins didn’t come into wide use until the 90’s, though perhaps there’s old traditional medicine in things like red yeast rice, but hardly popular in the West back in the day.

So we can’t really put it all down to medications. I have a similar objection to pesticides and various industrial toxins. It seems to me these might worsen PD, or maybe initiate/trigger in vulnerable individuals, but there must be some underlying pathology, otherwise everyone exposed to those meds, toxins and pesticides would be getting PD.

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#529

Of course, statins aren’t the cause of PD. Just better to avoid them if you have PD or are at risk of it.

PD didn’t exist before the Industrial Revolution.

Yes, probably some genetic susceptibility combined with environmental exposure.

#530

I don’t know that we should be so sure that PD did not exist before the IR (obviously not under that name!). From the paper I posted above:

“Parkinson’s disease was first medically described as a neurological syndrome by James Parkinson in 1817, though fragments of Parkinsonism can be found in earlier descriptions (Parkinson 1817). As examples, Sylvius de la Boë wrote of rest tremor, and Sauvages described festination (Sylvius de la Boë 1680; Sauvages 1768; Tyler 1992). Much earlier, traditional Indian texts from approximately 1000 BC and ancient Chinese sources also provide descriptions that suggest Parkinson’s disease (Manyam 1990; Zhang et al. 2006).”

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#531

There’s no evidence that these earlier texts referred to Parkinson’s disease (not under that name ofc) as its symptoms can be mimicked by other conditions (starting with essential tremor).

I found this paper quite convincing: Parkinson’s Disease Is Predominantly an Environmental Disease 2024

Still, whether it’s environmental exposure or not, we don’t know the cause at the biological level.

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#532

And the answer: Parkinson’s Disease is Predominantly a Genetic Disease 2024

#533

Korean paper + mice + toxin model (does not represent the disease well) but still: Combination treatment with rapamycin and glucocorticoid protects the death of mesostriatal dopaminergic neurons in animal model of Parkinson’s disease 2025

  • Reduced concentrations of rapamycin and dexamethasone synergistically enhance cell survival.
  • The combination treatment effectively protects mesostriatal dopaminergic neurons in an MPTP-induced PD model.
    In vitro experiments with the SH-SY5Y cell line revealed that 10 μM rapamycin significantly increased the survival rate of cells treated with 6-hydroxydopamine to induce cell death, while both dexamethasone and prednisone at 50 μM exhibited an evident increase in survival rates. The combination treatment with reduced concentrations (rapamycin: 5 μM, dexamethasone: 25 μM) showed a more effective recovery in survival than singular treatments with high concentrations of rapamycin, prednisone, or dexamethasone.
    In vivo experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD animal model revealed that the combination treatment effectively mitigated defects in motor function. The combination treatment completely blocked the loss of tyrosine hydroxylase (TH)–positive neurons in the substantia nigra pars compacta and partially prevented the reduction of TH-positive fibers in the striatum caused by the MPTP treatment. It also reduced the microglial levels caused by the MPTP treatment. Although not significant, it demonstrated an increase in survival rates of MPTP-induced PD model mice. In conclusion, the combination treatment with reduced concentrations of rapamycin and glucocorticoids may serve as potential therapy for PD, albeit further research and clinical trials are warranted to validate its efficacy and safety.

So rapa might cross the BBB in mice? (at least when combined with dexamethasone?)

#534

Chinese paper, but Shanghai:

Caffeic acid reduces A53T α-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson’s disease

Does anyone want to wade into the mess of coffee consumption and PD? I don’t want to beat a dead horse. Is CA a possible factor in this context?

#535

The latest good paper on caffeine is here: Parkinson's disease - #449 by adssx

#536

What about caffeic acid?

#537

I have no idea! (But I guess all the “obvious” hits for PD have already been considered and studied so low chance of being useful?)

#538

Well, I was hoping the Chinese paper I posted above had some value wrt. caffeic acid, but yes, I don’t expect much. Caffeine has been extensively studied, but there are other agents in coffee, and I was hoping someone looked into caffeic acid.

#539

@TomParkinson

Dear Tom, I’m so sorry for what you’re going through :frowning: -

Have you looked into a supplement called “The DeAnna Protocol” on Amazon? …It, itself, is rather expensive ($170 a jar/1 month), but look into buying the ingredients separately, and maybe you can do it cheaper!

Also, look into a supplement called “Plasmalogen” - a compound from sea-sources (scallops, sea squirts, etc), and available in different brands …prices I have seen, run about $80 for the basic dose, but if one has a condition, probably will want to take a higher dose… And I think I did read clinicals, supporting it for Parkinson’s - and other neurological conditions!

I hope these help - God bless you!

.

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#540

NBC report on the Parkinson’s Belt in the USA. They believe it’s caused by chemicals.

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#541

I would be doing everything I could to reduce my SASP burden.

Aging, cellular senescence and Parkinson’s disease

We then discuss the hallmarks of cellular senescence in the context of neuroscience and review studies that directly examine cellular senescence in PD. Studying senescence in PD presents challenges and holds promise for advancing our understanding of disease mechanisms, which could contribute to the development of effective disease-modifying therapeutics. Targeting senescent cells or modulating the senescence-associated secretory phenotype (SASP) in PD requires a comprehensive understanding of the complex relationship between PD pathogenesis and cellular senescence.

https://journals.sagepub.com/doi/10.1177/1877718X251316552

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#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?

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#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.

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#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:.

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