That sounds like them (dopamine neurons) turning sensecent.
Another great reason to take Metformin. 
adssx
#95
Yes, but high-quality RCT > preprint MR, so I trust the RCT more regarding statins and PD.
On the other hand, this preprint MR is all we have regarding PCSK9i and PD, so it’s enough for me to wave a “red flag” (or maybe just yellow/orange? ) on PCSK9, for now.
That’s an interesting point, thanks.
It doesn’t need to cross the BBB to cause damage.
Is this the source? I agree with the author. There’s an increase of all NDDs (not only PD, also AD) after infections (not only Covid, also just the flu), see: Virus exposure and neurodegenerative disease risk across national biobanks 2023. So there we’ll see an increase in NDDs in the next few years. Long Covid is just the tip of the iceberg. It doesn’t mean we need to panic, but it’s good to be aware of the risk and to take preventive measures to avoid viral infections and help the body recover after unfortunate infections (we can’t avoid 100%).
It’s probably good at a low dose, indeed. At high doses, metformin is toxic to mitochondria and is associated with higher rates of PD.
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Yes. I think if you take Metformin, it should be 500 mg or less daily.
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adssx
#98
Thanks.
Not the best journal and authors not from the most prestigious institution but still an interesting article: Urolithin A in Health and Diseases: Prospects for Parkinson’s Disease Management 2023
Interesting conclusion:
Even though the compound can be produced from naturally occurring polyphenols in plant foods – ellagitannins and ellagic acid, the impact of direct UA supplementation on human health and its potential beneficial impact must be assessed. […] Safety, bioavailability, pattern of distribution, and mechanism of action in humans must be established. Regarding PD, given the recent advancement in detecting prodromal individuals before diagnosis and the potential prognostic value of the α-synuclein biomarker, research into selecting the right time for UA intervention shows promise to delay PD onset or progression to people at an increased risk [102]. Nevertheless, as predicted by computer modelling, low brain bioavailability of UA is orders of magnitudes lower than concentrations that provide neuroprotective effects [96], and thus should be managed by any supplementation scenario. Advanced nutritional approaches enabling the delivery of UA in a calibrated manner are likely to play a key role in bridging the gap created by the natural heterogeneity of the gut microbiome to deliver health benefits. […] In this context, UA was recently suggested as a potential biomarker of gut dysbiosis and disease stage in PD patients. Taken together, the data gathered herein support the health-promoting activity of UA. Regarding PD, UA-based intervention offers new strategies to improve the prevention, treatment, and even diagnostics of the disease.
For those who want to know more about UA, see: Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU
Thanks A LOT again @Neo for pointing me towards UA! 
2 Likes
Neo
#99
Thanks for a good share - have you - or anyone else - seen anyway to test our levels?
adssx
#100
The article cites this paper: Urolithins: potential biomarkers of gut dysbiosis and disease stage in Parkinson’s patients 2022
There they say:
Urolithin detection in urine is a feasible, non-invasive and fast approach that can reflect gut microbiome dysbiosis and intestinal inflammation in Parkinson’s disease patients.
Stool samples were collected for the gut microbiota analysis at baseline, while urine samples were collected for the urolithin analysis after consuming 30 g of walnuts for three days, a short polyphenol-rich intervention in which participants can produce urolithins. Urolithins were determined in urine samples by ultra performance liquid chromatography–electro spray ionization–quadrupole time of flight–mass spectrometry (UPLC-ESI-qToF-MS) as previously described.
They cite:
Ellagitannins and ellagic acid (EA) are metabolized by the gut microbiota to produce urolithins that could be responsible for the health effects attributed to ellagitannin-containing food products. Several urolithin aglycones could be present in fecal samples while glucuronide and sulphate conjugates are mainly found in plasma and urine. So far, the lack of available standards has made difficult their correct identification and quantification. In the present study, UV and MS spectra characteristics of urolithins and their phase II metabolites have been determined using different systems based on liquid chromatography (LC) coupled with diode-array or mass spectrometer detectors with different analyzers (triple quadrupole (QqQ) and quadrupole time-of-flight (QTOF)). Chromatographic separation was achieved on a reversed-phase Poroshell C18 column (3×100mm, 2.7μm). Elution order, characteristic UV spectra, and relative response factors (RRFs) with respect to their parental compound (EA) and the most common metabolite urolithin A (Uro-A) were determined. This contribution, along with the most important mass spectra characteristics (MRM transitions, qualifier/quantifier ratio, accurate mass and fragmentation pattern) will allow the determination of urolithin metabolites in different biological samples and their quantification even if not all metabolites are commercially available. The methods developed in the three systems have been fully validated in terms of linearity, sensitivity, precision, recovery, matrix effect, selectivity and stability. After that, they were successfully applied to complex biological matrices (urine, feces and plasma) from two human studies in which volunteers consumed ellagitannin-containing foods, such as walnuts and pomegranate extracts.
So you need UPLC-ESI-QTOF-MS. How much does this cost? Or can you access it from a lab?
[Update: OK 10 to 100k$: Waters SYNAPT G2 ]
1 Like
Neo
#101
Seems like something that one of the current testing companies, perhaps Jinfinity, Genova Diagnostics or Iollo could offer.
There was another source I think you or something else shared the last day or two where one could just do it from a blood spot card.
Wonder what Mitopure did for their different clinical tests. @RapAdmin did they even offer to test people’s levels in the past or something - I think I recall something like that from some post you made, but perhaps it was something else than Mitopure/UA?
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adssx
#102
I’d be ready to pay to rent a UPLC-ESI-QTOF-MS from a lab and test my sample…
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ng0rge
#103
I think they offered a free test to see if your gut microbiome could produce urolithin A from pomegranate juice.
https://www.timelinenutrition.com/blog/making-a-natural-anti-aging-nutrient-available-to-everyone
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Yes - I still have the kit in the bedroom… did the test, but never mailed it in because I got busy with other things. See here: Urolithin A - Virtual Clinical Trial by Timeline Nutrition
I remember a podcast with one of the guys at the Buck Institute and apparently its a pretty easy, quick and inexpensive test (In the Timeline trial, you just dripped a few drops of blood on a piece of paper and sent it to them). Someone needs to create a commercial version of this test - perhaps if a bunch of us emailed a few test labs like Merek, and Life Extension foundation, they would offer it.
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adssx
#105
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It will be interesting to see what diseases are affected by hitting the key aging pathways.
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adssx
#107
Cholesterol, dementia, and PD (Cont’d): Differential effects of cholesterol levels on cognition according to body mass index in Parkinson’s disease 2024
lower TC levels were associated with lower composite scores of frontal/executive function and a higher future risk of PDD conversion in the under-/normal weight group, whereas higher TC levels were associated with poor performance on frontal/executive items and more frequent PDD conversion in the obese group. These findings indicate that the association between TC levels and cognition is moderated by BMI in patients with PD, suggesting that a cholesterol-lowering strategy could be applied differentially according to BMI.
Clinical studies have demonstrated that individuals with high levels of circulating TC are less likely to develop PD and have better long-term outcomes.
A recent investigation discovered that elevated cholesterol levels have a dual role in PD: they protect against lysosomal membrane permeabilization while also promoting α-synuclein accumulation
When examining the association between cholesterol levels and Alzheimer’s disease or vascular dementia, previous studies have shown inconsistent results, and this association seems to vary with age at measurement (mid-life [< 65 years] or later life [≥ 65 years]) and follow-up duration
Causal relationships could not be assessed in this study, and reverse causation should also be considered. For example, because TC levels are biomarkers of malnutrition, patients with PD who have low TC levels in the under-/normal weight group may be malnourished, which subsequently leads to poor cognitive outcome. In addition, a recent study showed that familiar patients with PD, particularly those with a glucocerebrosidase (GBA) mutation, have lower cholesterol levels than healthy controls and patients with sporadic PD. Considering the fact that GBA is associated with poor cognitive performance and the risk of PDD, poor cognitive outcomes in patients with PD and low TC levels in the under-/normal weight group may be attributed to underlying genetic risk factors.
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adssx
#108
In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation 2024
We found that both rapamycin and CTEP induced a significant reduction of α-syn fibrils in SH-SY5Y cells and this effect was associated with a reduction in mTOR signaling and enhancement in autophagic pathway factors. These data support the possibility that CTEP (or rapamycin) might be a useful pharmacological approach to target abnormal α-syn accumulation by promoting intracellular degradation or enhanced clearance.
And another paper about another immunosuppressant, tocilizumab: Researchers identify immunomodulatory drug as a potential treatment for Parkinson’s disease
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adssx
#109
Recent articles of various quality but pointing to the same direction: telmisartan seems good for PD.
Expect clinical trials of telmisartan in PD soon…
I am interested in any papers or animal trials related to Parkinson’s or even any anecdotal evidence of benefit of Rapamycin in Parkinson’s.
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It seems like it may provide some benefit. I recommend you hunt around on Pubmed…
There appears to be some linkage between age-related essential tremors and Parkinson’s disease.
FWIW:
Before I started rapamycin, I am 82 years old, I was experiencing age-related essential tremors. After a few months of rapamycin, they completely disappeared. This was something I was not expecting and did not notice it until it occurred to me that my hands were not shaking when eating.
This study was of course on mice, but it certainly gives some hope.
“Rapamycin can effectively alleviate symptoms of PD”
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