Well, I think you might have snuck into my house and gone through my cabinets.
Yes, I take Simvastatin. My cholesterol levels were pretty high, probably because I eat keto, and I have been eating keto since my diagnosis. (The statin works though–my levels are good now.) And, because of the statin I also take coQ10.
And thinking on it, you asked about the one thing I would not give up and I would probably say that: my diet. Also, before rapamycin I used to do four-day fasts. I still practice time-restricted eating, sometimes OMAD. And now I take Acarbose, which allows me to cheat a little…berries and such. I wear a CGM, not all the time, but enough to have a sense of what I can eat.
For whatever reason, I have been VERY lucky: I sleep well, and I am not particularly depressed. My right arm is stiff, and when I am nervous, my right hand shakes. Of course I get instantly nervous whenever I want to show someone how unaffected I am.
This was not expected as ambroxol has been shown to increase macroautophagy in human neuronal cells containing GBA1 mutations. The lower dose or different type of neuron might account for the discrepancy. […] The mechanism by which TFEB is activated following ambroxol treatment in mouse cortical neurons requires further investigation. For example, is it a compensatory mechanism due to the inhibition of macroautophagy following ambroxol treatment?
High-dose NR looks interesting, higher doses may be needed if it does not cross the BBB well?
Vitamin B3 supplement shows early promise for Parkinson’s 2022: “1000mg of nicotinamide riboside daily for 30 days […] The supplement also showed promising signs that it may improve metabolism and reduce inflammation in the brain, which could have protective effects in the brain. And the participants who showed the greatest increase in NAD levels also showed some mild improvements in their Parkinson’s symptoms.”
NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease 2023: “NR 1500 mg twice daily […] The trial met all prespecified outcomes. NR therapy was well tolerated with no moderate or severe adverse events, and no significant difference in mild adverse events. NR therapy was associated with clinical improvement of total MDS-UPDRS scores. However, this change was also associated with a shorter interval since the last levodopa dose. NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels.”
Nicotinamide riboside failed in the ITP in 2016 (1000 ppm, started at 8 mo, 1000 ppm for mice means about 1,400 mg for a 60 kg human if I’m not wrong). However, interestingly, the ITP still decided to test NR again in 2022, this time in a higher dose of 2400 ppm (so about 3,333 mg for a 60 kg human) and combined with metformin. I don’t know what their reasoning was, but there might be something here for PD in glycemic control (with low-dose metformin, GLP1RA, or SGLT2, probably to protect the neurons?) + NR (to promote neurogenesis?).
@TomParkinson: I think you’ve been testing high-dose NR for a few weeks, how is it going?
I wonder what else could promote neurogenesis, some ideas:
The initial theory about ambroxol (as far as I know) was that it only acted as a chaperone for missing/improperly-folded glucocerebrosidase. Glucocerebrosidase helps to digest particular sugars in the lysosomal membrane when it inverts and forms little vesicles of cellular garbage for digestion. If the vesicles aren’t digested, the lysosomes eventually fill up with their own membrane bits–no room left for anything else. It sure sounds like ambroxol would improve macroautophagy, doesn’t it?
And there seemed to be some evidence that many people with PD have low G-Case levels, whether or not they have a GBA mutation. I’m not sure I would bother if I didn’t, though.
BUT, just recently I read that ambroxol does something else, at the mitochondrial level. I think Simon Stott wrote an article on it in Science of Parkinson’s. I need to dig that paper up. And yes, if it’s a dose thing, I take over a gram a day.
Additionally, we noted previously unrecognized decreases in the naive B cell compartment in the defined PD and Prod patient group. Over time, we observed the proportion of innate immune cells in PD blood increased, but the proportion of adaptive immune cells decreased. We identified decreases in T and B cell subsets associated with REM sleep disturbances and early cognitive decline. […] Neutrophils can increase the permeability of the blood-brain barrier (BBB), giving all immune cells increased access to the CNS […] Comparing PD to HC, we found an increase in neutrophils and a decrease in monocytes and eosinophils. In PD patients, there is an increase in neutrophils and monocytes over time, with a consistent trend in the Prod group as well. We observed a slight decrease in monocytes in more symptomatic PD patients. […] We identified a strong decrease in CD4+ memory T cells and naive B cells in clinically defined and prodromal PD. In PD patients, we see a significant decrease in many adaptive immune cell populations over time, including all naive lymphocytes and memory T cells. In the prodromal group, there is a significant decrease in the naïve lymphocytes but not a significant trend in the memory compartments.
How can rapamycin impact the above? I checked a bit on the forum and most users report no changes in blood measures of neutrophils, lymphocytes, monocytes, eosinophils & basophils. (e.g., Concerns about immune suppression - #9 by RapAdmin ).
Of the 10 classes related to a lower risk of PD, there were 2 classes associated with a reduced PD risk of 30% or more, which were other nervous system drugs (N07) and antineoplastic drugs (L01). […] Similarly, the lower previous use of antineoplastic drugs (L01) among PD cases might also be related to a lower risk of smoking-related cancers in this group.
I’ve recently looked in the forum for data re: neutrophils because mine are elevated (not the absolute count but the %). In my case that’s because of a near chronic bladder infection I’ve been dealing with and only recently identified as such (the symptoms were UTI after UTI after UTI which basically means it never went away). In any case I looked specifically for that metric as I’m thinking more in terms of forensic clues for myself.
And rapa users are reporting DECREASED neutrophils while on rapa. This is anecdotal but I did hunt out pretty extensively on the forum and it seemed to be clearly a trend.
Continuation of lipophilic statins like atorvastatin is associated with decreased risk of Parkinson’s:
Results: Among the 43,810 statin initiators, the incidence rate for PD was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of PD (hazard ratio [HR] 0.42 [95% confidence interval 0.27–0.64]) as compared with statin discontinuation, which was not modified by comorbidities or medications. There was no association between hydrophilic statins and occurrence of PD. Among lipophilic statins, a significant association was observed for simvastatin (HR 0.23 [0.07–0.73]) and atorvastatin (HR 0.33 [0.17–0.65]), especially in female users (HR 0.11 [0.02–0.80] for simvastatin; HR 0.24 [0.09–0.64] for atorvastatin). As for atorvastatin users, the beneficial effect was seen in the elderly subgroup (HR 0.42 [0.21–0.87]). However, long-term use of statins, either lipophilic or hydrophilic, was not significantly associated with PD in a dose/duration-response relation.
Our study provides evidence that statins, especially atorvastatin, can reduce the risk of PD.
Possible prevention but not treatment?
This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson’s disease.
Yeah, probably doesn’t work for treatment…
Findings In this randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial involving 235 participants from 23 sites within the UK, participants in the simvastatin group had an additional deterioration in Movement Disorder Society Unified Parkinson Disease Rating Scale part III scores while not taking medication at 24 months compared with those in the placebo group (−1.52 points).
Some of the articles you shared are old. As you wrote, statins don’t work as a treatment; they cannot slow down the progression of Parkinson’s even in super early cases of PD who are not yet on med. It actually seems that high LDL is protective against PD (like obesity, diabetes, smoking and drinking coffee…) and that some statins might even be detrimental:
This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson’s disease.
The use of statins was lower in patients who developed PD and higher in patients who developed DLB compared to patients with AD. In patients with PD, the use of statins was associated with the development of dementia in the 5 years following PD diagnosis.
Friends of mine who are Parkinson’s researchers wonder whether the protective effect of statins seen in some older studies might just be linked to an increase in glucose levels and some confounders like diabetes and obesity: Statins use => (associated to or causing) More diabetes => Protection against PD. That’s a pure assumption; they’re crunching massive datasets at the moment to confirm or infirm the hypothesis.
Statins direct Acetyl-CoA away from creating cholesterol. This provides more Acetyl-CoA for other purposes. Other purposes include acetylation of the histone.
An alternative to inhibiting the creation of cholesterol is to increase the amount of Acetyl-CoA.
Atorvastatin, one of the lipophilic statins, did have a good association, and it has a lower incidence of diabetes compared to rosuvastatin, which is hydrophilic, about half the rate.
A good association wasn’t dependent on LDL lowering but statin use, so it might be pleiotropy driving the association.
If nicotine fails as treatment, it’s not surprising to me that statins do as well. If you believe nicotine works as prevention.
The therapeutic potential of non-nicotine components of smoke is suggested by studies supporting multiple alternative mechanisms ranging from monoamine oxidase inhibitors to gut microbiome disruption to antioxidant response induction by chronic exposure to low levels of carbon monoxide.
More than 200 years since the publication of James Parkinson’s An Essay on the Shaking Palsy (1817), many uncertainties regarding the progressive neurological disorder now known by his name remain. This issue of The Lancet carries our first-ever Series dedicated to Parkinson’s disease, which includes an exploration of some of the outstanding questions around the epidemiology, causes, and current treatment options for this disabling and currently incurable condition.
Parkinson’s is second only to Alzheimer’s disease in the list of most common neurodegenerative disorders and, with increasing life expectancies and fewer competing causes of death, its prevalence is expected to increase
The cause of Parkinson’s disease is multifactorial and, although there is consensus among experts that Parkinson’s is an age-related disease, questions regarding the extent to which Parkinson’s can be attributed to external drivers (such as pollutants) do not yet have clear answers.
I agree, and I think that curing Parkinson’s might be the first “easy” step in the long quest to cure ageing…
(Among the authors of the series, there’s Tom Foltynie, who’s behind the trials of exenatide for Parkinson’s btw)
My tl;dr after skimming through it (let me know if I made a mistake):
Mediterranean: good
MIND diet: good
Vegan: neutral, quality matters (“A recent UK biobank analysis found an association between a healthful plant-based diet and reduced PD risk (HR = 0.78 (95% CI: 0.61–0.99)), whereas an unhealthy plant-based diet was associated with a higher risk to develop PD (HR = 1.38 (95% CI: 1.08-1.74))”)
Keto: potential benefits but challenging and safety unclear
Dairy: bad? because of pesticides?
Alcohol: good? (but there might be confounders)
Coffee: good (but why?)
Vit D: useless?
Vitamin E and omega-3 fatty acids: good?
Vitamins B6, B9, and B12: might be good?
Vitamin B1:
Vitamin C: enhances levodopa absorption
Citicoline:
Fiber, prebiotics, and probiotics: might be good? but huge heterogeneity in the bacterial strains, dosages, treatment durations, and methods of administration between included trials
I’m not a doctor and this is in no way constitutes medical advice…but have you considered dapsone, it’s a really old drug discovered in 1908, and over the century has been used for different purposes in humans. The reason I mention it is, that it seems to up-regulates Parkin levels which may be useful in the treatment of Parkinson’s disease.
Blockquote
Disturbance of protein degradation by the ubiquitin-proteasome system might have a critical role in neurodegeneration. Parkin is a ubiquitin-protein ligase involved in protein degradation as collaborating with the ubiquitinconjugating enzyme UbcH7. PD patients show loss of this ubiquitin-protein ligase activity [66, [67]
Interestingly, long-term treatment with dapsone (2 mg/kg) restores parkin levels through its up-regulation. Furthermore, chronic treatment with dapsone prevents neuronal loss related to normal aging and reduces oxidative stress in mice with MPTP-induced PD [[68]
I assume by 2030 (hopefully way earlier), everyone will get a PD blood test at age 40, then every five years. And if the test is positive, they’ll start taking whatever drug to slow down the progression (e.g., exenatide, empagliflozin, telmisartan, GlyNAC, etc., who knows?).
This is candesartan, really close to telmisartan, but the trial had to be terminated early because of the Covid pandemic, still, it’s safe (even though 1/ many people with PD have low BP and 2/ they tested a high dose, the lowest dose would have been 2 mg) and interesting result on apathy, a common pre-PD symptom: “In terms of efficacy, candesartan 8 mg for 24 weeks did not show positive effects for the main cognitive primary endpoint (PD-CRS). However, a significant and positive effect on apathy was observed in the active treatment group, mainly driven by PDD subjects.” (A randomized clinical trial of candesartan for cognitive impairment in Parkinson’s disease 2023)
“By leveraging the National Health Insurance Research Database, a Taiwanese study [78] found that the dementia risk was lower in telmisartan users compared with other ARB users (hazard ratio, 0.72; 95% CI, 0.53 to 0.97; p = 0.030). The authors attributed this to the greater effect of telmisartan on increasing PPAR-γ expression.” (Angiotensin Receptor Blockers and Cognition: a Scoping Review 2023)
