#181

Cure Parkinson’s and Van Andel Institute announce funding for a phase 1 clinical trial of low-dose lithium in Parkinson’s disease

Here’s the trial: ClinicalTrials.gov

This study will examine the effects of lithium 20mg/day compared to placebo on MRI and blood-based biomarkers among 20 early-stage Parkinson’s disease patients.
10mg, 2x/day, 5mg of elemental lithium/capsule

Results are expected in early 2026…

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#182

Related paper: Reduced Prevalence of Parkinson’s Disease in Patients Prescribed Calcineurin Inhibitors 2024

We analyzed electronic health records (EHRs) from patients prescribed the brain penetrant CNI tacrolimus (TAC), the peripherally restricted CNI cyclosporine (CySp), or the non-CNI sirolimus (SIR).
Our results suggest CNIs, especially those acting within the brain, may prevent PD. The reduced prevalence of PD in patients prescribed TAC, compared to patients prescribed SIR, suggests that mechanisms of calcineurin inhibition— other than immunosuppression, which is common to both drugs— are driving the reduction. Therefore, CNIs may provide a promising therapeutic approach for PD.

mTORC1-Dependent Protein and Parkinson’s Disease: A Mendelian Randomization Study 2023

The mTOR pathway is crucial in controlling the growth, differentiation, and survival of neurons, and its pharmacological targeting has promising potential as a treatment for Parkinson’s disease. However, the function of mTORC1 downstream proteins, such as RPS6K, EIF4EBP, EIF-4E, EIF-4G, and EIF4A, in PD development remains unclear. […] The genetic proxy EIF4EBP was found to be inversely related to PD risk (OR = 0.79, 95% CI = 0.67–0.92, p = 0.003), with the results from WM, MR-PRESSO, and MR-RAPS being consistent. […] Our unbiased MR study highlights the protective role of serum EIF4EBP levels in PD, suggesting that the pharmacological activation of EIF4EBP activity could be a promising treatment option for PD.”

Also, the debate about statins and PD continues (@AnUser FYI, I couldn’t add a reply so I’m editing this previous message), and it’s not getting clearer: 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 2024

The inverse association between statin use and Parkinson’s disease risk was significant after adjusting for multiple variables (odds ratio: 0.61; 95% confidence interval: 0.56–0.66). Compared with non-users, the dose analysis revealed varying odds ratios: 1.30 (1.12–1.52) for 1–30 total standard daily doses, 0.77 (0.64–0.92) for 31-90 total standard daily doses, 0.62 (0.52–0.75) for 91–180 total standard daily doses, and 0.30 (0.25–0.35) for >180 total standard daily doses. Statin use among older Japanese adults was associated with a decreased risk of Parkinson’s disease. Notably, lower cumulative statin doses were associated with an elevated risk of Parkinson’s disease, whereas higher cumulative doses exhibited protective effects against Parkinson’s disease development.

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People using low-dose statins have a higher PD risk than statin non-users but people using high-dose statins have a lower risk than non-users? I’m struggling to understand how this could make sense and not be the result of some confounding factors. They don’t address this problem seriously in the paper. But they note later:

Finally, our study was not adjusted for potential confounding factors. The absence of data on BMI, smoking, and alcohol consumption (potential confounders) may have led to an overestimation of the protective effects of statins in our study. We used the E-value to estimate the influence of the unmeasured confounders. If the unmeasured confounders were associated with both statin use and PD risk with an OR of 2.66 or higher, the result was explained by unmeasured confounders.29 Future studies should focus on comprehensive adjustments for these confounding variables to provide a more accurate assessment of the effects of statins.

As we know that low LDL is associated with PD and that this association might be causal, and that high BMI seems protective of PD, this is probably the cofounder: people on high-dose statin are overweight and had high LDL most of their life, which protected them from PD. The negative effect seen at low-dose might be for people with slightly elevated LDL, so who are not protected that much from PD, but who get the negative side effects of statins (glucose dysregulation and gut dysbiosis, that are detrimental for PD).

So I would conclude the exact opposite as the authors based on this paper: it probably confirms that non-statin lipid-lowering therapies should be used first in people with PD or at high risk of (family history, environment, genes, etc.).

#183

They controlled for diabetes and hypertension, that should probably be a pretty good proxy for BMI. I think it would be interesting to figure out if the Simvastatin negative result was because people in the trial switched from PIGD to TD subtype and gave a worse total score in the progress.

#184

Not really. Especially for people with BMI between 25 and 30 (overweight but not obese):

Hypertension and Socioeconomic Status in South Central Uganda: A Population-Based Cohort Study (OK it’s in Uganda but might be generalisable to other populations)

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Type 2 diabetes in East Asians: Similarities and differences with populations in Europe and the United States

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Check Table 3: Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Non-motor symptoms (NMSS, lower is better) increased in the simvastatin group while they decreased in the placebo group. So it’s not only a motor symptom subtype switch I think.

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#186

Yes, they say in the paper they’ll further analyze later. But the point stands: evidence around statins and PD is blurry at best, and while we’re waiting for more evidence, someone with PD or at high risk of might be better of on other lipid-lowering drugs (if these are enough to allow them to reach their targets. Of course they might need statins at some point if their LDL is still too high despite for instance ezetimibe + bempedoic acid).

#187

Since at worst it was neutral in that RCT (“we observed the expected rate of progression … in the simvastatin-allocated group”), it could be argued it is better than other lipid lowering treatments if that MR pre-print publishes. Since at worst it would be neutral, but at best MR studies and observational studies show positive data, while the other lipid lowering drugs afaik have not had RCT showing neutrality and positive MR/observational data (after all absence of evidence is not evidence of absence, when it comes to other lipid lowering drugs).

#188

Failed RCT, negative association studies, but one Chinese preprint MR that says it’s positive (while one good peer-reviewed MR says low LDL can cause PD) => That’s enough to be cautious for me. But of course, facing incomplete data, we all have to make decisions under uncertainty. It’s just that there are so many effective alternative lipid-lowering therapies (ezetimibe, bempedoic acid, and PCSK9i + GLP1-RAs that might help, and also lifestyle interventions) and the science on this is evolving so quickly that I think it’s reasonable (for people with/at risk of PD) to prefer non-statin interventions and potentially reassess in a couple of years.

#189

That’s applicable to all lipid lowering treatments, not only statins.

#190

Yes, that’s why I put this between brackets.

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#191

Diet and the gut microbiome in patients with Parkinson’s disease 2024

Our predicted functional pathway results further strengthen the taxa-based findings; a healthy diet reduces lipopolysaccharide biosynthesis and taurine degradation. […] Our results also suggest that the reduction of taurine degradation in PD patients with higher HEI score may help maintain higher systemic levels of taurine, potentially providing neuroprotective effects on the nervous system with better diet quality. Recent studies have demonstrated that plasma taurine levels are sharply reduced in PD patients and inversely correlated with severity of motor symptoms, supporting the potential neuroprotective role of taurine in PD. Furthermore, in a mouse model, increased taurine degradation was observed in PD mice with fewer Ruminococcaceae. Our findings indicated that a better diet in PD patients was associated with higher levels of Ruminococcaceae family genera, which may support taurine metabolism and lead to reduced degradation of taurine by gut microbiota.

Gut microbiota-associated taurine metabolism dysregulation in a mouse model of Parkinson’s disease 2023

The abundances of microbial transporter and enzymes participating in the degeneration of taurine were disturbed in PD mice. More importantly, taurine supplement is protected from MPTP-induced motor deficits and DA neuron loss. The detection of disturbed taurine metabolism in PD mice suggests a mechanism whereby dysregulation of the microbiota-metabolism axis contributes to the etiology of MPTP-treated mice.

A case for taurine supplementation in PD or PD prevention? @AnUser: do you take taurine?

#192

No not yet, I just added ezetimibe and a bunch of supplements (Zinc picolinate 15 mg, 1 mg methylcobalamin, 3000 IE D3, 400 mg EPA+DHA, 2 tsp Creapure) to rosuvastatin, so I will wait awhile and take some blood tests then add more.

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#193

Just published @AnUser (poke @Neo as well): Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study 2024

PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).
Nonetheless, neither PCSK9 inhibitors nor HMGCR inhibitors were significantly associated with the risk of AD

This time it’s not a preprint. It’s not from the best researchers (Sichuan University…), neither in the best journal (Brain and Behavior). The other Chinese preprint found: “Genetic variations in HMGCR were significantly associated with a reduced risk of PD (odds ratio [OR] = 0.54”[…] However, there was no apparent correlation between genetic variations in NPC1L1 and PCSK9 and the risk of PD." So one of them is wrong… I think the recent one is more likely to be correct as we have a really good MR finding that low LDL is casually linked to PD and it’s confirmed by longitudinal data (again, from good papers).

Also, for AD, although non significant, PCSK9i seems perfectly neutral while HMGCRi trends towards detrimental:

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Also just published (and also from China): Cholesterol Metabolism in Neurodegenerative Diseases

Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. Future direction: Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. Additionally, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptom

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#194

That’s interesting, do you think the genetic data can be generalized to the drug treatments if it also inhibits PCSK9 and HMGCR in the brain?

#195

I don’t know and I don’t think anyone knows. That’s why my strategy at this stage is to reach my ApoB targets with non-statin drugs. Hopefully, obicetrapib will solve this conundrum (wishful thinking? maybe…). I also hope we’ll get more longitudinal, MR, and RCT data on ezetimibe (to confirm or infirm the potential reduced AD risk).

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#196

I try not to trust a Chinese study unless it’s backed up by a western one. They just make stuff up over there to keep their positions. Too many flying pigs, unicorns and monkeys coming out of asses for me to put my faith in a Chinese study. (See Procyanindins as senolytics). I can’t believe how many people have been duped into using grape seed extract over one Chinese study.

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#197

I agree. Still, MR studies are easier to reproduce and check so they’re less likely to be wrong (although here we have an example of one among the two that is wrong…).

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#198

Alchemab identified a target it believes may contribute to disease resistance. Its research explores how the prostaglandin pathway impacts disease progression, using comprehensive genetic and molecular analyses.

Prostaglandins are a group of lipid compounds that have diverse hormone-like effects in animals. They play a crucial role in inflammation and are believed to be involved in the pathogenesis of Parkinson’s disease. Funded by the MJFF, Alchemab’s research will focus on understanding how the prostaglandin pathway influences disease progression and whether modulating this pathway with specific antibodies can provide therapeutic benefits.

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#199

In regard to your earlier post. Looks like others are also pursuing this.

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#200
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#201

Selectively Enhancing Mitophagy to Treat Parkinson’s - Andy Lee

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