Parkinson's disease

[AnUser]

@adssx

We’ve already discussed this, so I don’t understand why you bring back this nonsense, see this recent review in the official journal of the International Parkinson and Movement Disorder Society: Parkinson’s disease - #77 by adssx

@adssx

This is the editorial commenting on “Transdermal Nicotine Treatment and Progression of Early Parkinson’s Disease”, one of the trials that ruled out nicotine.

I don’t know how generalizable a change in Total UPDRS score is for preventing the disease in the first place?

[adssx]

Parkinson’s patient moves freely again after world-first implant of lab-grown cells into his brain 2024

Parkinson’s patient Thomas Matsson was the first in the world to receive 7 million lab-grown brain cells in 2023. Today, he can smell and play sports.
“The vision is that it could be given as a one-time treatment and the hope is that the patients can reduce their medication, avoid side effects of the drug treatment and get a long-term good motor effect from the cells for life,” Gesine Paul-Visse, a senior physician in neurology at Skåne University Hospital and adjunct professor at Lund University, told Swedish broadcast SVT in 2023 when the first trials started.
So far, five subjects have undergone surgery using the researchers’ lab-grown cells.
Soon three additional patients will receive a double dose, with 14 million brain cells each.
If all goes well with the first eight patients, the research team will continue with larger studies in collaboration with a pharmaceutical company.
“There is absolutely hope. Absolutely there is!” said Paul-Visse as a message to people living with Parkinson’s disease.

[AnUser]

Open label study, but selegiline improved total UPDRS score:

Long-Term Selegiline Monotherapy for the Treatment of Early ... : Clinical...

When is there enough evidence that it might suggest that it prevents PD?

[adssx]

They didn’t do a washout period. Without a washout period, you can’t tell if the effects are disease-modifying (slows down the progression) or just symptomatic.

[AnUser]

Thanks, now I understand why the GLP-1 agonist data is so exciting.

[AnUser]

@adssx

PCSK9 inhibitors might not be better according to this preprint: “Our analysis suggests that the use of HMGCR and NPC1L1 inhibitors may contribute to the transition of PD patients from PIGD subtype to TD subtype, while the use of PCSK9 inhibitors may pose a risk of worsening PD.” (Genetic Associations of Lipid-Lowering Drugs and Parkinson’s Disease: A Mendelian Randomization Study 2024)

HMCGR inhibition showed decrease PD risk in that pre-print.

Genetic variations in HMGCR were significantly associated with a reduced risk of PD (odds ratio [OR] = 0.54, 95% CI 0.34-0.86).

If that’s true I don’t understand why the simvastatin trial had a negative result.

[adssx]

@AnUser

HMCGR inhibition showed decrease PD risk in that pre-print.

The preprint found a decreased risk of one specific PD subtype, not of PD itself. And it’s a preprint (from a random Chinese team if I recall correctly?) and it’s an MR. Other MR studies found a potential causal link between HMCGR inhibition and worse cognition: https://www.sciencedirect.com/science/article/pii/S0735109722053086?via%3Dihub

See also this recent (about low LDL, not HMCGR inhibition): Lipids, Apolipoproteins, and the Risk of Parkinson Disease 2019

[AnUser]

No, it sounds to me like it was overall risk.

The SNP’s seems to have reduced hyperlipidemia and CAD risk as expected:

HMGCR inhibition did change to a more favorable PD subtype in that MR pre-print as well, compared to an unfavorable one:

Another discovery from this study implied that incorporating HMGCR inhibitors may facilitate the shift
of PD patients from the less favorable PIGD subtype to the more favorable TD subtype.

[adssx]

You’re right “Genetic variations in HMGCR were significantly associated with a reduced risk of PD (odds ratio [OR] = 0.54, 95% CI 0.34-0.86). However, variation in HMGCR was associated with an increased risk of the tremor-dominant (TD) subtype compared to the postural instability/gait difficulty (PIGD) subtype (OR = 8.43, 95% CI 2.12-33.52).” If this MR preprint is correct, it contradicts some other published MR studies. Let’s imagine that others are wrong and this one is correct, then the problem might be with statin’s side effects (and not with HMGCR inhibition itself), for instance their negative impact on the gut and GLP-1 levels that seem so important in PD. But that’s pure speculation at this stage. Still, I think people with PD or at high risk might be better off achieving their LDL/ApoB targets with non-statin therapies if they can (ezetimibe, bempedoic acid, PCSK9i, and hopefully soon obicetrapib). If not, it is still better to take statins and avoid a heart attack, even at a low risk of getting PD in the future.

[adssx]

@adssx

• Prefer non-drug treatments for anxiety and depression (e.g., low-dose lithium?)

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…

[adssx]

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.

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.).

[AnUser]

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.

[adssx]

@AnUser

They controlled for diabetes and hypertension, that should probably be a pretty good proxy for BMI.

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)

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

@AnUser

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.

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.

[adssx]

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).

[AnUser]

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).

[adssx]

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.

[AnUser]

@adssx

while one good peer-reviewed MR says low LDL can cause PD

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

[adssx]

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

[adssx]

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?

[AnUser]

@adssx

@AnUser: do you take taurine?

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.