#635

This is why I get stressed about identifying causes. If the cause can be mitigated then we end up with fewer symptoms to worry about.

Hence if the cause is a shortage of melatonin increasing melatonin levels (at the right time and ideally in the right place, but otherwise systemically) should reduce the effects. The problem, however, is that if the problem results in damage to mtDNA simply increasing melatonin levels won’t necessarily fix the mtDNA even if it stops it being damaged as quickly.

Research that would be useful is more of a study of CSF levels. It would be possible to see if blocking the pineal recess in an animal model causes Parkinsons for example.

I would be inclined to see what further study could be done in some way of CSF melatonin levels. The problem is that this varies from place to place in the CSF and the best places to measure are also the hardest places to measure.

1 Like
#636

If that hypothesis has some truth in it, then interventions that can’t cross the BBB (like rapamycin, immunosuppressants, etc.) could work to prevent the onset of the disease as the vagus nerve is not protected by a BBB.

3 Likes
#637

I don’t know if low CSF levels of melatonin are the cause of PD but there’s an easy way to check if melatonin is neuroprotective:

Sleep disturbances are an early symptom of PD. Especially rapid eye movement (REM) sleep behavior disorder (RBD). People with RBD act out their dreams. The vast majority of people with RBD develop PD or DLB in the 10 years following their RBD diagnosis.

The first line treatment of RBD is melatonin: Clinical trials in REM sleep behavioural disorder: challenges and opportunities 2020

Melatonin, for its more favourable side effect profile, is frequently preferred as initial therapy for RBD. In higher doses (6 to 18 mg at bedtime) melatonin improved frequency and severity of RBD symptoms in up to 70% of patients, as documented in several observational studies. Lower doses (2 mg slow release and 3 mg immediate release) in conjunction with a ‘30 min prior to bedtime, always at the same clock time’ dosing regimen showed improvement in over 90% of patients with iRBD in open-label trials. Unfortunately, a recent placebo-controlled trial using extended-release melatonin was also negative. The mechanism of action of melatonin in RBD is unclear, but the persistent effect after melatonin discontinuation is hypothesised to be due to action on the circadian system. Clinical synucleinopathies are mostly accompanied by a substantial dysfunction of the circadian system. Considering that endogenous melatonin signalling is dampened in synucleinopathies, one can hypothesise that melatonin may improve RBD via a restructuring and resynchronisation of circadian rhythmicity, a hypothesis that needs to be further studied.

The part in bold cites: A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder 2010

Patients received placebo and 3 mg of melatonin daily in a cross-over design, administered between 22:00 h and 23:00 h over a period of 4 weeks.
Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (–16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment).

Improvements after a discontinuation and a washout period hint at neuroprotection. So, I don’t know why melatonin is only considered symptomatic.

Also: could extended-release be worse than immediate release @John_Hemming? The XR trial failed: Prolonged–release melatonin in patients with idiopathic REM sleep behavior disorder 2020

In this 4-week, randomized, double–blind, placebo–controlled pilot study, 30 participants with polysomnography–confirmed iRBD were assigned to receive PRM 2 mg per day, PRM 6 mg per day, or placebo. Medication was administered orally 30 min before bedtime.
Our findings suggest that PRM may not be effective in treating RBD–related symptoms within the dose range used in this study. Further studies using doses higher than 6 mg per day are warranted.
Although the difference in the RBDQ-KR Factor 2 score decreased from 36.4 to 31.8 at 4 weeks after treatment with PRM 6 mg/day, the standard deviation was relatively high and its p → P value did not show a trend toward statistical significance (P = 0.477).

This XR trial also failed: Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s disease: A Randomised Controlled Trial 2019, “Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD.”

It should also be easy to look at longitudinal data: are people with RBD who take melatonin less likely to convert to PD than those who do not? Is there a dose–response relationship?

1 Like
#638

It’s remarkable how little we actually know about both PD and the mechanism of Rapamycin on the brain.

BBB integrity seems to be an important factor, and Rapamycin might impact this, as might Omega 3 fatty acids.

Here is one article on that issue.
Samuel Barnes and Gary E Fraser - 2021 - Omega-3 fatty acids are associated with blood-brai.pdf (7.7 MB)

Rhonda Patrick has an interesting discussion on needing to potentially move over to Omega 3’s that are in Phospholipid form in inidividuals with ApoE4’s, I suspect the same is likely true for PD.

1 Like
#639

We need to understand why DHA supplementation causes depression. And yes DHA needs to be in the brain because high serum DHA is associated with a HIGHER risk of dementia: The shift in the fatty acid composition of the circulating lipidome in Alzheimer’s disease 2024

Higher levels of docosahexaenoic acid in CSF were associated with a lower risk of MCI-to-AD progression.
Higher levels of docosahexaenoic acid in plasma were associated with a greater rate of MCI-to-AD progression.
These observations were also confirmed by Arellanes et al. who demonstrated that only a small percentage of plasma DHA is transported to CSF and that APOE ɛ4 is associated with reduced delivery of this FA to the brain. These findings indicate that DHA concentrations in plasma and CSF are affected by APOE isoforms. A recent investigation has demonstrated that the APOE ɛ4 isoform disrupts BBB function in the hippocampus and medial temporal lobe compared to the other APOE isoforms (ε2/ε3). A large percentage of our progressive MCI patients were APOE ɛ4 carriers (63%), and we found a significant difference in the plasma levels of DHA between carriers and noncarriers of APOE ɛ4 (p = 0.012). Therefore, our results may indirectly indicate a disruption in the transport of DHA from plasma to CSF. In agreement with our hypothesis, Coughlan et al. reported an inverse association between serum DHA levels and spatial navigation performance in APOE ɛ4 carriers. The existence of deficiency in DHA transporters across the BBB is another possibility that may have led to this result. Major facilitator superfamily domain containing 2A (MFSD2A) transports DHA in the form of lysophosphatidylcholine across the BBB. A recent study demonstrated progressively lower blood levels of this transporter in mild and severe AD patients compared to controls. Therefore, it is possible that more rapidly progressing MCI patients have lower levels of transporters, which, in turn, would limit DHA access to the brain (CSF) but increase DHA levels in the blood.

This might align with Rhonda Patrick’s theory.

1 Like
Predicting Alzheimers & Dementia (and minimizing risk)
#640

Unfortunately, it looks like Rhonda Patrick is wrong based on this article just published by a Canadian team: Providing lysophosphatidylcholine-bound omega-3 fatty acids increased eicosapentaenoic acid, but not docosahexaenoic acid, in the cortex of mice with the apolipoprotein E3 or E4 allele

And also this French paper: Investigation of Lysophospholipids-DHA transport across an in vitro human model of blood brain barrier 2024

Researchers principally studied the cerebral accretion of Lysophosphatidylcholine (LysoPC-DHA), the furthermost vital Lysophospholipid-DHA (LysoPL-DHA) in blood plasma. Nevertheless, the cerebral bioavailability of other LysoPL-DHA forms including Lysophosphatidylethanolamine (LysoPE-DHA), and Lysophosphatidylserine (LysoPS-DHA) were not extensively examined even though their vital biological functions in the brain.
Furthermore, LysoPS-DHA exhibited the highest intracellular accumulation (10.39 ± 0.49 %) in hBLECs in comparison to all other tested lipids. Finally, differences in 3D structures and molecular electrostatic potential maps calculation of LysoPL-DHA could explain the dissimilar cerebral uptake of LysoPL-DHA. Altogether, our findings raise the novel hypothesis that LysoPS-DHA may represent a preferred physiological carrier of DHA to the brain.

1 Like
Predicting Alzheimers & Dementia (and minimizing risk)
#641

A video of Nick Norwitz on ketones for PD. (might reduce progression)
He did RCTs on PD in his PhD so his point of view might be interesting. Ketones are already known to be useful for other brain issues.

#642

The KD is a high-fat, low-carbohydrate diet, which, among other mechanisms [36], may circumvent bioenergetic deficits in PD where affected neurons are unable to efficiently utilize glucose for energy production but likely continue to be able to use ketone bodies such as body beta-hydroxybutyrate, generated in response to a high-fat, low-carbohydrate diet [37]. Ketone bodies may enable neurons to feed electrons into the mitochondrial respiratory chain at complex II, bypassing PD-related deficiencies in complex I metabolism [38]. Four recent RCTs have investigated the feasibility, safety and short-term efficacy of KDs in PD [36]. In an 8-week pilot study comparing a KD to a low-fat diet in 38 participants with PD, both groups showed improvement on all four parts of the UPDRS, with the KD group showing greater improvement in Part I scores [39]. However, worsening tremor and/or rigidity was noted in the KD group 1–4 weeks into the diet intervention, leading to two participant withdrawals. In an open-label, non-controlled pilot study of 16 PD participants on a 12-week KD intervention, significant improvements were seen in UPDRS Part I and total Parkinson Anxiety Scale scores [40]. An 8-week study comparing a ketogenic (n = 7) versus high-carbohydrate (n = 7) diet in individuals with PD and mild cognitive impairment reported improvements in lexical access and memory in the ketogenic diet arm [10]. Another study of 68 participants with PD reported improvements in voice quality following three months of a ketogenic diet [41].

Still, ketones are interesting and trial will soon start about that. That’s also why I think that SGLT2 are great (they increase ketogenesis).

4 Likes
#643

Normal krill oil doesn’t seem to work either in APOE4 mice: LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4 2021

image

We next determined whether the higher plasma DHA and LPC-DHA levels in mice treated with LT-krill oil diets translated to higher brain levels, and we focused on the hippocampus due its role in learning and memory. APOE, sex, treatment, treatment × APOE genotype, and treatment × sex all impacted hippocampal DHA levels (Figure 1C). For independent effects, DHA levels in the hippocampus were lower with APOE4 compared with APOE3, in females compared with males, and followed LT-krill oil > krill oil = control. The treatment × APOE genotype interaction was likely driven by the fact that that krill oil alone enriched hippocampal DHA levels in APOE3-TR but not APOE4-TR mice by 12% and that for every treatment DHA levels were higher in APOE3-TR mice. For example, the magnitude of hippocampal DHA enrichment was greater in APOE3-TR (1.8-fold) than in APOE4-TR mice (1.5-fold) for LT-krill oil diets (Figure 1C), consistent with plasma levels of LPC-DHA (Figure 1B, right).

So if I understand correctly, as of today, supplements are all useless to increase brain DHA in people with APOE4?

1 Like
Predicting Alzheimers & Dementia (and minimizing risk)
#644

I posted this in the dementia/AD thread:

But I’m crossposting it in this thread on account of the pop-sci writeup:

Evidence expanding that 40Hz gamma stimulation promotes brain health

Which contains this:

“Indeed the review points to studies at MIT and other institutions providing at least some evidence that GENUS might be able to help with Parkinson’s disease, stroke, anxiety, epilepsy, and the cognitive side effects of chemotherapy and conditions that reduce myelin such as multiple sclerosis. Tsai’s lab has been studying whether it can help with Down syndrome as well.”

3 Likes
#645

A case of prazosin in treatment of rapid eye movement sleep behavior disorder 2024

We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out.
Symptoms of DEB continued despite gradual up-titration of the melatonin dose from 3 mg to 9 mg at bedtime.
Prazosin was initiated at 1 mg at bedtime and gradually increased (to avoid orthostatic hypotension) to 5 mg at bedtime. With the addition of prazosin 5 mg at bedtime, DEBs greatly improved except for occasional brief episodes of mild sleep talking. As his DEB symptoms improved, the patient (without the knowledge of the prescribing physician) reduced his prazosin dose to 1 mg at bedtime. Shortly thereafter, DEBs returned, and he again jumped out of bed during sleep, fell, and sustained a shoulder injury. Prazosin was again gradually increased to 5 mg at bedtime, with resolution of large motor movements during dreaming. The patient has been maintained on prazosin 5 mg and melatonin 9 mg at bedtime for the past year and has not had any DEB except occasional brief episodes of sleep talking. To determine the effect of prazosin alone vs prazosin and melatonin combination therapy, we gradually discontinued melatonin. The patient’s DEBs remained optimally controlled without change in the prazosin-alone therapy. As a result, the patient has since been on prazosin alone.

Terazosin, of the same family as prazosin, was found to increase serum citrate levels: A pilot dose-finding study of Terazosin in humans 2024

A trial of terazosin in PD is about to start in the UK.

If prazosin also increases citrate levels (I think it does as both prazosin and terazosin activate PGK1 and enhance glycolysis) then the potential synergy between melatonin and prazosin is interesting @John_Hemming.

Lewy Body / Parkinsons
#646

Citrate levels, however, are a direct driver of cytosolic acetyl-CoA, whilst melatonin prevents mtDNA damage.

From a sleep perspective, however, melatonin is a hormone rather than an anti-oxidant (of course it is both).

1 Like
#647

UK’s First Patient to Use Parkinson’s Implant

He was diagnosed at 33, so early onset PD. Seems the implant is working brilliantly. Sometimes complete symptom resolution is good enough for QOL improvement back to almost normal, at least for a time.

2 Likes
#648

However, I think it can actually be reversed and/or stopped as well.

1 Like
#649

You cannot reverse the lost neurons I’m afraid.

But theoretically you could stop the degeneration process + improve symptoms (including with aDBS). That would solve the problem, especially if diagnosed early.

2 Likes
#650

Yes, that is what I was thinking, the lost neurons are not recovered. And I don’t clearly see how this can completely stop further deterioration, since that’s a biochemical process. Stimulation might be helpful, but how does that influence this process and at what juncture? Of course I’m very happy this is working as well as it is, and hopefully starting early before there is much deterioration might be more beneficial in the long run, so fingers crossed. I wonder how practical it is to implement on a large scale.

#651

A few paper on PD and DNA damage (or defective repair):

  • Defective DNA repair: a putative nexus linking immunological diseases, neurodegenerative disorders, and cancer 2025
  • Aging, cellular senescence and Parkinson’s disease 2025: “DNA damage appears to be a prominent feature of PD neuropathology and may also drive neurodegeneration in the nigrostriatal pathway. Histological analysis of SNpc tissue from human PD subjects shows an increase in dopaminergic neurons and microglia with γH2A.X foci, a marker for DNA damage. Additionally, El Saadi et al. recently showed that dopaminergic neurons in the SNpc have relatively high baseline levels of genomic instability in mice. Low concentration infusion of paraquat into the SNpc also elicits genomic instability in neurons, with dopaminergic neurons exhibiting enhanced sensitivity to this PD-linked toxin. […] Treatment of primary neurons with α-synuclein PFFs also induces DNA damage which appears to be driven by accumulation of nitric oxide. Interestingly, DNA damage can subsequently activate PARP-1, leading to the accumulation of cytosolic poly-ADP-ribose (PAR) polymer. […] Activation of PARP-1 via DNA damage can lead to a type of controlled cell death called parthanatos, which could be a major contributor to dopaminergic neurodegeneration in PD. […] Cross talk between DNA damage and PD: Environmental toxicants are an important factor in the pathogenesis of sporadic PD. Notably, many PD-related toxicants can induce genomic DNA damage and can eventually lead to DNA damage-dependent dopaminergic neurodegeneration. Whether cellular senescence contributes to this process is worth exploring. Mutations in familial PD-linked genes, including SNCA, LRRK2, parkin, and DJ-1 can also cause defects in DNA damage repair pathways. Disruption of DNA damage repair pathways may partially explain the accumulation of DNA damage in PD subjects. Additionally, mitochondrial DNA (mtDNA) damage, can produce reactive oxygen species (ROS), which can further damage genomic DNA, RNA and proteins, potentially contributing to PD neuropathology.”
  • DNA damage and its links to neuronal aging and degeneration 2025
  • DNA Damage and Parkinson’s Disease 2024
  • Association Between Occupational Pesticide Exposure and Parkinson’s Disease Risk: An Observational Study In The South Indian Population 2024: “Research by Alves et al. demonstrated that workers exposed to complex pesticide mixes exhibited DNA damage as revealed by the comet assay. Additionally, soybean field workers exposed to a cocktail of pesticides reported increased DNA damage measured by the comet assay and other biochemical markers.”
  • Exploring Mitochondrial DNA Damage in Neuronal Complex I Deficient Parkinson’s Neurons 2024
  • Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression 2024: “Our findings revealed that PD patients exhibit disrupted DNA repair pathways and biased suppression of longer transcripts, indicating the presence of age-related, transcription-stalling DNA damage. Notably, this DNA damage signature was only detected in patients with more severe motor symptom progression over a three-year period, suggesting its potential as a predictor of disease severity.”
1 Like
#652

Growing new neurons is the hardest bit. Fixing the mitochondria in remaining neurons is easier. I think HIF can help with neurogenisis, but to be honest the starting priority has to be with the cells that remain.

#653

Targeting the glymphatic system to promote α-synuclein clearance: a novel therapeutic strategy for Parkinson’s disease 2025

The excessive buildup of neurotoxic α-synuclein plays a pivotal role in the pathogenesis of Parkinson’s disease, highlighting the urgent need for innovative therapeutic strategies to promote α-synuclein clearance, particularly given the current lack of disease-modifying treatments. The glymphatic system, a recently identified perivascular fluid transport network, is crucial for clearing neurotoxic proteins. This review aims to synthesize current knowledge on the role of the glymphatic system in α-synuclein clearance and its implications for the pathology of Parkinson’s disease while emphasizing potential therapeutic strategies and areas for future research. The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance. It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson’s disease, as well as the effect of glymphatic dysfunction on α-synuclein accumulation in Parkinson’s disease models. Subsequently, the review summarizes the mechanisms of glymphatic system impairment in Parkinson’s disease, including sleep disturbances, aquaporin-4 impairment, and mitochondrial dysfunction, all of which diminish glymphatic system efficiency. This creates a vicious cycle that exacerbates α-synuclein accumulation and worsens Parkinson’s disease. The therapeutic perspectives section outlines strategies for enhancing glymphatic activity, such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization. Promising interventions include deep brain stimulation, melatonin supplementation, γ-aminobutyric acid modulation, and non-invasive methods (such as exercise and bright-light therapy), multisensory γ stimulation, and ultrasound therapy. Moreover, identifying neuroimaging biomarkers to assess glymphatic flow as an indicator of α-synuclein burden could refine Parkinson’s disease diagnosis and track disease progression. In conclusion, the review highlights the critical role of the glymphatic system in α-synuclein clearance and its potential as a therapeutic target in Parkinson’s disease. It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfolded α-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson’s disease. Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducing α-synuclein deposits and mitigating the progression of Parkinson’s disease.

2 Likes
#654

This is an essay by a poet with PD, her musings about her disease and how she deals with it. There is a little bit about some biochemical aspects, the history of PD and therapeutic approaches (boxing! who knew!), and practical observations about attention and intentionality in symptom control, but really it’s about everything else around, not the science of PD - it’s a poetic look at our cultural environment.

Because this is obviously not “science”, if you find it “noise”, please feel free to remove this post! I posted it here, because I personally found it quite moving - but YMMV:

Beware the man whose handwriting sways like a reed in the wind

2 Likes