#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.

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#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.

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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.

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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).

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#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?

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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.”

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#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).

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#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.

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#648

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

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#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.

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#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.”
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#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.

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#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

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#655

Libyan, Egyptian, Jordanian paper:

Rheumatoid arthritis drugs and the risk of Parkinson’s disease – a meta-analysis 2025

26 studies (15 case-control and 11 cohort) were included in the analysis with a total number of 4,321,104 participants including 150,703 PD cases. Analysis showed a statistically significant lower risk of developing PD among individuals who received corticosteroids (RR 0.80, 95% CI 0.77 – 0.84, P<0.00001) and DMARDs (RR 0.69, 95% CI 0.55 – 0.86, P<0.001). Subgroup analysis by individual drugs showed a decreased risk with dexamethasone (RR 0.69, 95% CI 0.60 – 0.79, P<0.00001) and hydroxychloroquine (RR 0.77, 95% CI 0.66 – 0.90, P<0.001). Our findings showed that individuals who were treated with corticosteroids (especially dexamethasone) and DMARDs (especially hydroxychloroquine) have reduced risk of developing PD compared to those not receiving these medications.

Others:

  • NSAIDs (aspirin, ibuprofen, diclofenac, and naproxen, etc.): 0.96 (0.83–1.11), p-value=0.57
  • Acetaminophen: 1.09 (1.01–1.18), p-value=0.02
  • Methotrexate: 0.92 (0.78–1.08), p-value=0.29

(There are mistakes in some parts of the text, double check with the figures)

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#656

Lots and lots of things will affect the mitochondria. Those of those things that get through the BBB will also affect the mitochondria in the brain.

1 Like
#657

Interesting things around vitamin B5:

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain 2024

Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum.
Despite the rarity of pantothenic acid deficiency, significantly lower levels of dietary pantothenic acid intake have been observed in individuals with PD in comparison to healthy individuals, with pantothenic acid levels displaying clinical importance in predicting the incidence of PD; in this study, UPDRS scores were also negatively correlated with pantothenic acid intake . As such, decreased dietary pantothenic acid intake may be associated with both PD incidence and severity. Pantothenic acid intake has also been associated with amyloid-β burden in individuals with mild cognitive impairment (MCI), indicating a potential link with AD. As such, despite a lack of outright pantothenic acid deficiency, supplementation may be a potential therapeutic option for the treatment of these neurodegenerative diseases.
Non-CNS disturbances in pantothenic acid and related pathways have also been observed in neurodegenerative diseases; for instance, pantothenate and CoA biosynthesis has been found to be disturbed in LC–MS metabolomics analyses of PD and healthy plasma and serum samples, with decreased pantothenic acid levels observed even in the early stages of PD. The presence of pantothenic alterations in the PD gut is disputed, with some studies showing no changes in stool sample levels while others have shown decreases, and with another study showing positive associations between fecal pantothenic acid levels and non-motor symptoms in PD. Both increased and decreased serum pantothenic acid levels were reported in a study of 50 individuals with non-specific dementia, and pantothenate and CoA biosynthesis pathway dysregulation has been reported in a multi-omic investigation of the AD brain, blood, and cerebrospinal fluid. As such, pantothenic acid disturbances may be a wider, multi-system issue that does not only affect the brain in neurodegenerative diseases; if so, this could make the administration of pantothenic acid supplementation a more straightforward and viable option for therapeutic trials.

Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism 2022

Previous studies revealed D-pantethine (D-pan), a close relative of vitamin B5 (pantothenate) and a metabolic substrate for CoA synthesis, could bypass PANK in CoA synthesis in a currently unclear biochemical pathway, and nicely rescue multiple animal PKAN models. We administered D-pan through diet to WT and PINK1 LOF flies. Similar to the genetic studies, D-pan treatment significantly rescued PINK1 LOF phenotypes, including abnormal wing posture (Fig. 3a and Supplementary Fig. 3b), flight activity drop (Supplementary Fig. 3c–e), thoracic ATP level reduction (Fig. 3b), mitochondrial aggregation (Fig. 3c–f) and DA neuron loss (Fig. 3g). We also observed elevated CoA and acetyl-CoA levels (Fig. 3h, i), which was consistent with the previous report and correlated well with the improved mitochondrial respirations (Supplementary Fig. 3f-3h). Again, we did not find any evidence of promoting complex-I activity (Supplementary Fig. 3i) or assembly (Supplementary Fig. 3j) by D-pan alimentation.

Should one use pantothenic acid (as calcium pantothenate) or pantethine? Here they note: “Although pantethine is considered the more biologically active form of vitamin B5, it is less stable than pantothenic acid and tends to degrade over time if it is not kept refrigerated”

Calcium pantothenate increased lifespan in rodents apparently: https://genomics.senescence.info/drugs/drug_details.php?compound_name=Calcium pantothenate

Pantothenic acid did the same in flies: https://genomics.senescence.info/drugs/drug_details.php?compound_name=Pantothenic acid

High B5 levels seem to be associated with better cognitive and motor symptoms:

High serum B5 seems to increase all-cause mortality though: Association between plasma Vitamin B5 levels and all-cause mortality: A nested case-control study 2022

People supplementing with pantothenic acid report better stress management and less oily skin :thinking: https://iherb.com/pr/now-foods-pantothenic-acid-500-mg-250-veg-capsules/326

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Vitamin B5: pantethine vs pantothenic acid (calcium pantothenate)
Vitamin B5: pantethine vs pantothenic acid (calcium pantothenate)