Evaluation of the neurotrophic peptide mixture in pathogenetic therapy of patients with Parkinson’s disease
This exploratory, single-group, open-label study investigated 17 patients with Parkinson’s disease (PD) using a pre-post design. Motor and non-motor outcomes were assessed through clinical scales, biochemical and genetic analyses, and machine learning models (Gradient Boosting Machines, Random Forests). After treatment with a neurotrophic peptide mixture, improvements were observed in daily activity (16%), cognition (11%), depression (10% reduction), and reactive anxiety (23% reduction). Biological changes included a 45% increase in platelet δ-granules, higher mitochondrial counts, elevated gene expression (notably BDNF in women, p = 0.046), and modulation of oxidative stress markers (17% reduction in TBARS, 30% increase in GSH). Machine learning identified BDNF and PINK1 expression, along with MOCA and MMSE scores, as key predictors of UPDRS improvement. These findings suggest that neurotrophic peptide therapy may influence clinical, structural, and molecular domains in PD. Larger, controlled trials are warranted to confirm therapeutic potential and clarify associations with cognitive and neurotrophic parameters.
The researchers identified severe dysfunction in the somato-cognitive action network (SCAN)—a brain network essential for planning, coordinating, and executing actions—as the core feature of PD. In patients, this network shows abnormally high functional connectivity with deep brain regions, a signature not observed in other movement disorders such as essential tremor. “Our work shows that the disease is rooted in a much broader network dysfunction,” noted Prof. Hesheng Liu. “The SCAN is hyperconnected to key subcortical regions in PD, and this abnormal hyperconnectivity disrupts not only movement but also related cognitive and automatic functions.”
For too long, we have viewed Parkinson’s through a reductionist lens—a simple shortage of dopamine in a specific corner of the brain. However we can no longer deny that this disease is far more complex than a single chemical deficit could explain.
Yesterday’s paper in Nature from Profs Jianxun Ren, Nico Dosenbach, Hesheng Liu and colleagues, identifies the Somato-Cognitive Action Network (SCAN) as an intriguing structural “map” for what some have long suspected: Parkinson’s is not just a motor disorder; it is a systemic failure of communication.
If Parkinson’s is truly a “SCAN-opthy,” then our goal changes. We are no longer just chasing dopamine; we are tuning the instrument. We are learning to quiet the hyperconnectivity and restore the natural rhythms of the brain.
To test this new treatment approach, the researchers conducted a clinical trial in which 18 Parkinson’s patients received the SCAN-targeted transcranial stimulation for two weeks and they were compared with 18 Parkinson’s patients who received stimulation to another brain region (this was the control group). The SCAN targeting treatment involved four 10-minute stimulation sessions per day with 50-minute intervals in between over the two weeks of the study (Click here to read more about the design of the study).
The SCAN targeted group showed a 56% response rate after two weeks, compared to just a 22% response rate in the control group. Response rate was measured using the standard clinical rating scale (the MDS-UPDRS-III).
Videos of the pre and post treatment performance has been posted on social media (Twitter) – click here, here and here if you would like to view these films.
While more than 30% of patients with Parkinson’s disease (PD) are prescribed statins, the impact of statin use on the progression of PD remains incompletely elucidated. We aimed to comprehensively investigate the impact of statin use on PD progression. We analyzed longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI) to examine associations between statin use and clinical manifestations and cerebrospinal fluid (CSF) biomarkers. Mendelian randomization and Bayesian colocalization analyses were employed to assess genetic relationships between HMGCR inhibition (a proxy for statins) and PD phenotypes. Multi-omics analyses utilized postmortem substantia nigra RNA-seq data and CSF proteomics from living patients to explore potential mechanisms. In the PPMI cohort, statin use was associated with a faster cognitive decline among PD patients during longitudinal follow-up, which was partially mediated by reduced CSF Aβ42. Genetic analyses indicated detrimental effects of HMGCR inhibition on cognitive function, dyskinesia, and restless legs syndrome in PD. In addition, RNA-seq analysis of substantia nigra suggested that HMGCR expression gradually decreases with PD progression, showing significant reductions in moderate and advanced stages. Finally, CSF proteomics revealed that statin use was associated with 238 upregulated and 203 downregulated proteins in PD, among which 28 proteins were linked to cognitive decline and significantly enriched in pathways related to substantia nigra development and PD. Our study suggests that statins may accelerate cognitive decline in PD patients through mechanisms potentially involving reduced CSF Aβ42 levels, inhibition of HMGCR in the substantia nigra, and disruption of PD-related protein pathways.
Cholesterol has a function. I wonder if the same analysis could be done, but distinguishing between different statins and particularly those that target the liver rather than cholesterol more generally.
Yeah, I’m afraid too much evidence has accumulated to show statins as negatives in the context of PD, regardless of the Japanese study observations. Time to put that on the shelf of “done deal”. The remaining question is about statins and NDDs in general and why there would (or would not) be differeces between effects in case of PD specifically. Is PD unique in this respect?
These findings highlight the therapeutic potential of NALL for PD by its protective effects on α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.
We identified 26 annotated metabolites and 23 metabolic pathways associated with air pollution exposure, particularly PM2.5 and traffic-related pollutants, in PD patients and controls. Metabolic profiles observed in controls aligned with prior studies, supporting external validity. Profiles in PD patients additionally indicated disease-specific disruptions. Air pollution was associated with inflammation-related lipid metabolism (e.g., increased leukotrienes; decreased eicosatrienoic acid and docosahexaenoic acids) and several amino acids (e.g., alanine, aspartate, and glutamate) in PD patients. We also found a reduction in tyrosine levels, possibly related to PD. Togethger, these findings suggest that air pollution may contribute to PD through inflammation, oxidative stress, and mitochondrial dysfunction.
Results revealed a sex-specific effect of dairy intake, a significant association with a higher risk of Parkinson’s disease in males (HR 1.28, 1.05-1.56), whereas no association was observed in females (HR 1.02, 0.80-1.30). For milk intake only, estimates were 1.36 (0.97-1.90) for males and 1.19 (0.94-1.51) for females.
Yeah, I guess. But the point is prevention of the conditions leading to alpha-synuclein misfolding in the microglia in the first place. By the time disequilibrium in calcium homeostasis appears it’s already too late (why I pay attention to calcium channels) - inflammation is downstream from this. I keep reading about how misfolding spreads prion-like, but the real crux is why the misfolding happens in the first place. The misfolding doesn’t just happen, it’s triggered. To be honest, I’m not impressed, sorry.
Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction
“Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder”
Older illustration:
Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s Disease
Yes, it is plausible, but not as a simple universal rule.
Reduced histone acetylation can alter alternative splicing because chromatin state affects how RNA polymerase II moves through a gene and how splicing factors are recruited to nascent RNA. In general, histone acetylation tends to open chromatin, while reduced acetylation tends to make chromatin more compact and can change exon recognition during co-transcriptional splicing. That general chromatin–splicing link is well established.
The important caveat is that the effect is context-dependent. Reduced acetylation does not always mean “more aberrant splicing” in exactly the same direction for every exon. Some exons are promoted by slower elongation and tighter chromatin, others are skipped; the outcome depends on the local gene architecture, splice-site strength, recruited chromatin readers, and which splicing regulators are present. Reviews of the field consistently describe histone marks as part of a combinatorial “splicing code,” not a one-way switch.
So for the SNCA / α-synuclein isoforms discussed above, the careful answer is: reduced histone acetylation could contribute to aberrant splicing in principle, but I do not see strong direct evidence from these sources that reduced histone acetylation is an established primary driver of the specific SNCA splice isoforms linked to α-synuclein misfolding. The SNCA literature more clearly supports altered splicing itself and altered chromatin regulation of SNCA expression, while the direct bridge from histone hypoacetylation → specific SNCA isoform shift → misfolding remains less firmly demonstrated.
There is also an interesting bidirectional possibility: α-synuclein pathology may itself feed back on chromatin. Reviews cite work showing nuclear α-synuclein can inhibit histone acetylation and promote neurotoxicity, which raises the possibility of a vicious circle in which misfolded or overabundant α-synuclein worsens chromatin regulation, potentially including splicing regulation indirectly. That is biologically plausible, but still not the same as proving that reduced histone acetylation was the initial cause of the splice abnormality.
So my bottom line is:
Reduced histone acetylation is a credible upstream contributor to aberrant splicing, including potentially the splice-isoform changes relevant to α-synuclein biology, but it would be too strong to say it is likely the sole or proven cause of the SNCA aberrant splicing above. A better phrasing would be that it is a possible and biologically well-motivated modulator.
I can also set this out as a step-by-step mechanism from histone hypoacetylation → polymerase kinetics/chromatin readers → exon skipping/inclusion → α-synuclein isoform balance → aggregation risk.
In the paper you cited above: “Caffeine was shown to decrease Mg2+ reabsorption in the kidney tubular system [58,59], thus contributing to Mg depletion. In general, Mg deficiency is considered to be a key player in all phases of addiction (including caffeine and nicotine) pathophysiology [60]. These findings run counter to the idea that Mg deficiency is one of the factors raising the likelihood of developing Parkinson’s disease (PD) as magnesium administration weakens one of the environmental protective variables (nicotinism) while caffeine use may cause magnesium deficiency.”
(fwiw when I tried Mg threonate it gave me skin rash and I chose to stop and threw it away. Retrospectively, that was maybe a positive sign of it acting or “clearing an infection” as @John_Hemming would say?)
First, let me restate again - that list is based on speculation, mostly because of desperation: the research moves so slowly (to my eyes!) and the need is so urgent, that out of desperation I am forced to speculate and go out on a limb, taking chances which may not pan out. One general remark - some of the speculative agents may not work, not because they’re not useful, but because they need other things to allow them to work. PD (or any complex pathology) has so many systems go wrong, that you need multiple steps to fix things. For example, dietary copper doesn’t work against PD, but that’s because of other steps that need to be taken, and so you frequently get the effect of something being simultaneously in excess (copper) accelerating alpha-sinuclein formation and deficit blocking critical enzyme formation depending on tissue location.
Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?
Re B1/B2. I was thinking of benfotiamine.
The Beneficial Effects of a Combination Therapy of Oral Benfotiamine and Methylcobalamin in the Treatment of Parkinson’s Disease: Case Reports and Review of the Literature
Here I was trying a multistep approach - not focusing on a single compound like magnesium or B1 or astaxanthin etc., but on a hopefully synergistic effect. So, for example since there is an issue with magnesium getting into the brain, you need to find ways of assisting that process by taking in other compounds - there is the hypothesis that magnesium deficit in the brain is an issue of transporter malfunction. Fix or get around that by other compounds, and all of a sudden magnesium makes sense, where magnesium by itself may not have seemed sensible.
I keep seeing papers to the effect “compound X works/does not work against PD”. I am very tired of this. Clearly that’s not how you should approach the problem. It’s like looking at a ladder with multiple broken steps and you call in a bunch of engineers and they deliver to you a report like Engineer A “fix step #6”, Engineer B “fix step #9”, Engineer C “fix step #12” and so on. It’s nonsense. You must fix ALL the steps or you can not climb up the ladder! PD is a ladder with many, many broken steps. It wil require many things. You can’t look at a screw (f.ex. astaxanthin) and say: this will not allow you to climb up the ladder (fix PD) - no, but the screw can be used to fix one of the steps and be part of the solution. By itself it may do nothing. In concert with other measures it will be part of fixing the ladder.
Again apologies for desperation speculation - but that’s all we have with such sloooooow pace of research - CAUTION: Chinese paper, shit model (mice with induced PD by MPTP injections )
Benfotiamine protects MPTP-induced Parkinson’s disease mouse model via activating Nrf2 signaling pathway
So, astaxanthin to me is not in the context of generalized lowering of inflammation, but specifically the Nrf2 pathway. Again, apologies for mice model - desperation speculation
Astaxanthin-loaded brain-permeable liposomes for Parkinson’s disease treatment via antioxidant and anti-inflammatory responses
Astaxanthin is neuroprotective in an aged mouse model of Parkinson’s disease
Astaxanthin suppresses endoplasmic reticulum stress and protects against neuron damage in Parkinson’s disease by regulating miR-7/SNCA axis
Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications
Magnesium - that is correct: elevated serum levels are the result of malfunctioning transport mechanisms. That is a frequent phenomenon - some substance is elevated in blood precisely because of defects in tissue absorbtion, therefore serum levels do not reflect tissue levels and you can actually have a deficit in the tissues. The issue here is that the magnesium doesn’t get into the brain efficiently, therefore elevated serum or CSF levels don’t help. The idea is that the threonate form can more easily get to the brain, especially if we assist it with other compounds.
Re: tributyrin. Direct tributyrin gets around the frequent problem in PD of poor microbiome profile and gut wall integrity.
Dietary tributyrin supplementation in Parkinson’s disease: An open-label target engagement study
Yet again: this is extensive speculation. My idea is to take a target, such as for example substantia nigra necrosis, look at all the steps leading up to it, and systematically attempt to repair or get around each step (like fixing all the steps on a ladder) using many compounds at once. Of course, this is very hard because there is still a ton we just don’t know - what exactly is the etiology of various pathologies in different ways PD presents. But you gotta start somewhere and I refuse to wait while research is moving at a snail’s pace. YMMV.
Preprint + China + Tier 2 university + mice cell model 
)