adssx
#956
New type of PD model: A human striatal-midbrain assembloid model of alpha-synuclein propagation 2025
Animal models of the pathology of Parkinson’s disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cells (hPSCs)-derived neural organoids have provided improved access to study PD etiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modeling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways.
Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present and the neurons such as dopaminergic (DA) neurons and GABAergic neurons were electrophysiologically active in the hSMAs. hSMA development in the presence of increased α-syn from SNCA overexpression, induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to DA neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to pathological form in human patients, was accumulated in midbrain area of hSMAs. Treatment with protein aggregation inhibitor (Anle138b) and autophagy inducer (Rapamycin) reduced α-syn aggregation, indicating potential of hSMAs for drug testing.
This study established hSMAs as a novel platform for modeling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.
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The electrical field across the membrane is really strong.
**Skin intraneural phosphorylated α-synuclein is a highly specific biomarker for early Parkinson’s disease **
“In contrast, olfactory function, although more impaired in PD than in non-PD patients, only seems to have a more limited diagnostic accuracy.”
Certainly in my case. I have a highly reduced sense of smell, and I don’t have PD.
https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awaf313/8249109?redirectedFrom=fulltext&login=false
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Tried this? I’ve heard good things about this
Have not tried this.
I’ve tried several other nootropics but none of them did enough to justify the cost/benefit ratio.
adssx
#961
Forgot to cross post here, SGLT2i seem like a no-brainer for people at risk of PD: Canagliflozin - Another Top Longevity Drug - #1847 by adssx
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adssx
#962
Turkish preprint: Personalized Metabolite Biomarker Predictions Reveal Heterogeneous Characteristics of Parkinson’s Disease 2025
Furthermore, certain metabolites such as melatonin, sphingosine, and biliverdin, though not identified by the general approach, showed distinct secretion patterns across patient clusters. For instance, an undersecretion pattern of melatonin, possibly associated with the sleep disturbance symptom of PD, was detected exclusively in one subgroup.
While certain metabolites like melatonin, prostaglandins, sphingosine, biliverdin, tyramine, and betaine etc., which are associated with PD or neurodegeneration, were not predicted as potential biomarkers in the classical approach, they demonstrated group-specific patterns in the cluster-based approach.
For instance, melatonin, 6-hydroxymelatonin, and L-iduronic acid exhibit an undersecretion pattern in cluster C3, while no clear trend is observed in clusters C1 and C2.
@John_Hemming: they looked at serum and not CSF I guess, still, there might be people with PD who benefit more from melatonin supplementation than others.
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I think the nub of the issue is neurodegeneration which results from damage to the mitochondria. That could have many causes and the symptoms will still be the same. Once things get beyond a certain limit the mitophagy fails.
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adssx
#965
adssx
#966
Cure PD UK update: Ibuprofen, methylcobalamin, benfotiamine, probucol and chlorogenic acid failed in PD models (fwiw):
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Ouch. I’m taking benfotiamine partially because it was supposed to be neuroprotective. This sucks. I wonder if chlorogenic acid levels likely to be obtained from coffee are clinically relevant, I always found it unsatisfying in association studies with coffee that given everything that is actually present in coffee, we’re not measuring amounts, makes it very noisy.
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adssx
#968
HMGCR genetic variability in Parkinson’s disease in a Spanish cohort: associations with lipid metabolism and early onset 2025
I don’t understand much but I thought people smarter than me here could interpret it. ChatGPT says that this paper “Suggests that some individuals might have altered baseline HMGCR activity (due to variants), which could interact with statin therapy in ways that differ by genotype. Flags that genetic variation in HMGCR might modulate susceptibility or phenotypic expression of PD — which is relevant for personalized medicine hypotheses involving statins. Thus, while it doesn’t provide evidence for or against statin use in PD, it offers mechanistic/biological plausibility that modulation of that pathway might affect disease in some patients.”
Might explain the discrepancy in results regarding statin and PD risk.
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adssx
#969
On tanganil, it made MSA worse: Acetyl-DL-leucine (Tanganil™) in three patients with advanced multiple system atrophy 2025
Three patients with advanced-stage MSA and severe cerebellar symptoms—two of whom also had moderate RBD—were treated with ADLL (TanganilTM), titrated to 5g/day over 10 days. While both patients with RBD reported self-assessed decrease of RBD symptoms within 2–3 weeks on the full dosage (approximately four weeks after treatment initiation), all three patients had major worsening of gait and balance during the same period, leading to sudden falls and overall health decline. These adverse events prompted early discontinuation of therapy. Gait improved within two weeks after discontinuation of therapy in two patients. In parallel, the RBD phenotype reoccurred. In the third, who had very advanced MSA and concurrent infections, gait only slowly improved over time and it remains unclear whether his worsening of truncal ataxia was attributable to ADLL (TanganilTM), or whether it was related to his concurrent infections with slow recovery.
While ADLL improved RBD, it was poorly tolerated in these three patients with advanced-stage MSA of predominantly cerebellar type. Further studies are needed to evaluate its safety and efficacy in different, preferably early, stages of MSA.
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adssx
#970
Association between ultra-short heart rate variability and risk of Parkinson’s disease: A prospective cohort study 2025
We found that lower usHRV parameters were significantly associated with an increased PD risk. Notably, an L-shaped association was observed between corrected root mean square of successive differences and PD risk. Temporal trend analysis suggested usHRV levels of patients with PD started to decline approximately 10 years before diagnosis. Mediation analysis revealed that thalamus-related fiber tracts, plasma inflammatory and neuroendocrine markers mediated the association between usHRV and PD risk.
Our findings provide evidence supporting that usHRV may serve as an early, convenient, and noninvasive biomarker of PD risk up to a decade before diagnosis.
In contrast, our prospective study utilized ultra-short term (15s) ECG recordings and demonstrated that five time-domain HRV parameters, i.e. RMSSD, SDNN, SDSD, as well as inter-beat interval corrected RMSSD and SDNN, were associated with PD risk. Furthermore, we observed an L-shaped association between inter-beat interval corrected RMSSD and PD risk, which suggested that the risk of PD increased markedly only when inter-beat interval corrected RMSSD fell below a specific threshold. Specifically, the analysis of HRV quartiles also revealed that only participants in the lowest quartile exhibited a markedly higher risk of developing PD compared to those in the highest quartile. Taken together, these findings emphasized the potential significance of this threshold as a critical predictive cut-off point.
We found that HRV parameters in patients with incident PD were found to decline up to 10 years prior to diagnosis across different matching strategies, suggesting the presence of autonomic dysfunction in the preclinical stage of PD.
And related: Vagus Nerve Stimulation in Movement Disorders, from Principles to a Systematic Review of Evidence 2025
Current evidence supports the multimodal effect of VNS in MDs, particularly in PD, where the most consistent benefits were observed. Non-invasive taVNS represents a promising, safer alternative to iVNS. Larger randomized controlled trials with standardized protocols are needed to validate efficacy, optimize stimulation parameters, and determine long-term clinical and biological impact. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
adssx
#971
New theory: “proposing PD to be a disease specifically involving metabolic dysregulation of fatty acids, a ‘fatty acidopathy’”. See: Parkinson disease is a fatty acidopathy 2025
Therapeutic opportunities in this space: stearoyl CoA desaturase inhibition, hormone-sensitive lipase reduction, 15-lipoxygenase inhibitors, and fatty acid synthase modulators.
Things which intervene on the acetyl-CoA pathway are quite likely to have some effects. The last paper is behind a paywall.
@adssx has this paywalled paper been posted?
Rapamycin and Autophagy: Potential Therapeutic Approach for Parkinson’s Disease Treatment.
Goyal A, Kumari A, Verma A, Agrawal N.
CNS Neurol Disord Drug Targets. 2025 Oct 14. doi: 10.2174/0118715273401017250918141227.
Online ahead of print.
PMID: 41102966
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to characteristic motor symptoms such as bradykinesia, tremor, and rigidity, as well as a range of non-motor manifestations including cognitive impairment, mood disturbances and autonomic dysfunction. Among the multiple cellular mechanisms implicated in PD, the dysregulation of autophagy has gained significant attention in recent years. Autophagy is a crucial intracellular degradation pathway responsible for the removal of misfolded proteins and damaged organelles, processes that are particularly relevant in neurodegenerative diseases. Impairment of autophagic flux contributes to the accumulation of toxic protein aggregates and cellular stress in PD. Rapamycin, a compound originally isolated from Streptomyces hygroscopicus, is a well-established inhibitor of the mechanistic target of rapamycin (mTOR), a central regulator of autophagy. Preclinical studies have shown that rapamycin can stimulate autophagic pathways by suppressing mTOR signalling, leading to increased expression of autophagy markers. These effects have been associated with reduced neuronal damage, improved motor performance and decreased accumulation of pathological proteins in PD models. This review provides an overview of current preclinical research on rapamycin’s neuroprotective potential in PD through autophagy enhancement. Although findings are promising, translating these outcomes into clinical practice necessitates a thorough understanding of rapamycin’s pharmacodynamics, optimal dosing strategies, potential side effects and long-term safety. Further research is essential to establish its therapeutic viability in human populations.
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4 surprising things that may reduce your risk of Parkinson’s
Research on Parkinson’s is revealing several risk factors related to our lifestyles and environment, and you can act on some of them.
Although treatments are available that can manage symptoms, there is no cure or therapy that can slow disease progression. But ongoing research on Parkinson’s is revealing several risk factors related to our lifestyles and environment, some of which are actionable.
For example, moderate to vigorous exercise may reduce one’s risk, according to a 2018 meta-analysis, and some studies have shown that healthy diets focused on whole, unprocessed foods might help. Last year, a study found that higher levels of exposure to air pollution were associated with an increased risk of Parkinson’s.
read full story: 4 surprising things that may reduce your risk of Parkinson’s (WaPo)
