I think the delay of onset of PD is probably the most relevant item for many individuals - and different approaches may be needed once one has disease, and may need to change with changing severity.
I currently think that the neuroprotective approaches for AD and PD are likely quite similar pre-disease, but need to start 20 years before one would have had a diagnosis of AD or PD.
The big issue is the need to change strategies and when those change, and on what evidence when dealing with early PD, advanced PD, or MCI, then early AD.
Once disease is present, especially once able to be diagnosed as having PD or AD it is more difficult to substantiate what modifies disease/progression. The sluggish movement of studies and data mining is going too slowly for those who have early disease, so many have to take their best guess based on inadequate information.
We know a lot more about how to risk decrease for AD, there is less on PD - however, many of the same interventions show significant risk reduction, such as Mediterranean diet, exercise, vitamin E, statins, CCBs, NSAIDS, baseline cognitive function, and others.
On the CCB question - you may look at these options - especially the first one as it has high penetration to brain:
|Drug|Half-life|BBB Penetration|
|Nimodipine|~1–2 h|High|
|Nicardipine|~2–4 h|Moderate|
I was looking at nifedipine as a short acting, and saw that you already posted the paper showing amlodipine with better ACM compared to nifedipine or felo, vera etc.
Calcium channel blockers, survival and ischaemic stroke in patients with dementia: a Swedish registry study
The problem is by the time I come across a paper, more likely than not, you already posted it , like below
Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders
I’m keeping my eye out on calcium handling, as I sense that this is the most promising practical approach to ameliorating early PD.
Nimodipine needs to be taken on an empty stomach (≥ 1 h before or ≥ 2 h after food) and can cause tachycardia. Nicardipine appears promising, but in many countries, it’s only available in IV form. I’ll have to do more research…
Parkinson’s disease (PD) is a progressive neurodegenerative condition affecting around 1-2% of the population over the age of 60. The lack of disease-modifying therapies highlights the need for insights into the etiology and pathogenesis of PD. Mitochondrial dysfunction is recognized to be a significant contributor to disease pathogenesis, resulting in bioenergetic deficits and subsequent neurodegeneration. Research indicates that changes in non-oxidative phosphorylation (non-OXPHOS) metabolism in PD may serve as an adaptive response to mitochondrial dysfunction, compensating for energetic failure and alleviating disease progression. This review explores mitochondrial dysfunction-driven alterations in non-OXPHOS metabolic pathways, such as glycolysis and the tricarboxylic acid cycle, emphasizing their role in maintaining energy metabolism and their dual contribution to neuroprotection and disease progression. Advances in neuroimaging techniques are also discussed, particularly their role in visualizing metabolic changes in vivo and their potential utility in identifying non-OXPHOS metabolism as a biomarker of mitochondrial dysfunction. By enhancing our understanding of the complex interplay between metabolic pathways in PD, this review underscores the importance of personalized therapeutic approaches that consider individual metabolic variations. Ultimately, these insights aim to pave the way for improved diagnostic utility and personalized treatment strategies that address the metabolic and mitochondrial dysfunctions underlying PD pathogenesis.
On glycolysis: “The evidence of glycolysis’ role in PD is conflicting, demonstrating the upregulation of specific glycolytic enzymes as a neuroprotective mechanism, while increased glycolytic flux results in the accumulation of toxic end-products, exacerbating neurodegeneration. The dual nature of glycolysis necessitates identifying the threshold balancing the compensatory benefits against neurotoxic effects. The lack of consistency suggests that the glycolytic reprogramming in PD is context-dependent, with factors such as cell type, disease stage, underlying genotype, and threshold of glycolytic flux shaping its contribution to disease progression.”
On TCA cycle: "This process is significantly disrupted in PD, as evidenced by findings from in vivo PD models. PDH catalyzes the first gatekeeping step of the TCA; however, its activity is compromised in PD. […] The consistent evidence of reduced PDH activity suggests TCA cycle decoupling from glycolysis, leading to elevated pyruvate levels and reduced glucose flux through oxidative metabolism. Elevated pyruvate levels are converted to lactate due to increased LDH activity in PD, signifying a metabolic shift towards anaerobic glycolysis. […] MPP±treated SH-SY5Y cells demonstrated reduced citrate synthase (CS) and isocitrate dehydrogenase activity (IDH)
Fatty acid β-oxidation: “Similarly to glycolysis, FAO appears to be differentially affected across disease stages – upregulated in early stages to meet energy demands and declining with the disease progression; however, this pattern remains controversial and not fully supported by all research available. […] Evidence linking dysregulated FAO to pathogenesis is increasing; for instance, protein analysis of post-mortem tissue revealed early-stage FAO upregulation, marked by increased expression of acetoacetyl-CoA thiolase, a key FAO enzyme [37]. Reduced mitochondrial complex I activity correlated with abnormal FAO, marked by increased plasma levels of isobutyrylcarnitine, reinforcing FAO dysregulation as a consequence of mitochondrial dysfunction [38]. Despite the evidence from some studies reporting FAO upregulation, its overall function is disrupted, as indicated by a shift from FA metabolism to lipid storage in PD.”
I need to read this when I have some time, but it all seems to report the consequences of a failing neuron being downstream of damage to Complexes 1 and 3.
Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.
His team discovered the presence of Human Pegivirus — a virus not previously linked to any known disease — in half of the Parkinson’s patients studied.
“This is a blood-borne virus that can be found in 5-to-10% of healthy blood donors. It’s related to hepatitis C — and we found it in 50% of brains of patients with Parkinson’s disease.”
Because the virus is similar to hepatitis C, researchers now plan to investigate whether existing hepatitis C medications might also help treat or even prevent Parkinson’s.
There is a correlation with a lot of chronic diseases and pathogens, especially with neurodegenerative disease.
This is why laboratory rodents live longer than wild, lack of predators (including pathogens).
This is why if humans were living an environment free of major pathogens and toxins (except for controlled bioflora) assuming good diet, exercise, sleep and lack of major stressors, they would live much longer IMO.
We already have evidence of that with hygiene, proper nutrition, clean water, vaccinations almost tripled the life span in the past 150 years… mainly by reducing premature deaths.
I performed a search of the site and did not see this study posted. If it had been, I apologize. I make a special effort to find French papers on PD. Obviously this is in women. Note however, again, it does matter which specific statin is used, here even a broad class effect of lipophilic vs hydrophilic. Rather counter to previous hypothesis, it’s the lipophilic that had a positive effect. Given how long symptomless period for PD can be prior to diagnosis, I wonder if 5 years is enough.
Statin Use and Incidence of Parkinson’s Disease in Women from the French E3N Cohort Study
Association of cholesterol and glycemic state biomarkers with phenotypic variation and Parkinson’s disease progression: The Oxford Discovery cohort 2025: “HDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behavior disorder, and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (e.g., UPDRS-II score with 1 SD increase in HDL-C −0.74, 95%CI −1.22 to −0.26, p = 0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression.”
Two RCTs tried lipophilic statins in early PD:
Simvastatin: worsening motor symptoms in the simvastatin-treated group.
Lovastatin: no significant difference in motor scores but possible beneficial effect in terms of dopaminergic cell loss.
Not PD but see also: Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function 2022: “Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.”
As a Black Sabbath fan since I was 14, my very first 8 track was Paranoid, I was saddened when he passed yesterday. I knew he had been ill with Parkinson’s for a while but did not know there are so many version of this disease.
Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson’s disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.
One prevailing strategy for estimating mitochondrial content is to measure the levels of citrate synthase (CS), a common marker of mitochondrial capacity, to normalize a given bioenergetic readout.
Notably, the activity of the CS protein was lower in the rotenone-treated cells than in the vehicle-treated cells, but it significantly increased after treatment with NMN, siCD38, and NAT (Figure 1l–o), indicating that the mitochondrial content was enhanced in the context of NAD+ boosters’ augmentation.
We then visualized the metabolites involved in regulating these pathways in a circos plot and found that citrate regulates multiple metabolic pathways, whereas prolyl, tryptophan, and adenine are involved in multiple sphingolipid pathways (Figure 10f). By combining the MSEA and pathway enrichment results, we preliminarily identified citrate as the key metabolite induced by NMN in the TCA cycle.
Consistent with our previous report, the mice treated with MPTP showed a robust CS decline in the striatum by immunofluorescence and western blot analysis, which was significantly offset by NMN treatment
Without reading the paper I don’t think CS is at the core of the issue. The quoted text is not clear on whether it is the quantity of CS or the activity of CS that they are looking at. The activity will be linked with pyruvate influx.
“Reconstructing the nigrostriatal pathway is one of the major challenges in cell replacement therapies for Parkinson’s disease due to the lack of enabling technologies capable of guiding the reinnervation of dopaminergic precursors transplanted into the substantia nigra toward the striatum. This paper examines nano-pulling, as a technology to enable the remote manipulation of axonal growth.”
Pesticide exposure is increasingly recognized as a potential environmental factor in idiopathic Parkinson’s disease, though the molecular mechanisms remain unclear. This study explores how pesticide exposure alters gene regulation in key brain regions using the rotenone rat model. We performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and motor cortex. Despite uniform complex I inhibition across regions, we observed region-specific epigenomic changes associated with rotenone exposure. RNA-sequencing confirmed transcriptomic alterations. We identified a strong, rotenone-induced immune response in the substantia nigra, including increased activity in the C1q complement pathway, suggesting immune involvement driven by regulatory mechanisms. In contrast, the cortex showed dysregulation of synaptic function at the gene regulatory level. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology and selective vulnerability that characterise Parkinson’s disease.
Pesticide exposure in rats changes epigenetic signatures in different brain regions (poke @John_Hemming).
, like below
