Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease 2025
a The top 10 drugs identified by upward perturbation of genes. The hypothetically therapeutic genes were discovered by increasing their expressions by 10% and observing the effect of disease progression within 2 years. The drugs were obtained by comparing the identified therapeutic genes with the transcriptomic effect of drugs from CMAP database. The drugs are ranked by the combined score (odds ratio × −log(p-value)).
b The top 10 drugs identified by downward perturbation of genes.
They don’t discuss rapa though but melatonin (poke @John_Hemming):
Current treatments for PD are symptomatic, hence the search for disease-modifying treatments addressing the underlying pathology is a priority. While the mainstay of PD treatments are dopamine-based drugs, their effectiveness largely varies with disease subtype and stage. Interestingly, among the top 20 putative PD drugs identified in our study, there are three dopamine-based drugs, including levodopa, the current first line treatment for PD (Fig. 5a, b). Even though dopamine-based drugs are considered symptomatic, our analysis does not preclude the identification of disease-modifying treatments, given the drugs were discovered through the genes underlying the disease’s multifactorial mechanisms. Moreover, due to the limited number of subjects, we performed the drug identification at the population level and could not determine which drugs may confer disease-modifying effects on distinct patient subtypes. Nevertheless, apart from dopamine-based drugs, we identified multiple immune-related and anti-inflammatory drugs, including naproxen (a non-steroidal anti-inflammatory drug) and tetracycline. Other drugs such as vinpocetine, chlorogenic acid and melatonin have also been reported to modulate inflammation. Although vinpocetine is typically prescribed for treating memory loss in aging and dementias (including PD patients with dementia), it has been demonstrated to regulate the circulation of inflammatory molecules in PD patients. Chlorogenic acid, found in coffee, is suggested to offer neuroprotective roles in animal models of PD. Similarly, melatonin, which may improve sleep disturbance in PD, has also been shown to reduce neuroinflammation66. The convergence of these medications on immune system/inflammation highlights the need to consider this pathway for drug discovery and repurposing.
On cholesterol they note:
The benefits of physical activity to PD symptoms and progression are widely acknowledged. Even though the biological mechanisms mediating these benefits are not fully understood, it has been hypothesized that physical activity may promote neuronal plasticity and survival of dopaminergic neurons by simulating the expression of neural growth factors. Here, we found that physical activity is associated with PD through two principal pathways, namely, cholesterol biosynthesis and inflammation via toll-like receptors. A previous study of animal model of PD showed that MPTP-bearing mouse had reduced α-synuclein and downregulation of toll-like receptors after eight weeks of treadmill exercise. Although the results on the association of cholesterol with PD are mixed, several PD-related genes are involved in cholesterol homeostasis. Moreover, cholesterol biosynthesis has been shown to decrease in the fibroblasts of PD patients. The most compelling insights into the tripartite association between PD, cholesterol and physical activity was demonstrated recently. The authors found that physical activity activates PPARα in the dopaminergic neurons of PD mouse model. Activation of PPRAα alone suppressed the aggregation and spreading of α-synuclein in the mouse. As PPRAα is a transcription factor that regulates the expression of genes involved in fatty acid oxidation, the mouse was treated with fenofibrate, a PPRAα medication for abnormal cholesterol level. The authors observed that one month of daily treatment with fenofibrate conferred similar benefits as two months of regular exercise. Despite that our analysis does not rule out the bidirectional relationship between PD and physical activity, our results are consistent with the foregoing studies. However, the mode and intensity of exercise remains an open question. A meta-analysis of 19 randomized human clinical trials showed that different modes and regimens of exercise provide different forms of benefits to PD symptoms. Indeed, our findings could guide a more personalized prescription of physical activity in PD, tailored to individual biological mechanisms and associated predisposition. Perhaps, leisure-related activities (likely shorter duration, higher intensity) would be more beneficial to patients having abnormal cholesterol levels while home- or work-related activities (likely repetitive and lower intensity) could help with neuroinflammation-induced PD pathogenesis. Furthermore, personalized physical activity regimen can be prescribed by comparing the gene-neuroimaging parameters of a patient with the parameters of other patients who have benefited from a particular exercise regimen.
