Parkinson’s disease: innovative avenues of research

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, and the second cause of motor disability after stroke. In France, 160,000 people are affected by this pathology, with an incidence of 8,000 new cases per year, constantly increasing, in particular due to the aging of the population.

Thus, the main risk factor for developing Parkinson’s disease is age, with a prevalence of 0.04% in people between 40 and 49 years old which increases to 2% in those over 80 years old.

On the occasion of the World Day dedicated to it on April 11, the Paris Brain Institute took stock of the research work it is carrying out against this disease. Indeed, while advances have been made in terms of motor symptoms, the mechanisms at the origin of neurodegeneration have not been fully elucidated. And there is still progress to be made to improve the diagnosis and prognosis of patients, and to optimize existing therapies. Three projects developed at the Brain Institute meet these needs.

The first focuses on microglial cells, cells involved in immuno-surveillance in the central nervous system. These cells are already known to be active in the brains of people with Parkinson’s disease, but their precise contribution to the neurodegenerative process remains to be clarified. This is why the team of Olga Corti (Inserm) and Jean-Christophe Corvol (Sorbonne University, AP-HP) is developing an innovative project based on bringing into play human cerebral organoids (mini-brains) and complex co-cultures of human cells, to explore the role of the microglial component in the context of mutations of the LRRK2 and PRKN (Parkine) genes, genes found in familial forms of the disease and involved in the regulation of mechanisms relating to immunity and inflammation. The idea is to identify new pathways involved in the neuronal death present in Parkinson’s disease, so as to reduce the progression of the disease, and ultimately find new therapeutic molecules.

The second project developed at the Brain Institute plans to use imaging and artificial intelligence to refine the diagnosis and prognosis of the disease. The MOV’IT team, led by Marie Vidailhet (Sorbonne University, AP-HP) and Stéphane Lehéricy (Sorbonne University, AP-HP) thus used a magnetic resonance imaging biomarker, neuromelanin, which recently allowed important advances in the follow-up of Parkinson’s disease. Thanks to this neurotransmitter, an algorithm can automatically detect changes in volume and signal of the substantia nigra, region mainly affected in the disease. In addition, the researchers highlighted differences between patients with a prodromal stage of the disease and those already showing clinical signs. “This automatic, fast and rater-independent algorithm is therefore a valuable tool for studying changes in the neuromelanin of the substantia nigra, allowing a direct and non-invasive evaluation of the neurodegenerative modifications of this structure, emphasizes the Brain Institute. These measurements could provide relevant biomarkers to assess the efficacy of treatments modifying the progression of Parkinson’s disease. »

Finally, a third project aims to improve existing therapies – and in particular deep brain stimulation, which replaces L-Dopa treatments – thanks to new technologies. Thus, the “Experimental Neurosurgery” team, led by Brian Lau (CNRS) and Carine Karachi (Sorbonne University, AP-HP) at the Institut du Cerveau is seeking to test the implantation of a new stimulation device on several patients. , capable of recording intracerebral activity on board. “This allows brain activity to be recorded at different times of daily life, to better understand the dysfunctions of deep brain networks in disease and the effects of deep brain stimulation. »

Another project, developed by Nathalie George (CNRS) in this team, is based on neurofeedback methods, which consist of “teaching patients to regulate themselves certain brain activities associated with the disease, for example by varying a curve displayed on a screen representing the activity of their brain”, specifies the Institute of the brain. But there is still a long way to go in this area before this method can be used in clinical trials. In particular, it thus appears necessary to better understand the learning mechanisms of neurofeedback, the regulation of cerebral activity, etc., as well as to find new methods of analysis of the signal and its “very sophisticated” recording. .

Towards an early biological diagnosis

Parkinson’s disease is marked by a diagnostic delay due to the fact that the symptoms only appear late in the evolution of the disease, at a time when the loss of dopaminergic neurons is already well advanced. A team of researchers from Grenoble therefore worked to identify a biological signature that would lead to an early diagnosis of the disease. UA biological analysis which would make it possible to establish the diagnosis in a formal way would be a precious help for the doctors. If this analysis were also sensitive enough to spot the disease in its early stages, it could help in the development of curative drugs, which would target the mechanisms of disease progression. “, explain Sabrina Boulet and Florence Fauvelle (unit 1216 Inserm/Grenoble Alpes University, Grenoble Institute of Neurosciences). Indeed, when the disease is expressed, the brain damage is generally too great to be able to use curative drugs.
By observing animal models, the two researchers first demonstrated the existence of changes in the composition of metabolites associated with Parkinson’s disease – regardless of the stage of the disease, and therefore even in the early stages. They then succeeded in defining a biomarker comprising several specific compounds, and showed that this biological signature made it possible to diagnose people with Parkinson’s with an accuracy of 82.6%.
Scientists hypothesize that this biomarker could also be used in humans to identify patients at the early stage. The next step is therefore to validate this approach using samples from patients whose disease was still silent at the time of sampling, but who were subsequently diagnosed as affected. Scientists have already filed a patent: “ Nuclear magnetic resonance analysis of a blood sample is a quick, easy to perform and inexpensive test. details Florence Fauvelle. If validated, one can imagine that this biomarker could be used in routine clinical practice, to diagnose people suspected of being affected or who have a high risk of developing the disease. »

New therapeutic avenues are also being considered, targeting in particular pyruvate and mithochondria. ” The level of pyruvate, a substance that is used by the mitochondria of neurons, is elevated in sick animals and in samples from patients, says Sabrina Boulet. This suggests that Parkinson’s disease may be associated with mitochondrial dysfunction. »
According to a press release from Inserm, March 15, 2022, and The Journal of Clinical Investigation, December 2021 (https://www.jci.org/articles/view/146400)

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Parkinson’s disease: innovative avenues of research


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