For Parkinson’s disease, a new therapeutic target for gait disorders

July 15 2010

The second leading cause of handicap due to neurological causes in the elderly, Parkinson’s disease affects nearly 150,000 people in France. The trembling and stiffness that characterise the disease are due to changes in the neurons in the brain that transfer dopamine. The team of Chantal François and Etienne Hirsch (Research Centre at the Brain and Spine Institute, CNRS/Inserm/UPMC) now suggests that gait disorders observed in patients at an advanced stage of the disease are linked to degeneration of a different type of neuron, known as a cholinergic neuron. According to the researchers, the neurons may constitute a potential new target for pharmacological treatment for patients who have become resistant to the initial dopamine treatment. Conducted in close cooperation with Pitié-Salpêtrière (Assistance Publique - Hôpitaux de Paris) clinicians, the research was published in the August issue of The Journal of Clinical Investigation.

In Parkinson’s disease, motor symptoms are due to the death of dopaminergic neurons, i.e., those that use dopamine as a chemical messenger. The symptoms generally disappear with dopamine treatment. In the advanced forms of the disease, however, resistance to treatment appears, resulting in gait disorders and falls. The most likely hypothesis is the presence of a structure that is not mediated by dopamine and implicated in the control of equilibrium. The pedonculopontine nucleus (PPN), a brain structure composed in part of neurons using acetylcholine (cholinergic neurons) as a chemical messenger, is a potential candidate for researchers.

To determine its role in controlling gait and posture, researchers and clinicians took an original interdisciplinary experimental approach using functional magnetic resonance imaging (fMRI), anatomy and neurosurgical techniques. On the basis of analysis performed on both healthy and sick subjects, several observations led to appreciating the importance of the PPN in controlling gait and posture. The observations also strengthen the hypothesis that gait disorders observed in Parkinson’s were due to a lesion or a dysfunction of the small brain structure.

Using research on healthy subjects, the researchers demonstrated that the PPN is “activated” when the subjects imagine themselves walking down a hallway. Activation increases as imagined walking accelerates. Analysis of post-mortem brain tissue also showed that only Parkinson's patients affected by gait and equilibrium disorders had a loss of cholinergic neurons in the PPN. In elderly primates with Parkinson's, a strong correlation between loss of equilibrium and loss of cholinergic neurons in the PPN was also observed. Finally, the researchers demonstrated that experimental lesion of cholinergic neurons in the structure leads to gait disorders and postural defects.

“The results are very promising and provide a new lead in research for developing different therapeutic strategies. As an example, for patients with advanced Parkinson’s, cholinergic neurons on the brainstem could be stimulated to aid equilibrium disorders,” explain Chantal François and Etienne Hirsch.


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Source
Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease.
Journal of Clinical Investigation, advance online publication date 12 July 2010

Research contacts
Etienne Hirsch
Tel: 01 42 16 22 02
Chantal François
Tel: 01 42 16 00 68
David Grabli
Tel: 01 42 16 17 94

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