Mounting evidence suggests that a small structure at the bottom of the brain called pedunculopontine nucleus is involved in the development of gait failure and postural instability in PD. We propose that pedunculopontine nucleus lesions in parkinsonian models might represent a pertinent model to study gait failure and postural instability which are the most debilitating dopa-resistant symptoms in advanced PD.
In this context, we wish to determine whether pedunculopontine nucleus lesions specific to cholinergic neurons (a subpopulation of cells in this brain region and which degenerate in Parkinson's disease) are able to induce axial symptoms in normal pre-clinical models, or whether large, non-specific lesions of the pedunculopontine nucleus are necessary to do so. Specific toxins will be used to destroy selectively cholinergic neurons. This study should lead to a better identification of the brain region involved in these symptoms and allow testing therapeutic interventions such as specific pharmacologic manipulation or low frequency deep brain stimulation. One can hope that patients with intractable locomotor and postural deficit might benefit from such a novel therapeutic approach.
Final Outcome
Because pedunculopontine nucleus (PPN) and dopaminergic nigral lesions occur simultaneously in Parkinson’s disease, the researchers hypothesized that the combination of these two types of lesions in the same models should provide insights into the specific contributions of each to the behavioral deficits seen in PD.
The researchers were able to induce walking and postural symptoms through cholinergic lesioning of the PPN. These symptoms were not alleviated by dopaminergic manipulation. This suggests that PPN lesions may be involved in the genesis of dopamine-resistant gait and posture disorders in Parkinson’s disease.
The team then created models of dopaminergic nigral lesions. These induced akinesia, cog-wheel rigidity of the extremities, gait disturbances and posture deficits. These symptoms were reversed by treatment with a dopamine agonist.
As the next step, the researchers are combining nigral dopaminergic lesions and PPN cholinergic lesions in the same models. The team expects to observe a worsening of axial rigidity and postural instability that should not be reversed (or be only partially reversed) through treatment with a dopamine agonist. The creation of this model of severe Parkinson disease with persistence of axial signs will hopefully open new avenues for pre-clinical testing of Symptoms & Side Effects pharmacological or surgical strategies to address dopamine-resistant symptoms.
Researchers
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Chantal Francois, PhD