Think before you leap

The early recognition that many Parkinson disease (PD) symptoms could be reversed by replenishing a single neurotransmitter, dopamine, has widely influenced subsequent neurology research. Surely there must be other neurotransmitter deficiencies in this and other CNS disorders similarly responsive to therapeutic replenishment. Some central neurotransmitters are too widespread and fundamental to lend themselves easily to this strategy (e.g., glutamate, GABA, glycine). However, the biogenic amines and acetylcholine remain targets of such therapeutic approaches by virtue of their more limited anatomic distribution and function.

Furthermore, not all PD symptoms respond to dopamine replenishment and, late in the course, nondopaminergic problems take center stage, including dementia and levodopa-refractory motor symptoms. Of the latter, falls are the most problematic and generally are not responsive to dopaminergic therapies. The substrate for such levodopa-unresponsive symptoms has been debated, but appears primarily to reflect more widespread proliferation of the Lewy neurodegenerative process into nondopaminergic brain regions.¹ However, which nuclei or brain circuits are the primary substrates for falls or other specific levodopa-refractory problems is unknown.

Last November in Neurology®, Bohnen and colleagues² proposed that falls in PD may reflect degeneration of cerebral cholinergic circuits, …