Neurophysiological Correlates of Motor Behaviour in Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that dramatically affects the cognition of the patients. Its effect on the motor cortex is not clearly established despite clinical observations implying some dysfunction at disease onset. From the mild stage, AD patients display a motor behavior different from normal, that is, restricted movement with slowness, delayed reaction to external stimuli and diminished facial expression. This pattern gradually changes as the disease progresses; in fact, at the more advanced stages the patients show an increased mobility with nervous movements, pacing, akathisia and falls. These observations have been the basis of our investigation of the function of the motor cortex through transcranial magnetic stimulation (TMS) in a group of AD patients with mild disease. Patients were compared to a group of normal individuals in order to find a neurophysiological correlate of their altered motor behavior. The experiments were performed in two phases, before and after the oral administration of an acetylcholinesterase inhibitor (donepezil) taking into consideration the significant role of the cholinergic hypothesis in the pathogenesis of AD. The active motor threshold (aMT) which reflects cortical excitability and the silent period (SP) which reflects cortical inhibition were measured during the TMS experiments. These measurements give an overview of the motor control in early AD, from the activation of the pyramidal cells in the primary motor area to the temporary inhibition of the contraction of the peripheral muscle. An increased aMT was observed in the early AD patients representing decreased excitability of the primary motor cortex. Also, an increased duration in SP due to its being scattered by multiple electromyographic breakthroughs called late excitatory potentials (LEP) was measured, representing impaired cortical inhibition. The administration of donepezil restored both neurophysiological parameters to normal indicating a key role of the cholinergic system in the regulation of the mechanisms which determine motor control in early AD. Additional neurophysiological and pharmacological sub experiments that we performed completed these observations. Our results combined with recent data from the literature argue in favor of a functional disturbance in the cholinergic system instead of cholinergic neuronal loss in early AD. The recently demonstrated existence of a direct connection between the basal forebrain and the primary motor area enable us to present an original physiological model explaining our findings. This model gives a complete explanation of the changes in the function of the primary motor cortex at the early stages of AD under the regulation of the cholinergic system.