Dopaminergic modulation of cortical plasticity in Alzheimer's disease patients

Abstract

In animal models of Alzheimer's disease (AD), mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are impaired. In AD patients, LTP-like cortical plasticity is abolished, whereas LTD seems to be preserved. Dopaminergic transmission has been hypothesized as a new player in ruling mechanisms of cortical plasticity in AD. We aimed at investigating whether administration of the dopamine agonist rotigotine (RTG) could modulate cortical plasticity in AD patients, as measured by theta burst stimulation (TBS) protocols of repetitive transcranial stimulation applied over the primary motor cortex. Thirty mild AD patients were tested in three different groups before and after 4 weeks of treatment with RTG, rivastigmine (RVT), or placebo (PLC). Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) or continuous TBS protocols. Short-latency afferent inhibition (SAI) protocol was performed to indirectly assess central cholinergic activity. A group of age-matched healthy controls was recruited for baseline comparisons. Results showed that at baseline, AD patients were characterized by impaired LTP-like cortical plasticity, as assessed by iTBS. These reduced levels of LTP-like cortical plasticity were increased and normalized after RTG administration. No effect was induced by RVT or PLC on LTP. LTD-like cortical plasticity was not modulated in any condition. Cholinergic activity was increased by both RTG and RVT. Our findings reveal that dopamine agonists may restore the altered mechanisms of LTP-like cortical plasticity in AD patients, thus providing novel implications for therapies based on dopaminergic stimulation.

Figures

Figure 1

After effects of the cTBS (a) and iTBS (b) protocols on MEP amplitude in the different groups of Alzheimer's disease patients at baseline before starting the treatment with RTG, RVT, and PLC. A group of age-matched HS was included for comparison at baseline only. Error bars indicate SEM. Asterisks indicate p<0.05 when comparing AD patients of the different groups.

Figure 2

After effects of the SAI protocol on MEP amplitude in the different groups of Alzheimer's disease patients at baseline before starting the treatment with RTG, RVT, and PLC. A group of age-matched HS was included for comparison at baseline only. Error bars indicate SEM. Asterisks indicate p<0.05 when comparing AD patients of the different groups.

Figure 3

After effects of the cTBS (a) and iTBS (b) protocols on MEP amplitude in Alzheimer's disease patients at baseline (pre) and after 4 weeks (post) of treatment with RTG, RVT, and PLC. Error bars indicate SEM. Asterisks indicate p<0.05 when comparing AD patients of the different groups.

Figure 4

After effects of the SAI protocols on MEP amplitude in Alzheimer's disease patients at baseline (pre) and after 4 weeks (post) of treatment with RTG, RVT, and PLC. Error bars indicate SEM. Asterisks indicate p<0.05 when comparing AD patients of the different groups.

Figure 5

After effects of the cTBS (a) and iTBS (b) protocols on MEP amplitude in the RTG Alzheimer's disease patients group at baseline (pre), after 4 and 12 weeks of treatment with RTG. (c) After effects of the SAI protocols on MEP amplitude in the RTG Alzheimer's disease patients group at baseline (pre), after 4 and 12 weeks of treatment with RTG. The figure shows the results of the subgroup of patients (n=7) involved in the whole 12 weeks course. Error bars indicate SEM. *p<0.05 between the 4 weeks and the baseline evaluation. ^p<0.05 between the 12 weeks and the baseline evaluation.