P 159. D2 agonist administration restores impaired LTP-like cortical plasticity in AD patients

Abstract

In animal models of Alzheimer’s disease (AD), amyloid beta fragments interfere with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) and with cholinergic transmission. In a recent study with theta burst stimulation (TBS) we showed that LTP-like cortical plasticity is impaired in AD patients, while LTD seems to be preserved. The neuromodulator dopamine has a strong role in neuroplasticity induction and modulation and has been recently invoked in the pathophysiology of AD. We recently showed that in AD patients the treatment with a subtype-2 receptor dopaminergic agonist (D2) leads to an enhancement of short latency afferent inhibition (SLAI) that is a neurophysiological measure known to be under cholinergic control, but its effect on cortical plasticity has not yet been explored. we aimed at investigating whether administration of a D2 agonist could modulate cortical plasticity induced with TBS over primary motor cortex (M1) in AD patients. We tested the impact of two weeks administration of D2 agonist (rotigotine) on LTP/LTD-like effects induced respectively by means of intermittent (i-) and continuous (c-) TBS delivered over M1 in eight mild AD patients. Each patient was separately evaluated for iTBS and cTBS plasticity induction before and after the two weeks treatment. In each session 20 MEPs were collected at the baseline and then, over the same hot-spot, at 1–5, 6–10, 11–15, 16–20 and 21–25 min after TBS protocols. We also investigated SLAI circuits before and after rotigotine administration. All patients underwent a comprehensive neuropsychological evaluation. We found that at baseline AD patients showed an impaired LTP-like and a normal LTD-like cortical plasticity as assessed by iTBS and cTBS respectively. The efficacy of SLAI circuits was also reduced. After two weeks of D2 agonist administration we observed a marked change in the iTBS protocol effects, revealing that LTP-like plasticity was strikingly enhanced (p > 0.05), while the cTBS protocol did not show similar remarkable modifications. As expected, SLAI was also partially restored by D2 agonist therapy, confirming our recent findings. These preliminary results increasingly highlight the role of dopamine in the pathophysiology of AD and in particular suggest that a dysfunction of D2-like receptors is involved in abnormal cortical plasticity in AD. Clinical studies are needed to better understand and identify the potential place of this class of drugs in AD treatment.