Cholinesterase inhibitors affect brain potentials in amnestic mild cognitive impairment

Abstract

Amnestic mild cognitive impairment (MCI) is an isolated episodic memory disorder that has a high likelihood of progressing to Alzheimer's disease. Auditory sensory cortical responses (P50, N100) have been shown to be increased in amplitude in MCI compared to older controls. We tested whether (1) cortical potentials to other sensory modalities (somatosensory and visual) were also affected in MCI and (2) cholinesterase inhibitors (ChEIs), one of the therapies used in this disorder, modulated sensory cortical potentials in MCI. Somatosensory cortical potentials to median nerve stimulation and visual cortical potentials to reversing checkerboard stimulation were recorded from 15 older controls and 15 amnestic MCI subjects (single domain). Results were analyzed as a function of diagnosis (Control, MCI) and ChEIs treatment (Treated MCI, Untreated MCI). Somatosensory and visual potentials did not differ significantly in amplitude in MCI subjects compared to controls. When ChEIs use was considered, somatosensory potentials (N20, P50) but not visual potentials (N70, P100, N150) were of larger amplitude in untreated MCI subjects compared to treated MCI subjects. Three individual MCI subjects showed increased N20 amplitude while off ChEIs compared to while on ChEIs. An enhancement of N20 somatosensory cortical activity occurs in amnestic single-domain MCI and is sensitive to modulation by ChEIs.

Fig. 1

Grand average somatosensory evoked potentials (N20, P30, N40, P50) to median nerve stimulation are shown as a function of diagnosis (top panels : Control, MCI) and of ChEIs treatment (lower panels: Treated MCI, Untreated MCI) for the interstimulus intervals (ISIs) of 1500 ms and 500 ms. The vertical line indicates stimulus onset.

Fig. 2

Grand average visual evoked potentials (N70, P100, N150) to a reversing checkerboard are shown as a function of diagnosis (top panels : Control, MCI) and of ChEIs treatment (lower panels: Treated MCI, Untreated MCI) for the interstimulus intervals (ISIs) of 1500 ms and 500 ms. The vertical line indicates stimulus onset.

Fig. 3

Test visits are shown for three MCI individuals as a function of ChEIs treatment. The filled black line indicates on treatment with ChEIs (On ChEIs) and the dashed black line indicates off treatment with ChEIs (Off ChEIs). Subject 1 was tested after discontinuing ChEI for two weeks and retested after four weeks of ChEI treatment. Subject 2 was studied on six separate occasions: one time before starting treatment, three times after taking ChEIs, and two times after discontinuing the medications. Subject 3 was untreated at the time of the initial test and then retested after taking ChEI.

Fig. 4

Somatosensory evoked potentials and N20 amplitude tested while on and off ChEI treatment in three individual MCI subjects for the ISI of 1500 ms. These MCI subjects were not taking ChEIs at the time of the initial evoked potential tests and were subsequently treated with ChEIs, and retested. N20 amplitude was reduced approximately in half when untreated with ChEIs (black/white stripe bars) compared to when treated (black bars). Somatosensory potentials shown in top panels were from the first and second tests. In the lower panels, numbers below the x-axis show subject’s test number. The horizontal dashed line indicates the mean amplitude of N20 component for control (−1.9 μV) with arrow representing ±1 SD of the control mean. ChEIs = cholinesterase inhibitors. On ChEIs = treated with cholinesterase inhibitors (Donepezil: 10 mg/day). Off ChEIs = untreated with cholinesterase inhibitors.