Pupil-linked arousal, cortical activity, and cognition in Alzheimer's disease.

Arousal dysfunction contributes to impairments seen in Alzheimer's disease. However, the nature and degree of this dysfunction have not been studied in detail. We investigated changes in tonic and phasic arousal using simultaneous pupillometry-EEG, relating these changes to locus coeruleus integrity, a key arousal nucleus. Forty Alzheimer's disease participants and 30 controls underwent neuropsychological testing using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), MRI designed to show contrast in the locus coeruleus as a measure of integrity and simultaneous pupillometry-EEG during 5 min of eyes-open resting-state. Pupillometry-EEG was then also applied during an oddball task which included a passive session and sessions in which responses to target stimuli were required, to test the effect of salience. Alzheimer's disease had lower locus coeruleus integrity (b = -0.26, P = 0.02) and lower peak alpha frequency (tonic arousal) (b = -1.09, P < 0.001). Both were related to ADAS-Cog. There was a very strong relationship between pupil size and both periodic and aperiodic EEG power. Cortical slowing in Alzheimer's disease affected this relationship, particularly at low frequencies. During the attentionally demanding oddball task, Alzheimer's disease participants' behavioural performance was impaired, with reduced accuracy and slower and more variable reaction times. They also had reduced pupil responses to salient stimuli (phasic arousal) (estimate = -0.19, P < 0.001). EEG and pupil measures of pre-stimulus tonic arousal were strongly correlated and predicted behavioural responses in both groups. Arousal fluctuations at rest and in response to stimuli are abnormal in Alzheimer's disease as measured by combined pupillometry and EEG. Salient stimuli that require a behavioural response are accompanied by a phasic increase in arousal, demonstrated by pupil dilation to oddball stimuli. This response is slower and of smaller magnitude in Alzheimer's disease patients. Cortical slowing (reduced peak alpha frequency) is seen in Alzheimer's disease, and this is modulated by arousal level and relates to overall cognition. Pupil-linked arousal responses and alpha EEG fluctuations are tightly coupled, but cortical slowing in Alzheimer's disease influences this coupling. The tools used here to measure neurophysiological arousal level have potential in understanding the nature of arousal system dysfunction in Alzheimer's disease at the group level. These tools may also be used as biomarkers at the individual level in order to target patients most likely to benefit from arousal-modulating medications.