Biomarkers in Alzheimer's disease with a special emphasis on event-related oscillatory responses.

Alzheimer's disease (AD) is a devastating neurodegenerative dementing illness. Early diagnosis at the prodromal stage is an important topic of current research. Significant advances were recently made in the validation process of several biomarkers, including structural/amyloid imaging, cerebrospinal fluid measurements, and glucose positron emission tomography. Nevertheless, there remains a need to develop an efficient, low cost, potentially portable, noninvasive biomarker in the diagnosis, course, or treatment of AD. There is also a great need for a biomarker that would reflect functional brain dynamic changes within a very short time period, such as milliseconds, to provide information about cognitive deficits. Electrophysiological methods have the highest time resolution for reflecting brain dynamics in cognitive impairments. There are several strategies available for measuring cognitive changes, including spontaneous electroencephalography (EEG), sensory-evoked oscillations (SEOs), and event-related oscillations (EROs). The term "sensory-evoked" (SE) implies responses elicited upon simple sensory stimulation, whereas "event-related" (ER) indicates responses elicited upon a cognitive task, generally an oddball paradigm. Further selective connectivity deficit in sensory or cognitive networks is reflected by coherence measurements. When simple sensory stimulus is used, a sensory network becomes activated, whereas an oddball task initiates an activation in a sensory network and additionally in a related cognitive network. In AD, spontaneous activity reveals a topographically changed pattern of oscillations. In addition, the most common finding in spontaneous EEG of AD is decrease of fast and increase of slow frequencies. The hyperexcitability of motor and sensory cortices in AD has been demonstrated in many studies. The motor cortex hyperexcitability has been shown by transcranial magnetic stimulation studies. Also, the SEOs reflecting sensory network indicate a visual sensory cortex hyperexcitability in AD, as demonstrated by increased responses over posterior regions of the hemispheres. On the other hand, ERO studies reflecting activation of a cognitive network imply decreased responses in fronto-central regions of the brain in delta and theta frequencies. Coherence studies show the connectivity between different parts of the brain. Studies of SE coherence in mild AD subjects imply almost intact connectivity in all frequency ranges, whereas ER coherence is decreased in wide connections in alpha, theta, and delta frequency ranges. Moreover, alpha ER coherence seems to be sensitive to cholinergic treatment in AD. In further research in a search of AD biomarkers, multimodal methods should be introduced to electrophysiology in order to validate these methods. Standardization and harmonization of user-friendly acquisition and analysis protocols in larger cohort populations are also needed in order to incorporate electrophysiology as a part of the clinical criteria of AD.