Event-related Potentials and the Diagnosis of Alzheimer’s Disease—The COGNISION™ System researchers have become skeptical of the amyloid hypothesis.5 Many
others believe that memory symptoms are a relatively late development in AD and that a successful therapy, including an amyloid-based strategy, depends on intervening earlier in the disease process.
A New Definition of the Disease
In order to facilitate this strategy, a new and evolving definition of AD has been created that relies on biomarkers along with progressive cognitive decline. This approach defines AD more clearly as a brain disease of plaques and tangles, rather than strictly being a cognitive disorder or dementia. The three proposed categories include:
• Alzheimer’s disease dementia; •
mild cognitive impairment due to Alzheimer’s disease; and • pre-clinical Alzheimer’s disease.
This definition greatly expands the number of individuals counted as having the disease by including a large group of asymptomatic people. It is hoped that redefining AD in this way will facilitate a unified research program and prompt a search for earlier interventions. Under the old definition of AD that relies on clinical diagonsis, new drug development aimed at intervention at the earliest possible stage would be greatly hampered as the industry is reluctant to expend enormous resources on a condition that is not recognized as a disease.6
Developing Biomarkers
The new strategy depends on refining or developing a set of biomarkers that can reliably diagnose the condition as early in the process as possible. Current candidate marker approaches include:
• structural or functional magnetic resonance imaging;7
• cerebrospinal fluid protein analysis;8,9 •
and • PET scanning.
All of these approaches have advantages and disadvantages and may ultimately be suitable for various purposes or stages of disease. It is highly likely that combinations of biochemical and cognitive biomarkers may be necessary to achieve the desired level of diagnostic accuracy.
There are many challenges to implementing this new paradigm. The process of developing biomarkers is incomplete and ongoing. The expense and intrusiveness of obtaining certain markers limits their usefulness (e.g. lumbar puncture for cerebrospinal fluid or the lack of portability of diagnostic devices, such as advanced PET systems with radio-labeling compounds).
Expanded use of biomarkers will be much easier to implement as a research tool than in clinical practice. The cost and difficulty of screening large numbers of asymptomatic individuals for clinical purposes with lumbar puncture or PET are obvious.
Therefore, for the immediate future memory symptoms are likely to continue to be the trigger for clinical assessment. Physicians will need
US NEUROLOGY
blood or genetic markers using apolipoprotein E4 and other proteins;10
better diagnostic tools to clarify diagnosis in clinical practice, hopefully including some type of biomarker.
The use of Electroencephalography-based Technology The limitations of previously discussed AD biomarkers, in terms of evaluating cognitive deficit, leave room for additional approaches. One such approach is ERP. This is an electroencephalography (EEG)-based technology that can also serve as an AD biomarker. ERP is less expensive, intrusive and more portable than most currently proposed biomarkers, so it holds promise.
Certain ERP signals are believed to represent higher cognitive analysis or processing, rather than simple registration of an external signal (such as a tone or flashing light). Signals must usually be averaged over a number of repetitions of the same event to ‘average out’ background EEG ‘noise’.
Event-related Potentials in the Brain ERPs are a subset of EEG signals of cortical activity. ERP is a specialized form of EEG and may be thought of as a subset of evoked potentials. Evoked potentials are familiar to many neuroscientists as EEG waveforms provoked by sensory stimuli, often auditory or visual. Such evoked potentials are useful in various situations, such as brain mapping or in the diagnosis of certain types of deafness or blindness. The evoked potentials represent the brain’s reception and registration of the sensory input. However, ERPs occur later. They represent the brain’s higher cortical analysis of the initial signals. This is the essence of ERP utility in disorders such as AD. ERP is a cognitive biomarker representing actual changes and slowing in cognitive processing, as opposed to detecting the presence of an abnormal protein (a marker that may not have a causal link to cognitive changes). Compared with structural or physiological markers, ERP is an absolute rather than a relative marker, in that a single determination has meaning; scans may require multiple determinations over time for comparative purposes.11,12
Event-related Potentials as Cognitive Biomarkers of Alzheimer’s Disease The ‘Odd-ball Paradigm’
An ERP ‘odd-ball paradigm’ is routinely employed to assess novelty detection and memory storage of patients. The paradigm entails giving two different stimuli in random order, with one occurring less frequently. The subject is then asked to discriminate between the less frequent (target) and the more frequent (standard) stimuli. In this situation, the target stimulus elicits an ERP response (such as the P300), whereas the standard stimulus does not. The ERP signal reflects the higher cognitive processes required to make this discrimination. Despite having determined this, the exact mechanism of ERP signals is not known.11
Several published studies examine ERP and AD. Recent studies include one by Polich and Corey-Bloom, in which 16 early-stage AD patients were compared with normal elderly controls using ERP P300, with four different auditory and visual odd-ball tasks. P300 amplitude was lower and peak latency longer in the AD group, especially in relatively easier tasks. The authors concluded that P300 is sensitive to early brain changes in AD and that easier-to-perform stimulus discrimination tasks were the most useful.11
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