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Alzheimer's disease, using ERP P300 Amplitude to determine drug effectiveness of Anavex 2-73Anavex conducted several tests on Phase 2 patients to gather information on the effectiveness of Anavex 2-73 (A2-73). The tests used to gather ongoing information about the patients during the trial are: 1) Mini-mental state examination score (MMSE) 2) ADCS-ADL 3) Cogstate Brief Battery (CBB) Score and International Shopping List Task (ISLT) Score 4) Electroencephalographic activity, including event-related potentials (EEG/ERP) Anavex provided comments, and graphed results on 1, 2, 3 above. For 4, most of the reports have focused on "P300 ERP amplitude" (P300 Amplitude). They graphed the changes in P300 amplitude over time and provided diagrams of those in presentations. They have also provided graphs showing the average ERP waveform for patients at baseline before taking A2-73, the waveform of healthy patients and the waveform of people after taking A2-73 for a period of time. Additionally, after 5 weeks, they provided tabulated results in the spring 2016 showing P300 ERP amplitude, accuracy, false alarms and reaction time (ms). I think that one of the most compelling part of their reporting on changes during treatment with A2-73 are the graphs of the average P300 amplitude changes in patients taking A2-73. The P300 amplitude (P3b) is a measurement of electrical activity in the brain. The higher the amplitude, the more electrical activity. Therefore, consistently higher measurements of P300 amplitude in EEG/ERP testing in response to computerized questions supports the idea that the Alzheimer's patient is "thinking" better. More of their brain is responding appropriately to stimulus. Prior to using standardized and computerized testing methods in combination with the P300, results varied. The exact method used in testing along with how it is conducted influences results. Using standard methods improves the repeatability of results. Using standard methods along with computerized testing improves them even more. More information on P300: "The P300 component is a positive-going deflection occurring approximately 200–400 ms following stimulus onset. Also referred to as P3b or “classic P3” elicited by repetitive stimuli, it is distinguished from the P3a or “novelty P3 potential” elicited by infrequent stimuli (Knight et al., 1989)." link Given that there are several "metrics" that could be studied as part of the EEG/ERP testing, Is P300 amplitude an effective way to characterize Alzheimer's disease and to determine the impact of treatment with A2-73? The reason this is important is due to the fact that in several other Alzheimer's drug trials, the drug appeared somewhat effective in phase 2 trials but failed in phase 3 trials. Most of the other phase 2 trials were using different metrics to determine effectiveness in phase 2 trials. Usually those methods included the MMSE and ADCS-ADL. In some cases, they used the MMSE, ADCS-ADL and Cogstate battery but they did not use the EEG/ERP testing. Part of the reason is that in the past, the availability of EEG/ERP equipment was limited. But in the last few years, EEG/ERP testing is becoming more available and the tests easier to administer due to the testing becoming computerized. The large modern studies I can find using computerized EEG/ERP testing indicates that P300 amplitude is a good measurement to determine if someone does or does not have Alzheimer's disease. In the past, prior to computerized (and hence) more standardized testing, the literature does not uniformly support this contention and sometimes contradicts it. Examining several studies ... First one: "A clinical trial to validate event-related potential markers of Alzheimer’s disease in outpatient settings" Page "391" of the study published in 2015 shows that for P3A, amplitude is a much better marker of Alzheimer's disease than "latency". For P3B, amplitude is at least as good of a marker as latency. (This study used 103 people with probable mild Alzheimer's disease, and 101 healthy people of similar age to the Alzheimer's patients for controls.) The second study published in 2013 is, "Perceptual and response interference in Alzheimer’s disease and mild cognitive impairment" Table 1 on page "2391" show NC (normal controls), MCI (Mild Cognitive Impairment), AD (Alzheimer's disease) compared together. This study shows that both amplitude and reaction time are better than latency for distinguishing between AD and non-AD. (This study used 16 healthy people of similar age as controls, 15 people with MCI or mild cognitive impairment and 7 Alzheimer's patients.) The next study is an older one published in 1996. "Automatic and Effortful Processing in Aging and Dementia: Event-Related Brain Potentials" This study is quite interesting. They study three groups: Young, Elderly and Elderly with Alzheimer's disease. The study shows that P300 Amplitude, reaction time, number of false alarms and misses are good metrics for Alzheimer's disease. (This study used 16 young healthy people, 11 healthy elderly people, and 12 people who have Alzheimer's disease. The elderly people and people with Alzheimer's disease are of similar ages.) The next study is from 2014, "Evaluation of P300 components for emotion-loaded visual event-related potential in elderly subjects, including those with dementia" http://onlinelibrary.wiley.com/doi/10.1111/pcn.12162/pdf This study uses 48 elderly people of similar age divided equally based on MMSE and MRI results. They examine the impact of "crying" or "smiling" patients on ERP response. The 48 elderly people are divided into 4 groups: Group 1 (healthy group designated as HG); Group 2 ( Intermediate group - not Alzheimer's disease but also not healthy and assessed as low risk to become Alzheimer's disease designated as LRMG ); Group 3 is (Intermediate group - not Alzheimer's disease but also not healthy and assessed as high risk to become Alzheimer's disease designated as HRMG); Group 4 is (Dementia with Alzheimer's disease - designated as ADG). The four groups, (HG, LRMG, HRMG, ADG) are compared for P300 amplitude, P300 latency and for Reaction time. Interestingly, the amplitude for crying faces and smiling faces divide the 4 groups from low amplitude to high amplitude as ADG being the lowest amplitude, HRMG being the next highest, LRMG being the next and HG being the highest amplitude. The conclusion of the study indicated that both P300 amplitude and latency were significantly correlated with disease. The next study from 2015: "Distinctive Effect of Donepezil Treatment on P300 and N200 Subcomponents of Auditory Event-Related Evoked Potentials in Alzheimer Disease Patients" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501636/ This study features 22 Alzheimer's disease patients not taking an Alzheimer medication (AD-N), 22 patients taking 10mg/day of donepezil (AD-T) and 50 healthy controls. This study shows that donepezil increases amplitude, reduces response time and reduces latency. The five studies provide support for the hypothesis that amplitude is a very useful measurement for discriminating between people who do and don't have Alzheimer's disease. |
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