Predictive Power of Cognitive Biomarkers in Neurodegenerative Disease Drug Development: Utility of the P300 Event-Related Potential.

Neurodegenerative diseases, such as Alzheimer's disease (AD), and their associated deterioration of cognitive function are common causes of disability. The slowly developing pathology of neurodegenerative diseases necessitates early diagnosis and monitored long-term treatment. Lack of effective therapies coupled with an improved rate of early diagnosis in our aging population have created an urgent need for the development of novel drugs, as well as the need for reliable biomarkers for treatment response. These issues are especially relevant for AD, in which the rate of clinical trial drug failures has been very high. Frequently used biomarker evaluation procedures, such as positron emission tomography or cerebrospinal fluid measurements of phospho-tau and amyloid beta, are invasive and costly, and not universally available or accessible. This review considers the functionality of the event-related potential (ERP) P300 methodology as a surrogate biomarker for predicting the procognitive potential of drugs in clinical development for neurocognitive disorders. Through the application of standardized electroencephalography (EEG) described here, ERP P300 can be reliably measured. The P300 waveform objectively measures large-scale neuronal network functioning and working memory processes. Increased ERP P300 latency has been reported throughout the literature in disorders of cognition, supporting the potential utility of ERP P300 as a biomarker in many neurological and neuropsychiatric disorders, including AD. Specifically, evidence presented here supports ERP P300 latency as a quantitative, unbiased measure for detecting changes in cognition in patients with AD dementia through the progression from mild to moderate cognitive impairment and after drug treatment.

Machine Learning on Visibility Graph Features Discriminates the Cognitive Event-Related Potentials of Patients with Early Alzheimer's Disease from Healthy Aging.

We present a framework for electroencephalography (EEG)-based classification between patients with Alzheimer's Disease (AD) and robust normal elderly (RNE) via a graph theory approach using visibility graphs (VGs). This EEG VG approach is motivated by research that has demonstrated differences between patients with early stage AD and RNE using various features of EEG oscillations or cognitive event-related potentials (ERPs). In the present study, EEG signals recorded during a word repetition experiment were wavelet decomposed into 5 sub-bands (δ,θ,α,ß,γ). The raw and band-specific signals were then converted to VGs for analysis. Twelve graph features were tested for differences between the AD and RNE groups, and t-tests employed for feature selection. The selected features were then tested for classification using traditional machine learning and deep learning algorithms, achieving a classification accuracy of 100% with linear and non-linear classifiers. We further demonstrated that the same features can be generalized to the classification of mild cognitive impairment (MCI) converters, i.e., prodromal AD, against RNE with a maximum accuracy of 92.5%. Code is released online to allow others to test and reuse this framework.

Neural evidence that disengaging memory retrieval is modulated by stimulus valence and rumination.

To remember information from our personal past we need to be in a cognitive state where we treat stimuli as cues for memory retrieval. In this study we considered whether participants could exert control and disengage from a memory state when it was no longer required for the task at hand. In particular, we examined whether this ability was affected by the valence of the stimuli and participant's rumination scores. After a study phase participants completed test blocks where the task switched every two trials between a memory task (retrieving information from the study phase) and a perceptual task. Even though there was no episodic memory requirement in the perceptual task, a well-established event-related potential (ERP) index of memory retrieval was present for both trials when the stimuli were negative valenced pictures but not for neutral pictures. Furthermore, there was a positive correlation between the magnitude of this ERP memory index in the perceptual task and rumination scores but only for neutral stimuli and not negative. Thus, in this study participants generally had difficultly suppressing memory retrieval when negative stimuli were presented. However, for neutral stimuli only ruminators were more susceptible to memory intrusions.

Event-related potential and EEG oscillatory predictors of verbal memory in mild cognitive impairment.

Reliable biomarkers of memory decline are critical for the early detection of Alzheimer's disease. Previous work has found three EEG measures, namely the event-related brain potential P600, suppression of oscillatory activity in the alpha frequency range (∼10 Hz) and cross-frequency coupling between low theta/high delta and alpha/beta activity, each of which correlates strongly with verbal learning and memory abilities in healthy elderly and patients with mild cognitive impairment or prodromal Alzheimer's disease. In the present study, we address the question of whether event-related or oscillatory measures, or a combination thereof, best predict the decline of verbal memory in mild cognitive impairment and Alzheimer's disease. Single-trial correlation analyses show that despite a similarity in their time courses and sensitivities to word repetition, the P600 and the alpha suppression components are minimally correlated with each other on a trial-by-trial basis (generally |r s| < 0.10). This suggests that they are unlikely to stem from the same neural mechanism. Furthermore, event-related brain potentials constructed from bandpass filtered (delta, theta, alpha, beta or gamma bands) single-trial data indicate that only delta band activity (1-4 Hz) is strongly correlated (r = 0.94, P < 0.001) with the canonical P600 repetition effect; event-related potentials in higher frequency bands are not. Importantly, stepwise multiple regression analyses reveal that the three event-related brain potential/oscillatory measures are complementary in predicting California Verbal Learning Test scores (overall R 2 ' s in 0.45-0.63 range). The present study highlights the importance of combining EEG event-related potential and oscillatory measures to better characterize the multiple mechanisms of memory failure in individuals with mild cognitive impairment or prodromal Alzheimer's disease.

Brain state before a memory probe and associative retrieval in older adults.

Older individuals' difficulty in remembering events from a particular time and place may be explained by changes in retrieval-related control processes. We investigated how aging affects neural activity leading up to a retrieval probe and how such activity relates to later performance. Electrical brain activity was recorded while healthy younger and older humans memorized visual word pairs consisting of an object word (e.g., doll) preceded by a location word (e.g., garden). Only object words were presented during the memory test, the task being to decide whether an object had been presented earlier and, if so, what location had been paired with it. A warning signal before each test probe alerted to an upcoming object. A sustained negative-going event-related potential deflection preceded objects whose associated location could be remembered, especially in older individuals. The poorer an older individual's associative memory, the bigger was this deflection. Aging thus seems accompanied by changes in anticipatory brain states that relate to recollection. Such states may serve to mobilize control processes that aid the recovery of contextual details.

Cognitive Deficits and Associated ERP N400 Abnormalities in FXTAS With Parkinsonism.

Objective: To examine cognitive deficits and associated brain activity in fragile X-associated tremor/ataxia syndrome (FXTAS) patients with parkinsonism (FXTp+), in relation to FXTAS patients without parkinsonism (FXTp-), and normal elderly controls (NC). Methods: Retrospective reviews were performed in 65 FXTAS patients who participated in the event-related brain potential (ERP) study and also had either a videotaped neurological examination or a neurological examination for extrapyramidal signs. Parkinsonism was defined as having bradykinesia with at least one of the following: rest tremor, postural instability, hypermyotonia, or rigidity. Eleven FXTp+ patients were identified and compared to 11 matched FXTp- and 11 NC. Main ERP measures included the N400 congruity effect, N400 repetition effect, and the late positive component (LPC) repetition effect. Results: When compared with FXTp- and NC, the FXTp+ group showed more severe deficits in executive function, cued-recall, recognition memory, along with a significantly reduced N400 repetition effect (thought to index semantic processing and verbal learning/memory) which was correlated with poorer verbal memory. Across all patients, FMR1 mRNA levels were inversely correlated with delayed recall on the California Verbal Learning Test (CVLT). Interpretation: The findings of more prominent executive dysfunction and verbal learning/memory deficits in FXTp+ than FXTp- are consistent with findings in Parkinson's disease (PD), and may indicate that concomitant and/or synergistic pathogenetic mechanisms associated with PD play a role in FXTAS. These results have implications not only for understanding the cognitive impairments associated with the parkinsonism subtype of FXTAS, but also for the development of new interventions for these patients.