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ERPs for animal models of Alzheimer's disease
P726
Featured Research Sessions: F5-02: Vascular Cognitive Disorders: A VASCOG Update
FEATURED RESEARCH SESSIONS: F5-01 APPLICATIONS OF ELECTROPHYSIOLOGICAL METHODS IN THE FIELD OF ALZHEIMER’S DISEASE (PIA: ELECTROPHYSIOLOGY) F5-01-01
ERPS FOR ANIMAL MODELS OF ALZHEIMER’S DISEASE
Steven Leiser, Lundbeck Research, Paramus, New Jersey, United States. Background: Electroencephalography (EEG) and evoked or event-related potential (EP/ERP) measurements can be used to diagnose or predict the severity of certain neurological and psychiatric disorders. Thus, EEG and ERP hold a high promise of predicting early in development the likelihood that novel therapies or compounds will exhibit clinical efficacy. Quantitative EEG and ERPs can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical (animal) models and the clinic have not been well presented. More reports with both animal and clinical data are needed to firmly establish this claim. Results: Here we will reveal the similarities between rodent and human ERP measurements, particularly the auditory P300, and demonstrate its translatability through similar findings in both the rodent and man.
formation that is unavailable to traditional sparse array methods. We will focus on a cross-modal associative memory “old/new” task designed to elicit activity in medial temporal brain networks including the hippocampus. Results: We will present findings from four studies: (A) A controlled, multicenter trial evaluated the diagnostic accuracy of the test for untreated mild probable AD. A combination of temporal, topographic and behavioral scores showed 83% sensitivity/89% specificity. (B) Source localization methods showed that scalp topography differences in AD and vascular dementia can be attributed to different underlying generators in the brain, a finding consistent with differences in the distribution of the underlying pathology. (C) In a study of treatment effects of cholinesterase inhibitors (donepezil), we tested mild probable AD patients prior to first treatment, and again after one week, one month, and three months. We observed old/new effects that increased with treatment progression, and at three months the scalp topographies show evidence of partial recovery of function. (D) Nonlinear analysis methods can reveal spatial and temporal differences between AD patients and controls in the complexity of the EEG background activity during task execution. Patients showed decreased EEG complexity in left and right centro-temporal regions, and over coarser temporal scales, suggesting changes in the functional connectivity of the brain in AD. We will emphasize throughout the potential for clinical application of these methods, and also the contrasts observed in cognitively healthy adults aged 50-85.
F5-01-04 F5-01-02
ERPS FOR PRECLINICAL ALZHEIMER’S DISEASE AND MCI DUE TO ALZHEIMER’S DISEASE
Andrew Budson, Boston University Alzheimer’s Disease Center, Boston, Massachusetts, United States. Background: Event-Related Potentials (ERPs) have the ability to detect changes in brain physiology prior the onset of Alzheimer’s dementia, prior to the onset of symptoms, and even prior to changes on neuropsychological tests. Results: In this talk we will review a number of studies that have used ERPs to evaluate brain changes in patients with MCI due to AD and Preclinical AD. We will focus on two studies that used the same paradigm, in which participants are instructed to remember 50 pictures, and are then tested on 100 pictures, half old and half new. ERPs were recorded at test. In one study patients with MCI due to AD showed diminished parietal activity from 500-800 ms compared with healthy older adult controls (Ally et al., 2009). In another study changes were observed at several time points and regions including from 200-300 ms in frontal and occipital regions between cognitively normal subjects with the who carry the E280A mutation in the presenilin-1 (PSEN1) gene versus siblings without mutation approximately 10 years prior to the carriers’ development of symptoms (Quiroz et al., 2011). Other studies using ERPs to evaluate patients with MCI due to AD (Bennys et al., 2007; Lai et al., 2010) and individuals at risk for AD due to carrying an APOE-ε4 allele (Irimajiry et al., 2009), will also be reviewed. Conclusions: Throughout the talk, implications on using ERPs as both a diagnostic marker of the AD pathophysiologic process and as an outcome measure in clinical trials will be emphasized.
F5-01-03
HIGH-RESOLUTION EEG BRAIN MAPPING IN ALZHEIMER’S DISEASE
Kerry Kilborn, University of California at Davis, Sacramento, California, United States. Background: Clinically useful biomarkers are necessary to improve diagnosis of Alzheimer’s disease (AD), and to aid in drug development. We will review a series of studies that employ high resolution EEG brain mapping methods (e.g., 128 channel). These methods provide two important advantages in relating changes in brain activity to changes in cognition in AD. First, the excellent temporal resolution of EEG is highly sensitive to certain features of fast-acting cognitive operations. Second, high density electrode montages enable topographic analyses that can reveal neurophysiologic in-
INTRODUCTION TO ERPS FOR AD
John Olichney, University of California at Davis, Sacramento, California, United States. Background: This talk will provide an overview of Cognitive ERPs including its basic principles and best practices. The talk will also discuss several applications of the ERP technique to AD, including its potential utilities in animal studies, early diagnosis and drug development. Results: ERP studies of attention, memory and language processes which have demonstrated sensitivity to early AD will be discussed, as will the use of late potentials such as the P600 and N400 for monitoring disease progression in AD (e.g. from MCI to early AD dementia). Conclusions: The ERP literature on evaluating/measuring drug treatment effects will be reviewed. Strategies by which ERPs may play a valuable role in cohort selection, monitoring disease progression and cognitive improvement will be discussed.
FEATURED RESEARCH SESSIONS: F5-02 VASCULAR COGNITIVE DISORDERS: A VASCOG UPDATE F5-02-01
A CRITIQUE OF THE EXTANT CRITERIA FOR VASCULAR COGNITIVE DISORDERS AND A PROPOSAL
Perminder Sachdev, University of New South Wales, Sydney, Australia. Background: The concept of vascular dementia (VaD) has evolved since the 1960s, with several sets of diagnostic criteria having been published. The most commonly used criteria sets are the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria, the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) criteria, the DSM-IV criteria and the ICD-10 criteria. The correspondence of these criteria is modest and the low sensitivity and specificity of the diagnosis warrants a critical examination and updating of the extant criteria. Methods: The criteria were critically examined at a special symposium of the International Society for Vascular Behavioural and Cognitive Disorders (VASCOG) in 2009 in Singapore. A draft proposal for a new set of criteria was prepared, which was then reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Group of the DSM-5 Task Force of the American Psychiatric Association. It was finally discussed at the 2011 VASCOG conference in Lille France and subsequently revised. Results: Cognitive disorders due to vascular etiology are a heterogeneous
Featured Research Sessions: F5-02: Vascular Cognitive Disorders: A VASCOG Update
FEATURED RESEARCH SESSIONS: F5-01 APPLICATIONS OF ELECTROPHYSIOLOGICAL METHODS IN THE FIELD OF ALZHEIMER’S DISEASE (PIA: ELECTROPHYSIOLOGY) F5-01-01
ERPS FOR ANIMAL MODELS OF ALZHEIMER’S DISEASE
Steven Leiser, Lundbeck Research, Paramus, New Jersey, United States. Background: Electroencephalography (EEG) and evoked or event-related potential (EP/ERP) measurements can be used to diagnose or predict the severity of certain neurological and psychiatric disorders. Thus, EEG and ERP hold a high promise of predicting early in development the likelihood that novel therapies or compounds will exhibit clinical efficacy. Quantitative EEG and ERPs can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical (animal) models and the clinic have not been well presented. More reports with both animal and clinical data are needed to firmly establish this claim. Results: Here we will reveal the similarities between rodent and human ERP measurements, particularly the auditory P300, and demonstrate its translatability through similar findings in both the rodent and man.
formation that is unavailable to traditional sparse array methods. We will focus on a cross-modal associative memory “old/new” task designed to elicit activity in medial temporal brain networks including the hippocampus. Results: We will present findings from four studies: (A) A controlled, multicenter trial evaluated the diagnostic accuracy of the test for untreated mild probable AD. A combination of temporal, topographic and behavioral scores showed 83% sensitivity/89% specificity. (B) Source localization methods showed that scalp topography differences in AD and vascular dementia can be attributed to different underlying generators in the brain, a finding consistent with differences in the distribution of the underlying pathology. (C) In a study of treatment effects of cholinesterase inhibitors (donepezil), we tested mild probable AD patients prior to first treatment, and again after one week, one month, and three months. We observed old/new effects that increased with treatment progression, and at three months the scalp topographies show evidence of partial recovery of function. (D) Nonlinear analysis methods can reveal spatial and temporal differences between AD patients and controls in the complexity of the EEG background activity during task execution. Patients showed decreased EEG complexity in left and right centro-temporal regions, and over coarser temporal scales, suggesting changes in the functional connectivity of the brain in AD. We will emphasize throughout the potential for clinical application of these methods, and also the contrasts observed in cognitively healthy adults aged 50-85.
F5-01-04 F5-01-02
ERPS FOR PRECLINICAL ALZHEIMER’S DISEASE AND MCI DUE TO ALZHEIMER’S DISEASE
Andrew Budson, Boston University Alzheimer’s Disease Center, Boston, Massachusetts, United States. Background: Event-Related Potentials (ERPs) have the ability to detect changes in brain physiology prior the onset of Alzheimer’s dementia, prior to the onset of symptoms, and even prior to changes on neuropsychological tests. Results: In this talk we will review a number of studies that have used ERPs to evaluate brain changes in patients with MCI due to AD and Preclinical AD. We will focus on two studies that used the same paradigm, in which participants are instructed to remember 50 pictures, and are then tested on 100 pictures, half old and half new. ERPs were recorded at test. In one study patients with MCI due to AD showed diminished parietal activity from 500-800 ms compared with healthy older adult controls (Ally et al., 2009). In another study changes were observed at several time points and regions including from 200-300 ms in frontal and occipital regions between cognitively normal subjects with the who carry the E280A mutation in the presenilin-1 (PSEN1) gene versus siblings without mutation approximately 10 years prior to the carriers’ development of symptoms (Quiroz et al., 2011). Other studies using ERPs to evaluate patients with MCI due to AD (Bennys et al., 2007; Lai et al., 2010) and individuals at risk for AD due to carrying an APOE-ε4 allele (Irimajiry et al., 2009), will also be reviewed. Conclusions: Throughout the talk, implications on using ERPs as both a diagnostic marker of the AD pathophysiologic process and as an outcome measure in clinical trials will be emphasized.
F5-01-03
HIGH-RESOLUTION EEG BRAIN MAPPING IN ALZHEIMER’S DISEASE
Kerry Kilborn, University of California at Davis, Sacramento, California, United States. Background: Clinically useful biomarkers are necessary to improve diagnosis of Alzheimer’s disease (AD), and to aid in drug development. We will review a series of studies that employ high resolution EEG brain mapping methods (e.g., 128 channel). These methods provide two important advantages in relating changes in brain activity to changes in cognition in AD. First, the excellent temporal resolution of EEG is highly sensitive to certain features of fast-acting cognitive operations. Second, high density electrode montages enable topographic analyses that can reveal neurophysiologic in-
INTRODUCTION TO ERPS FOR AD
John Olichney, University of California at Davis, Sacramento, California, United States. Background: This talk will provide an overview of Cognitive ERPs including its basic principles and best practices. The talk will also discuss several applications of the ERP technique to AD, including its potential utilities in animal studies, early diagnosis and drug development. Results: ERP studies of attention, memory and language processes which have demonstrated sensitivity to early AD will be discussed, as will the use of late potentials such as the P600 and N400 for monitoring disease progression in AD (e.g. from MCI to early AD dementia). Conclusions: The ERP literature on evaluating/measuring drug treatment effects will be reviewed. Strategies by which ERPs may play a valuable role in cohort selection, monitoring disease progression and cognitive improvement will be discussed.
FEATURED RESEARCH SESSIONS: F5-02 VASCULAR COGNITIVE DISORDERS: A VASCOG UPDATE F5-02-01
A CRITIQUE OF THE EXTANT CRITERIA FOR VASCULAR COGNITIVE DISORDERS AND A PROPOSAL
Perminder Sachdev, University of New South Wales, Sydney, Australia. Background: The concept of vascular dementia (VaD) has evolved since the 1960s, with several sets of diagnostic criteria having been published. The most commonly used criteria sets are the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria, the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) criteria, the DSM-IV criteria and the ICD-10 criteria. The correspondence of these criteria is modest and the low sensitivity and specificity of the diagnosis warrants a critical examination and updating of the extant criteria. Methods: The criteria were critically examined at a special symposium of the International Society for Vascular Behavioural and Cognitive Disorders (VASCOG) in 2009 in Singapore. A draft proposal for a new set of criteria was prepared, which was then reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Group of the DSM-5 Task Force of the American Psychiatric Association. It was finally discussed at the 2011 VASCOG conference in Lille France and subsequently revised. Results: Cognitive disorders due to vascular etiology are a heterogeneous