Cognitive Event-Related Potentials: Biomarkers of Synaptic Dysfunction Across the Stages of Alzheimer’S Disease

Journal of Alzheimer’s Disease 26 (2011) 215–228 215 DOI 10.3233/JAD-2011-0047 IOS Press

Cognitive Event-Related Potentials: Biomarkers of Synaptic Dysfunction Across the Stages of Alzheimer’s Disease

John M. Olichneya,b,∗, Jin-Chen Yanga,b, Jason Taylorc and Marta Kutasd,e aDepartment of Neurology, University of California, Davis, CA, USA bCenter for Mind and Brain, University of California, Davis, CA, USA cMRC Cognition and Brain Sciences Unit, Cambridge, UK dDepartment of Cognitive Science, University of California, San Diego, CA, USA eDepartment of Neurosciences, University of California, San Diego, CA, USA

Abstract. Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to clinical deﬁcits, which could advance the early detection and diagnosis of “presymptomatic AD”.

Keywords: Alzheimer’s disease (AD), mild cognitive impairment (MCI), synaptic dysfunction, preclinical AD, event-related potentials (ERP), P300, N400, P600, Late Positive Component (LPC), EEG

INTRODUCTION/OVERVIEW P300 studies, the full potential of cognitive ERPs for diagnosing and/or treating AD patients has yet to be This article offers a concise overview of the scien- realized. In this era of rapidly evolving brain imaging tific literature on several event-related brain potential techniques, non-invasive electrophysiological data are (ERP) components with demonstrated sensitivity to increasingly important in advancing our understand- Alzheimer’s disease (AD). These components include ing of the what and where of cognition. Understanding the N200, P300, N400, and P600 (or LPC for late posi- the mechanisms by which AD causes an unraveling tive component), each of which taps different aspects of of many key cognitive processes, far broader than perceptual and/or cognitive processing. ERPs provide memory processes alone, is finally within the reach a flexible and powerful technique, with superb tem- of cognitive neuroscientists. poral resolution, which can be used to probe subtle, sometimes ‘subclinical’, abnormalities of cognition. COGNITIVE EVENT-RELATED Despite over 30 years of ERP research since the initial POTENTIALS (ERPS) ∗Correspondence to: Prof. John M. Olichney, M.D., Center for Mind and Brain, 267 Cousteau Place, Davis, CA 95618, USA. Fax: Cognitive ERPs provide a powerful, non-invasive, +1 530 297 4000; E-mail: [email protected]. tool for studying the brain’s synaptic function. ERPs

ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved 216 J.M. Olichney et al. / ERPs in Alzheimer’s Disease are an instantaneous reflection of the summated post- minals in mid-frontal cortex. Electron microscopy of synaptic excitatory (EPSPs) and inhibitory (IPSPs) cortical biopsies in early- to mid-stage AD shows membrane potentials, primarily of pyramidal cells in a 30% decrease in synaptic density and a 25% de- the neocortex [1–3]. The temporal immediacy of crease in synapses/ neuron [15]. Bertoni-Freddari et al. ERPs is especially advantageous in the study of [16] reported a large increase in the proportion of memory, given that memory encoding and retrieval deafferented synapses on hippocampal neurons from processes can be very fast, and in light of the evidence autopsied AD cases. In short, it is reasonable to con- that the temporal encoding of information may be ceive of AD as a diffuse deafferentation syndrome, in important if not essential for synaptic plasticity which both the neocortex and hippocampus have lost a [4, 5]. Because ERPs (like Magnetoencephalography critical proportion of their normal inputs [17]. Accord- or MEG) reflect the precise timing and temporal ingly, cognitive ERPs may provide a highly sensitive patterns of neuronal activity, they are very useful in biomarker for AD. quantifying the timing and sequence of the various stages or aspects of cognitive processing, more generally. In broad stroke, evoked potential (EP) and MIDDLE-LATENCY ERP COMPONENTS IN ERP research have shown that early brain responses AD DEMENTIA (P50, N100, P200 AND N200) (e.g., the visual N1) generally reflect the sensory input characteristics, while later responses are relatively In general, EP and ERP studies in AD have shown more dependent on the mental operations performed normal latency and amplitude of the early “sensory” on the stimuli as well as on non-sensory factors such components (e.g., visual and auditory N1 or N100). In as predictability, higher perceptual and semantic 1987, Goodin and Aminoff [18] reported normal audi- features. It is these slower, later, so-called endogenous tory N100 and P200 latencies in AD in response to components that have shown particular sensitivity to frequent, standard (i.e., non- target) tones in a classic Alzheimer’s disease (AD), a disease with predilection auditory “oddball” P300 paradigm (see also section on for the medial temporal lobes and higher association P300 studies of AD below). This finding was despite neocortical regions [6, 7]. the fact that their AD patient group was severely impaired (6 of 22 AD patients were too severe to be tested with the mini-mental state exam (MMSE)). N100 and AD AND SYNAPTIC DYSFUNCTION P200 latencies were also found to be relatively insen- sitive to normal aging, but sensitive to subcortical In recent years, several investigators have suggested dementias such as Huntington’s or Parkinson’s disease that AD may be primarily a disorder of the synapse and [19]. synaptic plasticity [8–10]. Several transgenic animal Delayed P200 latency to pattern reversal or to flash models of AD, for instance, have revealed promi- stimuli in AD has been reported in some (e.g., [20, nent inhibition of long-term potentiation (LTP) and/or 21]) but not other studies (e.g., [22]). A delayed flash reduced synaptic transmission before the appearance P200 has been suggested as useful in distinguishing of extensive AD pathology (amyloid plaques and AD from other dementias, particularly when normal neurofibrillary changes) or neuron loss [11, 12]. As flash P100 and pattern reversal P100 s are present [23, a consequence, much of the current basic research 24]. Martinelli et al. [20] also found delayed visual focuses on the mechanisms of synaptic dysfunction P200 in AD, using pattern visual evoked potentials. in AD and its relationship to A␤ oligomers [13]. Furthermore, they reported that P200 amplitude over Selkoe [9], for example, made a substantive change the right posterior scalp correlated with visuospatial in his model of AD pathogenesis, when he sug- abilities. However, Saitoh [25] used a visual target gested that the earliest changes in synaptic function P300 paradigm, and found normal P100, N100, and may be due to soluble forms of A␤ and precede P200 components in AD. the appearance of any extracellular amyloid deposits. Most investigations of verbal stimuli – spoken [26] Clinico-neuropathologic studies, likewise, have impli- or written [27] also have found normal (amplitude cated the synapse as a primary mediator of dementia and latency) N100 and P200 components in mild AD severity. Terry et al. [14], for example, found that patients. In response to non-verbal, auditory tones, nearly 90% of the variance in dementia severity could Golob and Starr [28] found robust P50 potentials (also be accounted for by the density of pre-synaptic ter- termed the auditory P1) in mild AD, which were sig- J.M. Olichney et al. / ERPs in Alzheimer’s Disease 217 nificantly enlarged compared to healthy elderly. One activity). This pattern of results (P300 s to target tones caveat for this result is that reduced slow-negative only) is dependent on attention. The P300 has been “readiness potentials” in AD also resulted in slightly extensively studied and well characterized in both nor- more positive pre-stimulus baseline voltage in the AD mal and neurologically-impaired populations. P300 group. latency is variable, and generally increases with the complexity of the stimulus evaluation and decisional processes demanded by the task. P300 amplitude and N200 latency are modulated by a variety of factors-subjective probability, stimulus saliency, availability of atten- Rather consistent abnormalities in auditory N200 tional resources [35] —and it appears to be generated latency have been reported in AD [19, 29, 30]. The by a distributed network of neural regions—infer- N200 is the earliest ERP component which consis- otemporal, perirhinal, prefrontal, cingulate, superior tently differentiates target from non-target stimuli in temporal and parietal cortices, as well as the hip- an “oddball” task, and immediately precedes the P300 pocampus [36, 37] —suggesting that P300 may index discussed below. It is also sensitive to normal aging, a heterogeneous set of cognitive processes. On the becoming smaller and slower with age [31] at a rate other hand, studies of patients with damage to the nearly as fast as the slowing of P300 latency [19] temporo-parietal junction have found that the auditory (e.g., estimated at 0.74 ms/year, in comparison to (although not visual) P300 response is eliminated [38], 1.15 ms/year for the P300). Duffy et al. [32, 33] have suggesting that this neocortical region may be criti- shown that visual motion-elicited ERPs may help iden- cal in generation or propagation of the scalp P300 (in tify a subtype of AD. AD patients with low ability to the auditory modality). In general, the P3b amplitude detect random dot motion also showed large decrease has proven more sensitive to sensory-perceptual than in their N200 amplitude response to optic flow with response selection and execution factors, in contrast to nearly absent N200 in response to radial motion of reaction time measures which are sensitive to both, It coherent dots. The authors interpreted this finding as is generally agreed that when a stimulus elicits a P300 implicating greater neuropathology in the extrastriate component, it is reasonable to assume that the stimulus visual cortex of this subgroup. has been encoded into working memory. This is gener- In sum, later components, such as the N200 and ally consistent with the hypotheses that P300 reflects P300 (discussed below) have shown better sensitiv- processes involved in updating of working memory ity to dementia than early sensory components, albeit [39], or the processes of stimulus categorization [40]. poor specificity in differentiating among the various dementias. P300 IN ALZHEIMER’S DISEASE P300: OVERVIEW With normal aging, the latency of the auditory The P300 (or ‘P3b’) component is a scalp positivity P300 increases ∼1–2 ms/year [19, 41]. In AD, an elicited by low-probability task-relevant stimuli dur- even greater latency increase (∼2 standard deviations ing stimulus classification tasks in auditory, visual, above the mean of normal older individuals) is com- and somatosensory modalities. In the canonical P300- monly reported, and some studies have found that eliciting experiment, the “auditory oddball” task, par- P300 latency may be useful to differentiate between ticipants are asked to detect (by counting or button AD pathology and other disorders (e.g., depression, press) a low-probability “target” (e.g., high-pitched) schizophrenia [42, 43]), although others have not [44, tone embedded in a stream of “standard” (e.g., low- 45]. The clinical utility of P300 latency measures pitched) tones. The target tones normally elicit a large is generally enhanced in combination with standard scalp positivity which peaks ∼300 ms post-stimulus neuropsychological tests. Goodin [46], for example, onset and is maximal over midline centroparietal found that in cases of equivocal dementia (50% pretest electrode sites (unlike the frontally distributed ‘P3a’ probability), those with concurrent P300 latency delay elicited by task-irrelevant stimuli, e.g., dog barking). showed a greater likelihood of having a dementing ill- The standard tones typically do not elicit a P300 ness (estimated at 90%). One study found change in (although see Squires et al. [34] for demonstration P300 latency was more sensitive to disease progression that standards may also occasionally elicit some P300 (over 1 year) than either the Cognitive Abilities Screen- 218 J.M. Olichney et al. / ERPs in Alzheimer’s Disease ing Instruments (CASI) or MMSE in both AD and MCI also reduced by stimulus repetition (reviewed in a later [47]. P300 amplitude also appears to be reduced in section). The effect of semantic congruity on N400 AD, although P300 amplitude reductions are also seen amplitude (the “N400 effect”) has been interpreted in several other neurological and psychiatric disorders to reflect the reduction in processing effort needed to (e.g., vascular dementia, schizophrenia). In summary, access the meaning of a stimulus, given a coherent pre- the literature indicates that auditory P300 measures dictable context [57, 58], i.e., “contextual integration” show moderate correlations with mini-mental status (though see Kutas & Federmeier [59] for an alternative exam (MMSE) scores [45, 48] and have greater sensi- account in terms of semantic memory activation). tivity to more advanced stages of dementia. Factors that appear to affect the clinical utility of N400 IN ALZHEIMER’S DISEASE P300 include the methodology used — especially with respect to attentional and memory-load demands — The presence or absence and amplitude of the N400 and the dementia severity of the patient group (see have been used to evaluate the integrity of semantic detailed review in Olichney and Hillert [49]). Abnor- memory in Alzheimer’s disease. Language dysfunc- mal P300 latencies are more likely to be reported in tion is evident relatively early in the course of AD, more complex tasks (e.g., counting) relative to simple patients often presenting with word-finding difficulties target-detection tasks. It is interesting to note, how- and poor performance on tests of letter and category ever, that this effect is not simply due to task difficulty fluency [60]. The latter is especially suggestive of a per se; Polich and Pitzer [50], for example, reported breakdown of semantic memory [61]. Indeed, behav- that increasing the difficulty of sensory discrimina- ioral studies (e.g., the triadic word task) have found tions actually decreased the discriminative sensitivity evidence that semantic associations are progressively of P300 latency and amplitude measures. Although the degraded in AD [62]. Nonetheless, it continues to be P300 response has been most commonly studied in a matter of debate whether the semantic impairment the auditory modality, studies using visual [50] and in AD is primarily a deficit in retrieving information olfactory [51] stimuli have reported greater sensitivity from an intact memory store, or a degradation of the to AD pathology. Morgan and Murphy [51] investi- representations themselves [63]. gated olfactory event-related potentials (OERPs) and The N400 response to written words is sensitive to found delayed P200 and P300 latencies, which were normal aging: N400 latency increases at ∼2 ms/year significantly correlated with AD dementia severity and N400 amplitude decreases at ∼0.07 ␮V/year and had a stronger (92%) value in differentiating AD across the adult lifespan [64, 65]. From ERP studies of from normal aging group than auditory P300 mea- semantic memory (reviewed below), it is apparent that sures. the N400 is usually abnormal in AD, typically reduced in amplitude and delayed in latency beyond that seen in normal aging. The progressive flattening of the N400 N400: OVERVIEW may be a manifestation of failing N400 generators. Quantitative measures of N400 latency may provide The N400 is a scalp negativity elicited in response to an accurate metric of dementia stage and progres- potentially meaningful stimuli that peaks 400 ms post- sion. Using multiple linear regression analyses, Iragui stimulus over bilateral posterior channels. The N400 and colleagues [66] found that neuropsychological test is typically larger over the right hemisphere for visual scores could explain >80% of the variance (R = 0.90) words, but sometimes shows a slight left-hemisphere in the N400 latency (fractional area latency of the dif- bias for spoken words [52, 53]. Intracranial record- ference wave contrasting incongruous and congruous ings have consistently found N400-like potentials in endings to statements defining opposites). the anterior fusiform and parahippocampal gyri bilater- ally [54, 55]; other candidate N400 generators include the superior temporal sulcus, and posterior parietal N400: SEMANTIC CONGRUITY EFFECTS and ventral prefrontal cortices [56]. N400 amplitude IN AD is sensitive to the semantic congruity of the eliciting stimulus with the (preceding) context, being smaller in Investigations of the N400 congruity effect in sen- a congruous context (e.g., a coherent sentence, a single tence processing have generally found abnormalities related word) than incongruous one. N400 amplitude is in AD. For example, Ford et al. [67] found that J.M. Olichney et al. / ERPs in Alzheimer’s Disease 219 the N400 expectancy/congruity effect to sentence- that, in both AD patients and controls, the effect was terminal words in speech was significantly reduced larger for subordinate labels. Furthermore, two studies (though still greater than zero) in AD relative to found evidence that anomia in AD may be independent age-matched controls. Revonsuo et al. [26] likewise of the integrity of the semantic system. Auchterlonie reported a reduced N400 congruity effect in speech et al. [70] observed that the N400 congruity effect for in AD patients. In that study, no overt response was pictures primed by words was similarly diminished required of the participants—they were simply told and for pictures, whether or not they were later named periodically reminded to attend to the sentences—so correctly. Ford et al. [27] also noted a dissociation the results are unlikely to be ‘contaminated’ by the between naming behavior and N400 response, albeit P300 component, known to be delayed in AD. In an the opposite one: AD patients showed small but signif- early study by Hamberger et al. [68], the N400 to visu- icant N400 congruity effects for word targets whether ally presented sentence-ending words was modulated primed by named or unnamed pictures. One possible by expectancy and semantic relation to virtually the explanation for this apparent discrepancy is that the same extent in AD patients as in young controls. Older semantic information contained in pictures may pro- controls showed a different pattern of N400 and RT vide a more powerful connection to the representations effects, which the authors attributed to a response strat- still present in the long-term memory of AD patients egy, although N400 amplitudes in the older controls than do written words. and AD patients were not reliably different. Studies using minimal semantic contexts to elicit an N400 effect have generally found that the effect to SUMMARY: N400 SEMANTIC CONGRUITY be diminished in AD. In a study by Schwartz et al. EFFECTS IN AD [69], participants heard a category name, then saw a word, and judged whether the word belonged to the Most ERP studies of semantic processing in AD named category (e.g., “animal” – ‘cow’). The N400 have shown smaller and later N400 congruity effects. effect — small negativity elicited by congruous rela- At the same time, AD patients have been found to tive to incongruous target words — was both smaller show a normal gradient of N400 congruity effects over and delayed in AD patients relative to age-matched different levels of category hierarchy and expectancy, controls. Iragui et al. [66] observed similar results. suggesting that the functional organization of semantic In that study, participants listened to short statements memory is relatively preserved in mild AD. Further- that defined a category (e.g., “a type of flower”) or more, ERP evidence has been used to argue that anomia an antonymic relation (e.g., “the opposite of tall”), in AD is not simply attributable to impaired semantic and then saw a word that was either congruous or processing. Thus, there appear to be an independent incongruous with the preceding statement; their task deficit in the retrieval of semantic information. The was to judge the congruity of the statement and target N400 component may provide a useful biomarker for word. The N400 effect was significantly reduced and monitoring the stages of disease progression in AD. delayed in AD patients relative to controls. Reduced N400 effects in AD also have been found with picto- rial stimuli used as primes for lexical targets [27], as LATE POSITIVE COMPONENT (LPC/P600): targets following lexical primes [70], and as both prime OVERVIEW and target [71–73]. Despite the preponderance of evidence suggesting Many ERP studies in normal subjects have identified that the N400 response is abnormal in amplitude and/or a Late Positive Component (LPC), sometimes called latency in AD, some of these studies have nonetheless the P600, which appears to be important in the media- found evidence of normal semantic network struc- tion of both memory encoding and retrieval processes. ture in AD. Hamberger et al. [68], for example, Subsequently recalled or recognized words generally found that AD patients’ N400 response followed the have larger late positivities than non-recalled words expected amplitude gradient across sentence ending [74, 75] and the size of this difference (often called types: unrelated-nonsense > unrelated-sense > related- “Dm” in the ERP literature) be reduced by “directed sense > best completion. Schwartz et al. [69] compared forgetting” instructions [76]. Intracranial studies in the N400 effect for target words primed by super- the human hippocampus have recapitulated the “Dm” ordinate and subordinate category labels and found effect of scalp ERPs [77], with larger positivities to 220 J.M. Olichney et al. / ERPs in Alzheimer’s Disease words subsequently recalled [78]. The scalp P600, between late positivity (P600) and conscious retrieval or ‘LPC’, is a late positivity with a centro-posterior processes. In AD patients, no late repetition effect maximum, which peaks 600 ms post-stimulus onset. was present, and an effect in early latency windows Intracranial studies also identified putative P600 gener- (300–500 ms) showed a distinctly frontal distribution. ators in the parahippocampal gyrus, many paralimbic The authors attributed this frontal old/new effect to cortical areas (e.g., temporal pole, rhinal & perirhinal familiarity [82]. Furthermore, patients’ source mem- cortex, posterior cingulate) and in multimodal asso- ory was at chance, suggesting that their above-chance ciation (e.g., ventrolateral prefrontal, lateral temporal recognition performance (62%) was due to a sense of cortex) [37, 56]. Intracranial depth recordings have familiarity (or another such implicit process) and not shown that very large (>200mV) P600-like potentials to recollection of the study event. Using a continu- are generated in the human hippocampus (HC) but it ous lexical decision task with incidental repetition at is unclear to what extent these potentials propagate to long lags (>90 items or >7.5 minutes), Schnyer et al. the scalp [37]. [83] likewise found a repetition positivity from 300 to 650 ms in controls, but no discernible effect in AD patients. N400/P600: QUANTITATIVE MEASURES A study in our laboratory [84] applied a word OF REPETITION EFFECTS repetition paradigm with semantically congruous and IN ALZHEIMER’S DISEASE incongruous words (details described in [85]) to patients with mild AD. Normal elderly demonstrated The neuropathology of AD affects the medial large decrement in P600 amplitude to repeated, rela- temporal lobes early in the course of the disease, and tive to new, congruous words, and the amplitude of deficits of episodic memory are usually the earliest this change correlated strongly with verbal memory presenting symptom. One might thus expect ERP performance [85]. Thus, we believe this P600 word word-repetition effects in AD to resemble those of repetition effect is a measure of the updating of work- medial-temporal amnesics. Studies of ERP word- ing memory with the content of long-term memory. repetition effects in AD, however, have produced a With efficient learning of category exemplars, this complex pattern of results. updating is not necessary for repeated target stimuli. Using a continuous semantic judgment task (button- As we had observed in patients with chronic amnesia, press required for ‘animal’ names) with incidental patients with mild AD had markedly reduced P600 repetition of non-targets (‘non-animal’ words were word-repetition effects (statistically ‘absent’ when repeated; average lag: 30 sec) in AD, Friedman et analyzed across all scalp channels). Unlike chronic al. [79] reported preserved late (700–1000 ms) rep- amnesia, patients with mild AD also showed signif- etition effects in most (6 of 10) mild AD patients. icant diminution of the N400 word-repetition effect. These authors attributed the residual repetition effects Thus, both the P600 and N400 repetition effects were to relatively preserved implicit memory processes in ‘lacking’ in the AD group [84]. The loss of the N400 AD. Rugg et al. [80] used a similar continuous task repetition effect may correspond to abnormal seman- with incidental repetition at somewhat shorter lags tic/conceptual priming, as has been found in several (average: 6–21 sec) and found ERP repetition effects behavioral studies of mild AD [86]. Furthermore, when (300–400 and 400–700 ms) in AD that were statisti- 10 th percentile (in normal elderly) cutoffs for the P600 cally indistinguishable from those in controls, although and N400 word-repetition effects were applied, all 11 a trend for a smaller repetition effect with longer mild AD patients were correctly classified as abnormal lags was noted. In contrast, Tendolkar et al. [81] on one or both measures (sensitivity: 100%; specificity: employing an explicit word-list memory task and a 82%), suggesting that this paradigm has promise for longer inter-item lag (∼5 minutes), found very dif- use in the diagnosis or early detection of AD. ferent results. In that study, controls exhibited a large repetition positivity for correctly recognized old items in both early (300–600 ms) and late (700–900 ms) FMRI STUDIES OF WORD REPETITION latency windows. This effect was further enhanced IN AD for items for which source memory was also correctly retrieved (words had been displayed in one The word repetition paradigm described above of two colors) from 600–900 ms, supporting a link has been adapted for functional Magnetic Resonance J.M. Olichney et al. / ERPs in Alzheimer’s Disease 221

Imaging (fMRI) studies, in order to identify the neural differentiated amnestic MCI subtype from MCI with generators underlying the P600 word repetition effect. other cognitive impairments beyond memory deficit Normal elderly showed activation to New > Old con- [96, 97]. Several studies have found N200 and P300 gruous words in a distributed network of putative P600 abnormalities in MCI, with some results suggest- generators, including bilateral cingulate and fusiform ing that amplitude or latency of N200 may have gyri, left medial temporal lobe (LMTL), and left infe- stronger value in discriminating MCI patients from rior frontal gyri (IFG) [87]. Furthermore, significant normal control [98–100]. However, Phillips et al. correlations were present between the magnitude of [101], using the Sternberg working memory task, New–Old activation in these regions and subsequent found no difference in either the P300 or N200 in memory performance, implicating this neural circuit MCI compared with controls (but their mild AD group as critical for successful verbal memory encoding. In had reduced P300 amplitude). In a sample of amnestic contrast, a group of mild AD patients showed weak mild cognitive impairment (aMCI), ERP components or absent response to New-Old congruous word con- reflecting familiarity and retrieval monitoring were trast, with only one such significant cluster (IFG) in preserved for picture, but not for word recognition the entire left hemisphere [88]. [102].

EEG OSCILLATORY ABNORMALITIES IN AD N400/P600: REPETITION EFFECTS IN MILD COGNITIVE IMPAIRMENT Event-related dysynchronization/synchronization (ERD/ERS), the time-locked change in power of EEG Another study in our laboratory used the congru- frequency band (i.e., delta, theta, alpha, beta, and ous/incongruous word repetition paradigm to evaluate gamma) activities [89], also has been employed to N400 and P600 repetition effects in MCI [103]. In explore cognitive and non-cognitive neural processing MCI, as in controls, target words that followed con- in AD. In a finger movement task, for example, AD gruous category statements elicited a positive shift in was found to show increased centromedial beta ERD N400 amplitude relative to incongruous pairings, but during movement and increased ipsilateral rolandic this effect (incongruous vs. congruous word voltage beta ERS in the post-movement period, with abnormal difference) was delayed in MCI. The N400 repetition frontal preponderance of both activities [90]. Dimin- effect—initial vs. repeated incongruous pairings—was ished ERD in 7–17 Hz frequency over temporal area likewise present but delayed in MCI. The P600 has been observed in the AD group during retrieval of repetition effect—initial vs. repeated congruous pair- a Sternberg memory task [91]. Another study using ings—was not significantly different from zero in the a two-back working memory paradigm found reduced MCI grand average. beta ERS at parietal sites of AD patients [92]. Event- Longitudinal follow-up with annual ERP assess- related oscillation analysis also has been used to ments [104] demonstrated that the N400 repetition evaluate the outcome of cholinesterase inhibitor treat- effect is diminished and spatially restricted at base- ment on AD. Both treated and untreated AD patients line (Year 1) in MCI patients who convert to dementia exhibited lower delta activity, while theta response within the next 3 years (“MCI converters”, see Fig. 1., was sensitive to the treatment with a reduction after 3rd column). One year later, when most of these cholinesterase inhibitor therapy [93, 94]. patients were still in the MCI stage, the converter group on average showed an absence of the N400 repetition effect (right side of Fig. 1.). The P600 repetition effect ERPS IN MILD COGNITIVE IMPAIRMENT also proved very sensitive to MCI converters, with no (MCI) statistically significant repetition effects at either year 1 or year 2. It is noteworthy that abnormalities of either In a 5 year follow-up study, Golob and colleagues the P600 or N400 repetition effect at baseline in MCI [95] demonstrated that both P50 amplitude and P300 carried a poor prognosis, with approximately 88% risk latency, elicited in an auditory oddball task, increase of conversion to AD within 3 years, compared to a with mild cognitive impairment (MCI). P50 ampli- 11–27% risk in those MCI cases with normal ERP tude predicted progression from MCI to AD, and repetition effects. 222 J.M. Olichney et al. / ERPs in Alzheimer’s Disease

Fig. 1. Spherical spline topographic maps illustrate the incongruous word repetition effect (ERPs to new minus old semantically incongruous words) in consecutive 50 msec epochs for normal old (left) and MCI stable (left middle) groups at year 1, and MCI converters at year 1 (right middle) and year 2 (right). J.M. Olichney et al. / ERPs in Alzheimer’s Disease 223

SUMMARY: N400/P600 REPETITION while still in the asymptomatic stage, from normal EFFECTS aging.

Recent work dissociating N400 and P600 repetition effects has found that MTL amnesics, whose EEG/ERP ABNORMALITIES ability to encode events into long term memory is IN PRECLINICAL AD compromised, show intact N400 but impaired P600 effects. This pattern of findings supports an associa- A rich literature has shown that EEG and ERPs tion between implicit and explicit processes and N400 can both be very sensitive tools for measuring brain and P600, respectively. In AD, both N400 and P600 aging. Prichep and colleagues [106], for example, repetition effects are severely diminished. In MCI, the applied quantitative EEG (QEEG) to elderly per- presence of either reduced N400 or P600 repetition sons with symptomatic memory complaints (“Reisberg effects appears very promising as a potentially use- FAST stage 2”) and found that certain QEEG abnor- ful biomarker for those individuals at highest risk for malities (e.g., increased theta power, slowed mean subsequent conversion to AD dementia. background frequency, changes in covariance among centro-parietal regions) were strongly predictive of subsequent cognitive decline over the next 7 years PRECLINICAL AD (logistic regression models achieved a predictive accu- racy of 90%). ERPs likewise have shown promise in In this era of sensitive biomarkers to amyloid depo- their sensitivity to preclinical stages of AD. Several sition (e.g., PiB-PET and CSF A-beta amyloid levels), ERP studies have reported various sensitivities in those many elderly persons now have AD-related changes at increased genetic risk for AD. Boutros and col- detected many years prior to observable cognitive leagues [107], for example, reported increased P50 symptoms, i.e. in the ‘preclinical AD’ stage. While and P300 amplitudes in a small group of normal sub- brain amyloid is necessary for the diagnosis of AD, it jects genetically at-risk for AD (first degree relatives may not suffice to produce cognitive decline in some of autopsy confirmed AD cases; mean age 53 yr old). elderly persons. As noted above, neuropathologic stud- Green and colleagues [108] reported delayed N200 and ies have implicated the synapse as the primary mediator P300 latencies in a similarly-aged group of apolipopro- of dementia severity in AD, with >80% of the variance tein E4 (the most common genetic risk factor for AD) in severity accounted for by the density of pre-synaptic carriers with a positive family history of AD. Murphy et terminals in mid-frontal cortex [14]. Transgenic ani- al. [109] presented names of odors previously encoded mals often show inhibition of LTP and/or reduced (targets) or not (foils) to carriers of ApoE4, and found synaptic transmission prior to the appearance of amy- significantly longer P300 latencies in the ApoE4 car- loid plaques and neurofibrillary changes [12]. This riers, consistent with prior reports of olfactory odor highlights the need for more accurate biomarkers for recognition memory impairment in ApoE4 carriers AD, especially biomarkers sensitive to emerging mem- [110]. Golob et al. [111] examined familial AD (FAD) ory failure (pre-‘MCI’). Therefore, recently proposed carriers (mean age = 34) with presenilin-1 (PSEN1) research criteria for Preclinical AD [105] divide this or amyloid precursor protein (APP) mutations with an entity into 3 stages, based on the presence of symptoms auditory oddball task and obtained delayed ERP com- and evidence of synaptic dysfunction (or neurodegen- ponents including N100, P200, N200 and P300 in this eration). Elevated CSF phospho-tau is one such marker group with familial AD while most were in the asymp- of synaptic dysfunction. To date, neither EEG nor ERP tomatic (CDR = 0) stage. Bobes and colleagues [74] markers have been incorporated into these criteria. observed that asymptomatic carriers of E280A PS-1 Non-invasive cost-effective measures of synaptic dys- mutation have a parietal distribution of N400 congruity function, as can be provided by ERPs and EEG, effect elicited by picture-pairs while normal elderly however, could potentially be very useful for the ear- show a central maximum. lier diagnosis staging of AD. In short, there is a Recent retrospective review of all our “normal” pressing need for improved electrophysiological mark- elderly controls, followed longitudinally by a NIH- ers of impaired synaptic plasticity and memory. One funded ADRC or ADC, identified 7 cases who were important application for such a marker would be to most probably in the early stages of Preclinical AD at aid in the differentiation of Preclinical AD, perhaps the time of their ERP recordings. All entered as nor- 224 J.M. Olichney et al. / ERPs in Alzheimer’s Disease

Fig. 2. Grand average ERPs to initial (dash line) and repeated (solid line) presentation of congruous words in “robust” normal elderly (RNE) (top row) and Preclinical AD patients (bottom). mal controls and continued to perform within normal This pattern of ERP findings is consistent with the limits on an annually administrated extensive neu- neuropathology of AD. Predilection sites in early AD ropsychological test battery. In the years following the include the medial temporal lobe, other limbic areas, ERPs, however, these cases showed cognitive decline and multimodal association cortices with relative spar- (to AD or MCI, n = 6) or had AD pathology verified ing of unimodal sensory cortex. Late endogenous at autopsy (n = 4, mean Braak stage = 3.0). Compared components in known paradigms can be useful for to 12 “robust” normal elderly (RNE) participants (top assessing specific hypotheses about the change in cog- row in Fig. 2), all of whom remained cognitively nitive processes in AD, MCI, and amnestic patients. normal (average follow-up = 9.1 years) with longitu- A P300 paradigm, for example, can be very useful in dinal neuropsychological testing, the Preclinical AD detecting a disorder of attention or in quantifying the group had significantly smaller P600 repetition effects effects of drugs which improve attention, such as the (mean amplitude of RNE = 3.28 ␮V; Pre-AD = 0.10 ± cholinesterase inhibitors. For the early diagnosis of AD 0.89 ␮V) [112]. The consistently abnormal (reduced or or other memory disorders, a word repetition paradigm absent) P600 effects seen in this small Preclinical AD (typically eliciting N400 and P600 modulations) with group shows the great promise which ERP biomarkers an explicit recognition task or one that fosters asso- such as the P600 have for the detection of the earliest ciative learning would be recommended. As discussed stages of synaptic dysfunction. above, the N400 has potential use in tracking AD progression. Last but not least, the sensitivities of a number of ERP components have great promise in the detec- CONCLUSIONS tion and quantification of synaptic dysfunction in the presymptomatic stages of Alzheimer’s disease. We reviewed several abnormalities in the cognitive ERPs of AD patients. Early, sensory-evoked, oblig- atory potentials (e.g., N100) are typically normal in ACKNOWLEDGMENTS AD (though see work on P50) whereas potentials start- ing around 200 ms and beyond are more consistently Supported by NIH grants R01 AG18442, R01 abnormal even in the earliest stages of AD and MCI. AG08313, and P30 AG010129. We would also like J.M. Olichney et al. / ERPs in Alzheimer’s Disease 225 to thank the UC Davis ADC and Center for Mind and [17] Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL Brain. (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168-1170. [18] Goodin DS, Aminoff MJ (1987) Electrophysiological differences between demented and nondemented patients with parkinson’s disease. Ann Neurol 21, 90-94. REFERENCES [19] Goodin DS, Aminoff MJ (1986) Electrophysiological differences between subtypes of dementia. Brain 109, 1103-1113. [1] Nunez PL (1990) Physical principles and neurophysiologi- [20] Martinelli V,Locatelli T, Comi G, Lia C, Alberoni M, Bressi cal mechanisms underlying event-related potentials. In: J.W. S, Rovaris M, Franceschi M, Canal N (1996) Pattern visual Rohrbaugh, R. Parasuraman, R. Johnson Jr. eds, Event- evoked potential mapping in Alzheimer’s disease: correla- related brain potentials, Oxford University Press, New York, tions with visuospatial impairment. Dementia 7, 63-68. pp. 19-36. [21] Swanwick GR, Rowan MJ, Coen RF, Coakley D, Lawlor BA [2] [2] Nunez PL, Srinivasan R (2006) Oxford University Press, (1999) Prognostic value of electrophysiological markers in Electric fields of the brain: the neurophysics of EEG (2nd Alzheimer’s disease. Am J Geriatr Psychiatry 7, 335-338. Ed.). New York, pp. 163-166. [22] Ruessmann K, Beneicke U (1991) P2 latency of the flash [3] Wood CC, Allison T (1981) Interpretation of evoked poten- visual evoked potential in dementia. Int J Neurosci 56, 273- tials: a neurophysiological perspective. Can J Psychol 35, 276. 113-135. [23] Moore NC (1997) Visual evoked responses in Alzheimer’s [4] Ang CW, Carlson GC, Coulter DA (2005) Hippocampal ca1 disease: a review. Clin Electroencephalogr 28, 137-142. circuitry dynamically gates direct cortical inputs preferen- [24] Philpot MP, Amin D, Levy R (1990) Visual evoked potentially at theta frequencies. J Neurosci 25, 9567-9580. tials in Alzheimer’s disease: correlations with age and [5] Schack B, Weiss S (2005) Quantification of phase synchro- severity. Electroencephalogr Clin Neurophysiol 77, 323- nization phenomena and their importance for verbal memory 329. processes. Biol Cybern 92, 275-287. [25] Saitoh E, Adachi-Usami E, Mizota A, Fujimoto N (2001) [6] Braak H, Braak E (1991) Neuropathological stageing of Comparison of visual evoked potentials in patients with Alzheimer-related changes. Acta Neuropathol 82, 239-259. psychogenic visual disturbance and malingering. J Pediatr [7] Katada E, Sato K, Ojika K, Ueda R (2004) Cognitive event- Ophthalmol Strabismus 38, 21-26. related potentials: useful clinical information in Alzheimer’s [26] Revonsuo A, Portin R, Juottonen K, Rinne JO (1998) disease. Curr Alzheimer Res 1, 63-69. Semantic processing of spoken words in Alzheimer’s dis- [8] Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s ease: an electrophysiological study. J Cogn Neurosci 10, disease: bridging the gap between plaques and tangles. Neu- 408-420. ron 24, 521-529. [27] Ford JM, Askari N, Mathalon DH, Menon V, Gabrieli [9] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. JD, Tinklenberg JR, Yesavage J (2001) Event-related brain Science 298, 789-791. potential evidence of spared knowledge in Alzheimer’s dis- [10] Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong ease. Psychol Aging 16, 161-176. Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch [28] Golob EJ, Starr A (2000) Effects of stimulus sequence CE, Krafft GA, Klein WL (2004) Synaptic targeting by on event-related potentials and reaction time during target Alzheimer’s-related amyloid beta oligomers. J Neurosci 24, detection in Alzheimer’s disease. Clin Neurophysiol 111, 10191-10200. 1438-1449. [11] Moechars D, Dewachter I, Lorent K, et al. (1999) Early [29] Takeda M, Tachibana H, Sugita M (1993) Multimodal phenotypic changes in transgenic mice that overexpress dif- evoked potentials in patients with dementia. Nippon Ronen ferent mutants of amyloid precursor protein in brain. J Biol Igakkai Zasshi 30, 1058-1067. Chem 274, 6483-6492. [30] Yokoyama Y, Nakashima K, Shimoyama R, Urakami K, [12] Rowan MJ, Klyubin I, Cullen WK, Anwyl R (2003) Synaptic Takahashi K (1995) Distribution of event-related potentials plasticity in animal models of early Alzheimer’s disease. in patients with dementia. Electromyogr Clin Neurophysiol Philos Trans R Soc Lond B Biol Sci 358, 821-828. 35, 431-437. [13] Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe [31] Iragui VJ, Kutas M, Mitchiner MR, Hillyard SA (1993) M, et al. (2002) Naturally secreted oligomers of amyloid beta Effects of aging on event-related brain potentials and reac- protein potently inhibit hippocampal long-term potentiation tion times in an auditory oddball task. Psychophysiology 30, in vivo. Nature 416, 536-539. 10-22. [14] Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, [32] Fernandez R, Kavcic V, Duffy CJ (2007) Neurophysio- Hill R, Hansen LA, Katzman R (1991) Physical basis of logic analyses of low- and high-level visual processing in cognitive alterations in Alzheimer’s disease: synapse loss is Alzheimer disease. Neurology 68, 2066-2076. the major correlate of cognitive impairment. Ann Neurol 30, [33] Kavcic V, Fernandez R, Logan D, Duffy CJ (2006) Neu- 572-580. rophysiological and perceptual correlates of navigational [15] Davies CA, Mann DM, Sumpter PQ, Yates PO (1987) impairment in Alzheimer’s disease. Brain 129, 736-746. A quantitative morphometric analysis of the neuronal and [34] Squires K, Wickens C, Squires NK, Donchin E (1976) The synaptic content of the frontal and temporal cortex in effect of stimulus sequence on the waveform of the cortical patients with Alzheimer’s disease. J Neurol Sci 78, 151-164. event-related potential. Science 193, 1142-1146. [16] Bertoni-Freddari C, Fattoretti P, Delfino A, Solazzi M, Gior- [35] Johnson R, Jr. (1986) A triarchic model of p300 amplitude. getti B, Ulrich J, Meier-Ruge W (2002) Deafferentative Psychophysiology 23, 367-384. synaptopathology in physiological aging and Alzheimer’s [36] Halgren E, Marinkovic K, Chauvel P (1998) Generators disease. Ann N Y Acad Sci 977, 322-326. of the late cognitive potentials in auditory and visual odd- 226 J.M. Olichney et al. / ERPs in Alzheimer’s Disease

ball tasks. Electroencephalogr Clin Neurophysiol 106, 156- 1. Intracranial distribution and neural generators. J Neurosci 164. 15, 1080-1089. [37] Guillem F, Rougier A, Claverie B (1999) Short- and long- [55] Nobre AC, Allison T, McCarthy G (1994) Word recognition delay intracranial erp repetition effects dissociate memory in the human inferior temporal lobe. Nature 372, 260-263. systems in the human brain. J Cogn Neurosci 11, 437- [56] Halgren E, Baudena P, Heit G, Clarke J, Marinkovic K, 458. Clarke M (1994) Spaciotemporal stages in face and word [38] YamaguchiS, Knight RT (1992) Effects of temporal-parietal processing 1 . Depth Recorded Potentials in Human Occip- lesions on the somatosensory p3 to lower limb stimulation. ital and Parietal Lobes. J Physiol Paris 88, 1-150. Electroencephalogr Clin Neurophysiol 84, 139-148. [57] Kutas M, Van Petten C (1988) Event-related brain potential [39] Donchin E, Coles MGH (1988) Is the p300 component a studies of language. In: Ackles PK, Jennings JR, Coles MGH manifestation of context updating? Behav Brain Sci 11, 357- (eds), Advances in Psychophysiology, vol.3. JAI Press, 374. Greenwich, CT, pp. 139-187. [40] Kok A (2001) On the utility of p3 amplitude as a measure [58] Osterhout l, Holcomb pj (1995) Event-related potentials and of processing capacity. Psychophysiology 38, 557-577. language comprehension Rugg M.D. Coles MGH. Elec- [41] Ford JM, Pfefferbaum A (1985) Age-related changes in trophysiology of Mind: Event-related Brain Potentials and event-related potentials. Advances in Psychophysiology 1, Cognition Oxford, UK Oxford University Press, 171-215. 301-339. [59] Kutas M, Federmeier KD (2011) Thirty years and counting: [42] Squires KC, Chippendale TJ, Wrege KS, Goodin DS, Starr finding meaning in the n400 component of the event-related A (1980) Electrophysiological assessment of mental func- brain potential (erp). Annu Rev Psychol 62, 621-647. tion in aging and dementia. In Poon L (ed). Aging in the [60] Monsch AU, Bondi MW, Butters N, Salmon DP, Katzman 1980s. American Psychology Association, Washington, DC, R, Thal LJ (1992) Comparisons of verbal fluency tasks in the pp. 125-134. detection of dementia of the Alzheimer type. Arch Neurol [43] Gordon E, Kraiuhin C, Harris A, Meares R, Howson A 49, 1253-1258. (1986) The differential diagnosis of dementia using p300 [61] Salmon DP, Butters N, Chan AS (1999) The deterioration latency. Biological Psychiatry 21, 1123-1132. of semantic memory in Alzheimer’s disease. Can J Exp [44] Pfefferbaum A, Wenegrat BG, Ford JM, Roth WT, Kopell Psychol 53, 108-117. BS (1984) Clinical application of the p3 component [62] Chan AS, Butters N, Salmon DP (1997) The deterioration of event-related potentials ii: dementia, depression and of semantic networks in patients with Alzheimer’s disease: schizophrenia. Electroencephalogr Clin Neurophysiol 59, a cross-sectional study. Neuropsychologia 35, 241-248. 104-124. [63] Ober BA, Shenaut GK. (1995) Semantic priming in [45] Patterson JV, Michalewski HJ, Starr A (1988) Latency Alzheimer’s disease: meta analysis and theoretical eval- variability of the components of auditory event-related uation. in: Allen PA, Bashore TR (eds). Advances in potentials to infrequent stimuli in aging, Alzheimer-type Psychology: Age Differences in Word and Language Pro- dementia, and depression. Electroencephalogr Clin Neuro- cessing. Elsevier, Amsterdam, pp. 247-271. physiol 71, 450-460. [64] King J, Kutas M. (1995) Do the waves begin to waver? [46] Goodin DS (1990) Clinical utility of long latency ‘cognitive’ ERP studies of language processing in the elderly. In: Allen event-related potentials (p3): the pros. Electroencephalogr PA, Bashore TR (eds). Advances in Psychology: Age Dif- Clin Neurophysiol 76, 2-5. ferences in Word and Language Processing. Amsterdam: [47] Lai CL, Lin RT, Liou LM, Liu CK (2010) The role of Elsevier, pp. 314-344. event-related potentials in cognitive decline in Alzheimer’s [65] Kutas M, Iragui V (1998) The n400 in a semantic cate- disease. Clin Neurophysiol 121, 194-199. gorization task across 6 decades. Electroencephalogr Clin [48] Tanaka F, Kachi T, Yamada T, Sobue G (1998) Auditory Neurophysiol 108, 456-471. and visual event-related potentials and flash visual evoked [66] Iragui V, Kutas M, Salmon DP (1996) Event-related brain potentials in Alzheimer’s disease: correlations with mini- potentials during semantic categorization in normal aging mental state examination and raven’s coloured progressive and senile dementia of the Alzheimer’s type. Electroen- matrices. J Neurol Sci 156, 83-88. cephalog Clin Neurophysiol 100, 392-406. [49] Olichney JM, Hillert DG (2004) Clinical applications of [67] Ford JM, Woodward SH, Sullivan EV, Isaacks BG, Tin- cognitive event-related potentials in Alzheimer’s disease. klenberg JR, Yesavage JA, Roth WT (1996) N400 evidence Phys Med Rehabil Clin N Am 15, 205-233. of abnormal responses to speech in Alzheimer’s disease. [50] Polich J, Pitzer A (1999) P300 and Alzheimer’s disease: odd- Electroencephalogr Clin Neurophysiol 99, 235-246. ball task difficulty and modality effects. Electroencephalogr [68] Hamberger MJ, Friedman D, Ritter W, Rosen J (1995) Clin Neurophysiol Suppl 50, 281-287. Event-related potential and behavioral correlates of seman- [51] Morgan CD, Murphy C (2002) Olfactory event-related tic processing in Alzheimer’s patients and normal controls. potentials in Alzheimer’s disease. J Int Neuropsychol Soc Brain Lang 48, 33-68. 8, 753-763. [69] Schwartz TJ, Kutas M, Butters N, et al. (1996) Electrophys- [52] Kutas M, Hillyard SA (1980) Reading senseless sentences: iological insights into the nature of the semantic deficit in brain potentials reflect semantic incongruity. Science 207, Alzheimer’s disease. Neuropsychologia 34, 827-841. 203-205. [70] Auchterlonie S, Phillips PA, Chertkow H (2002) Behavioral [53] Kutas M, Neville HJ, Holcomb PJ (1987) A preliminary and electrical brain measures of semantic priming in patients comparison of the n400 response to semantic anomalies dur- with Alzheimer’s disease: implications for access failure ing reading, listening and signing. Electroencephalogr Clin versus deterioration hypotheses. Brain Cogn 48, 264-267. Neurophysiol Suppl 39, 325-330. [71] Castañeda M, Ostrosky-Solís F, Pérez M, Bobes MA, [54] McCarthy G, Nobre AC, Bentin S, et al. (1995) Language- Rangel LE (1997) Erp assessment of semantic memory in related field potentials in the anterior-medial temporal lobe: Alzheimer’s disease. Int J Psychophysiol 27, 201-214. J.M. Olichney et al. / ERPs in Alzheimer’s Disease 227

[72] Ostrosky-Solís F, Castañeda M, Pérez M, Castillo G, Bobes [88] Olichney JM, Taylor JR, Chan S, Yang JC, Stringfellow MA (1998) Cognitive brain activity in Alzheimer’s disease: A, Hillert DG, Simmons AL, Salmon DP, Iragui-Madoz V, electrophysiological response during picture semantic cate- Kutas M (2010) Fmri responses to words repeated in a con- gorization. J Int Neuropsychol Soc 4, 415-425. gruous semantic context are abnormal in mild Alzheimer’s [73] Bobes MA, García YF, Lopera F, Quiroz YT, Galán L, disease. Neuropsychologia 48, 2476-2487. Vega M, Trujillo N, Valdes-Sosa M, Valdes-Sosa P (2010) [89] Pfurtscheller G, Lopes da Silva FH (1999) Event-related Erp generator anomalies in presymptomatic carriers of the eeg/meg synchronization and desynchronization: basic prin- Alzheimer’s disease e280a ps-1 mutation. Hum Brain Mapp ciples. Clin Neurophysiol 110, 1842-1857. 31, 247-265. [90] Babiloni C, Babiloni F, Carducci F, Cincotti F, Del Per- [74] Mangels JA, Picton TW, Craik FIM (1996) Neurophysio- cio C, De Pino G, Maestrini S, Priori A, Tisei P, Zanetti logical (erp) correlates of encoding and retrieval from verbal O, Rossini PM (2000) Movement-related electroencephalo- episodic memory. (Abstract) Soc Neurosci Abs 22, 1450. graphic reactivity in Alzheimer disease. Neuroimage 12, [75] Paller KA, Kutas M, Mayes AR (1987) Neural correlates 139-146. of encoding in an incidental learning paradigm. Electroen- [91] Karrasch M, Laine M, Rinne JO, Rapinoja P, Sinervä cephalogr Clin Neurophysiol 67, 360-371. E, Krause CM (2006) Brain oscillatory responses to an [76] Paller KA (1990) Recall and stem-completion priming have auditory-verbal working memory task in mild cognitive different electrophysiological correlates and are modiﬁed impairment and Alzheimer’s disease. Int J Psychophysiol differentially by directed forgetting. J Exp Psychol Learn 59, 168-178. Mem Cogn 16, 1021-1032. [92] Missonnier P, Deiber MP, Gold G, Herrmann FR, Millet [77] Paller KA, McCarthy G, Wood CC (1988) Erps predictive P, Michon A, Fazio-Costa L, Ibañez V, Giannakopoulos of subsequent recall and recognition performance. Biol Psy- P (2007) Working memory load-related electroencephalo- chol 26, 269-276. graphic parameters can differentiate progressive from stable [78] Fernandez G, Effern A, Grunwald T, Pezer N, Lehnertz K, mild cognitive impairment. Neuroscience 150, 346-356. Dumpelmann M (1999) Real-time tracking of memory for- [93] Yener G, Guntekin¨ B, Bas¸ar E (2008) Event-related delta mation in the human rhinal cortex and hippocampus. Science oscillatory responses of Alzheimer patients. Eur J Neurol 285, 1582-1585. 15, 540-547. [79] Friedman D, Hamberger M, Stern Y, Marder K (1992) [94] Yener GG, Güntekin B, Tulay¨ E, Bas¸ar E (2009) A com- Event-related potentials (erps) during repetition priming in parative analysis of sensory visual evoked oscillations with Alzheimer’s patients and young and older controls. J Clin visual cognitive event related oscillations in Alzheimer’s Exp Neuropsychol 14, 448-462. disease. Neurosci Lett 462, 193-197. [80] Rugg MD, Pearl S, Walker P, Roberts RC, Holdstock [95] Golob EJ, Irimajiri R, Starr A (2007) Auditory cortical activ- JS (1994) Word repetition effects on event-related poten- ity in amnestic mild cognitive impairment: relationship to tials in healthy young and old subjects, and in patients subtype and conversion to dementia. Brain 130, 740-752. with Alzheimer-type dementia. Neuropsychologia 32, 381- [96] Golob EJ, Johnson JK, Starr A (2001) Auditory event- 398. related potentials during target detection are abnormal in [81] Tendolkar I, Schoenfeld A, Golz G, Fernandez G, Kuhl KP, mild cognitive impairment. Clin Neurophysiol 113, 151- Ferszt R, Heinze HJ (1999) Neural correlates of recogni- 161. tion memory with and without recollection in patients with [97] Irimajiri R, Michalewski HJ, Golob EJ, Starr A (2007) Alzheimer’s disease and healthy controls. Neurosci Lett 263, Cholinesterase inhibitors affect brain potentials in amnestic 45-48. mild cognitive impairment. Brain Res 1145, 108-116. [82] Rugg MD, Mark RE, Walla P, Schloerscheidt AM, Birch [98] Papaliagkas VT, Kimiskidis VK, Tsolaki MN, Anogianakis CS, Allan K (1998) Dissociation of the neural correlates of G (2011) Cognitive event-related potentials: Longitudinal implicit and explicit memory. Nature 392, 595-598. changes in mild cognitive impairment. Clin Neurophysiol. [83] Schnyer DM, Allen JJ, Kaszniak AW, Forster KI (1999) [Epub ahead of print] An event-related potential examination of masked and [99] Papaliagkas V, Kimiskidis V, Tsolaki M, Anogianakis G (5) unmasked repetition priming in Alzheimer’s disease: impli- (2008) Usefulness of event-related potentials in the assess- cations for theories of implicit memory. Neuropsychology ment of mild cognitive impairment. BMC Neurosci 9, 107. 13, 323-337. [100] Bennys K, Portet F, Touchon J, Rondouin G (2007) Diag- [84] Olichney JM, Riggins BR, Morris SK, Salmon DP, Kutas nostic value of event-related evoked potentials n200 and M, Iragui VJ (2002) Reduced effects of word repetition on p300 subcomponents in early diagnosis of Alzheimer’s dis- the n400 and lpc event-related potentials are common in ease and mild cognitive impairment. J Clin Neurophysiol mild Alzheimer’s disease and mild cognitive impairment 24, 405-412. converters. Neurology 58, A216. [101] Phillips NA, Chertkow H, Leblanc MM, Pim H, Murtha [85] Olichney JM, Van Petten C, Paller K, Salmon DP, Iragui VJ, S (2004) Functional and anatomical memory indices in Kutas M (2000) Word repetition in amnesia: electrophysi- patients with or at risk for Alzheimer’s disease. J Int Neu- ological measures of impaired and spared memory. Brain ropsychol Soc 10, 200-210. 123, 1948-1963. [102] Ally BA, McKeever JD, Waring JD, Budson AE (2009) Pre- [86] Keane M, Gabrieli J, Fennema A, et al. (1991) Evidence for served frontal memorial processing for pictures in patients a dissociation between perceptual and conceptual priming with mild cognitive impairment. Neuropsychologia 47, in Alzheimer’s disease. Behav Neurosci 105, 326-342. 2044-2055. [87] Olichney JM, Taylor JR, Hillert DG, Chan SH, Salmon DP, [103] Olichney JM, Morris SK, Ochoa C, Salmon DP, Thal LJ, Gatherwright J, Iragui VJ, Kutas M (2010) Fmri congruous Kutas M, Iragui VJ (2002) Abnormal verbal event-related word repetition effects reﬂect memory variability in normal potentials in mild cognitive impairment and incipient ad. J elderly. Neurobiol Aging 31, 1975-1990. Neurol Neurosurg Psychiatry 73, 377-384. 228 J.M. Olichney et al. / ERPs in Alzheimer’s Disease

[104] Olichney JM, Taylor JR, Gatherwright J, Salmon DP, [109] Murphy C, Solomon ES, Haase L, Wang M, Morgan CD Bressler AJ, Kutas M, Iragui-Madoz VJ (2008) Patients with (2009) Olfaction in aging and Alzheimer’s disease: event- mci and n400 or p600 abnormalities are at very high risk for related potentials to a cross-modal odor-recognition memory conversion to dementia. Neurology 6, 1763-1770. task discriminate apoe epsilon4 + and apoe epsilon 4- indi- [105] Sperling R, Beckett L, Bennett D, et al. CRITERIA viduals. Ann N Y Acad Sci 1170, 647-657. FOR PRECLINICAL ALZHEIMER’S DISEASE (2010) [110] Gilbert PE, Murphy C (2004) The effect of the apoe epsilon4 http://www.alz.org/research/diagnostic criteria/preclinical allele on recognition memory for olfactory and visual stim- recommendations.pdf uli in patients with pathologically conﬁrmed Alzheimer’s [106] Prichep LS, John ER, Ferris SH, Rausch L, Fang Z, Cancro disease, probable Alzheimer’s disease, and healthy elderly R, Torossian C, Reisberg B (2006) Prediction of longitu- controls. J Clin Exp Neuropsychol 26, 779-794. dinal cognitive decline in normal elderly with subjective [111] Golob EJ, Ringman JM, Irimajiri R, Bright S, Schaffer B, complaints using electrophysiological imaging. Neurobiol Medina LD, Starr A (2009) Cortical event-related poten- Aging 27, 471-481. tials in preclinical familial Alzheimer disease. Neurology [107] Boutros N, Torello MW, Burns EM, Wu SS, Nasrallah HA 73, 1649-1655. (1995) Evoked potentials in subjects at risk for Alzheimer’s [112] Olichney JM, Pak J, Salmon DP, Yang JC, Gahagan T, disease. Psychiatry Res 57, 57-63. Nowacki R, Hansen L, Galasko D, Kutas M, Iragui-Madoz [108] Green J, Levey AI (1999) Event-related potential changes in VJ (2011) ERP studies of Preclinical Alzheimer’s Dis- groups at increased risk for Alzheimer disease. Arch Neurol ease (AD): P600 abnormalities are common in elderly 56, 1398-1403. persons who later develop MCI or AD pathology. (Abstract) Neurology Suppl 76, A233.