Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Individuals at risk for Alzheimer’s disease show differential patterns of ERP brain activation during odor identification

Individuals at risk for Alzheimer’s disease show differential patterns of ERP brain activation... Background: Studies suggest that older adults at risk of developing Alzheimer’s disease may show olfactory processing deficits before other signs of dementia appear. Methods: We studied 60 healthy non-demented individuals, half of whom were positive for the genetic risk factor the Apolipoprotein E ε4 allele, in three different age groups. Event-related potentials to visual and olfactory identification tasks were recorded and analyzed for latency and amplitude differences, and plotted via topographical maps. Results: Varying patterns of brain activation were observed over the post-stimulus epoch for ε4- versus ε4+ individuals on topographical maps. Individuals with the ε4 allele demonstrated different ERP peak latencies during identification of olfactory but not visual stimuli. High correct ApoE classification rates were obtained utilizing the olfactory ERP. Conclusions: Olfactory ERPs demonstrate functional decline in individuals at risk for Alzheimer’s disease at much earlier ages than previously observed, suggesting the potential for pre-clinical detection of AD at very early stages. Keywords: Alzheimer’s disease, Apolipoprotein E, Olfactory event-related potentials, Age, Smell impairment, Olfaction [6,7]. Presence of the ε4 allele increases the risk but does Alzheimer’s disease is a neurologic disorder accompan- ied by progressive memory loss, cognition loss and func- not guarantee future development of AD [8]. tional decline [1]. The cause or causes of AD are not yet Studies have found olfactory dysfunction in AD in- cluding impairment in olfactory threshold sensitivity, known and definitive diagnosis can only be made via postmortem autopsy or, while living, a brain biopsy. The odor identification, odor recognition memory, remote greatest risk factor for development of AD is advancing memory for odors, and odor fluency for review see [9]. Regions of the brain involved in the processing of olfac- age. Genetic research has confirmed that the ε4 allele of the apolipoprotein E (ApoE) gene is the strongest gen- tory information, such as the entorhinal cortex, prepiri- etic risk factor for AD [2-5]. Inheritance of a single form cortex, and the anterior olfactory nucleus show increased neuritic plaques and neurofibrillary tangles in ApoE ε4 variant increases a persons risk of developing AD by a factor of three in men and four in women, and AD, as well as cell loss, granulovacuolar degeneration having two copies of the ε4 allele increases risk up to and tangles in the olfactory bulb [4,10-15]. The neuro- 15-fold compared to persons without the ε4 variant pathological changes associated with AD have been shown to affect the primary regions of the brain involved in olfaction but have less effect on other primary sensory * Correspondence: cmurphy@sciences.sdsu.edu areas [16]. Greater hippocampal atrophy has been Department of Psychology, San Diego State University, San Diego, CA 92120, USA reported in non-demented ε4+ individuals compared to University of California San Diego Medical Center, San Diego, CA 92120, ε4- controls [17]. Studies of persons with the ε4 allele USA have also demonstrated olfactory deficits in odor Full list of author information is available at the end of the article © 2012 Morgan and Murphy; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 2 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 identification [18], odor detection [19] and odor memory 900 ms [50]. Neuronal recovery time of the olfactory [20], as well as odor recognition memory [21]. Odor system is much longer than other sensory systems identification appears to be particularly sensitive to cog- [38,51,52]. Auditory and visual stimuli can be presented nitive changes associated with dementia. Correct classifi- every 2–3 seconds in ERP research without significant cation rates of 100% have been obtained between adaptation [53-55] while in the olfactory system inter- persons at risk for AD from controls utilizing an odor stimulus intervals of 30–45 seconds are required. This identification test [22]. ε4+ individuals demonstrate sig- slower neuronal recovery is partially due to olfactory re- nificantly poorer odor identification than ε4- nondemen- ceptor cells that rapidly adapt and slowly recover [56] ted older adults [18,23]. Odor identification abilities and partially due to habituation [52]. Given longer inter- declined more rapidly in ε4+ persons than ε4- persons stimulus intervals in olfactory stimulation, fewer trials over a four year time period while during the same time are presented than in other systems in order to reduce period there was no significant change in odor threshold, potential subject fatigue and loss of vigilance. A nar- picture identification, or DRS scores [24]. Odor identifi- rower filter is also applied when processing the ERP data cation has been shown to be directly related to left hip- to compensate for the smaller number of trials. pocampal volume and to AD pathology in the brain The early components of the OERP, the N1, P2, and [25,26]. Given that areas of the brain that process olfac- N2 are considered exogenous sensory components that tory information are some of the earliest affected in AD have been associated with odor threshold and odor iden- and those at risk for AD, olfactory changes may be some tification [38,49,57]. The P3 component in general repre- of the earliest signs of the disease in the preclinical sents endogenous processing of a stimulus, reflecting phase. both stimulus classification speed and the ability to at- Neuroimaging studies have suggested a functional re- tend to and evaluate a stimulus [58,59]. OERP P3 latency cruitment hypothesis of age-related compensatory correlates with neuropsychological tests that measure changes where those with AD and those at risk for AD memory and cognitive processing speed [60]. Several utilize additional cognitive resources to bring memory- studies have demonstrated increased OERP peak laten- related performance to normal levels [27-33]. Persons cies associated with aging [36,38,39,41,60]. Older males with a positive family history (FH) of AD and those with produced significantly smaller OERP peak amplitudes both FH and the ε4 allele had greater activation predom- than older females when utilizing relatively short inter- inantly in the bilateral posterior cingulate/precuneus, bi- stimulus intervals, suggesting greater olfactory impair- lateral temporoparietal junction, and bilateral prefrontal ments in males [38]. Studies of the OERP have further cortex [34]. ApoE+ individuals produced greater brain documented olfactory deficits in AD [61], specifically activation in the bilateral fusiform gyri, right superior longer P2 and P3 latencies in AD patients compared to parietal cortex, left pyramis/uvula, left middle frontal controls. These latency measures also correlate signifi- gyrus, and medial frontal gyrus [29]. Similarly, partici- cantly with dementia status as measured by the Demen- pants diagnosed with Mild Cognitive Impairment or AD tia Rating Scale (DRS). Importantly, studies utilizing the demonstrate greater activation in the frontal areas of the OERP with persons at risk for AD, due to the ApoE ε4 al- brain [35]. These studies suggest the potential for detec- lele, have also demonstrated differences. ε4+ non- tion of AD and early preclinical stages using measures of demented older adults produced significantly longer brain response. OERP latencies than age-matched ε4- individuals [62]. Brain activity can be measured from the surface of the Additionally, high sensitivity and specificity was obtained scalp via the electroencephalogram and more specifically in classifying ε4+ and ε4- individuals based on OERP la- the event-related potential (ERP), a measure that is ex- tency alone. Utilizing a cross-modal odor recognition quisitely sensitive to the timing of the brain’s response. memory task differential brain activity was observed be- tween ApoE groups, such that ε4- participants differed Olfactory event-related potentials (OERPs) recorded in relation to olfactory stimulation has demonstrated sensi- from ε4+ participants in activation of the frontal elec- tivity to subtle changes in olfactory functioning asso- trode sites, supporting the compensatory hypothesis [63]. ciated with aging, disease, and ApoE status [36-45]. This study examines OERPs in an odor identification OERPs require odor stimulation via specially built olfact- task compared to a picture identification task in three ometers which control the exact timing of stimulus separate age groups and in persons positive and negative onset while avoiding simultaneous stimulation of other for the ε4 allele. We hypothesized that ε4+ individuals sensory modalities such as stimulation of the trigeminal would demonstrate differing topographical patterns of system [39,46-49]. These olfactometers also warm and brain activation compared to ε4- individuals as mea- humidify the air stream in order to prevent somatosen- sured by the ERP. As in previous studies we also sory cues. Reaction times to odors vary based on the hypothesized that ε4+ older adults would produce longer stimulus and subject characteristics but range from 800- OERP peak latencies than ε4- participants and that this Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 3 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 difference would be greater than differences measured acceptable ways of responding. Total number correct of the with an odor threshold test and a traditional odor identi- 6 most commonly identified odors was used for analysis. fication test (San Diego Odor Identification Test). ERP stimulus presentation Methods and materials Olfactory stimulation was performed via computer con- Participants trolled olfactometer incorporating designs of previous Participants were 60 adults divided into three age groups, olfactometers [39,46-49]. Odors were presented utilizing a Young Adults (10 M, 10F, Mean age = 22.8 years), Middle single stimulus paradigm for 200 msec and an interstimu- Age Adults (10 M, 10F, Mean Age = 50.5), and Older lus interval (ISI) of 30 sec. Participants employed Velo- Adults (10 M, 10F, Mean age = 70.7). Half of each group pharyngeal closure to restrict breathing to the mouth and were positive for the ε4 allele. Table 1 presents demo- thereby maintain a constant odorant flow rate [46,48,70]. graphic variables by age and ApoE groups. Participants Fourteen separate odors (banana, rose, cinnamon, peanut were recruited from the general community, from San butter, baby powder, mustard, chocolate, pine, lemon, or- Diego State University, and from an ongoing subject pool ange, vanilla, coffee, leather, wintergreen) were presented at the Lifespan Human Senses Laboratory. The research twice each in pseudo-randomized order. Six of these odors was approved by IRBs at San Diego State University and were chosen in order to replicate the most identifiable the University of California, San Diego and subjects gave odors from the San Diego Odor Identification Test informed consent. All participants were screened for odor [22,57,69]. All odorants were undiluted and two drops of sensitivity via odor threshold test and odor identification each odorant were placed into the olfactometer before test and any participants with threshold scores lower than each subject session. After each odor presentation the par- 4, or odor identification scores less than 3, were excluded ticipants were asked to identify the odor via button press from the study [22,64,65]. Participants were screened for from a list of four written options presented on the com- cognitive impairment using the Dementia Rating Scale, puter screen in front of them and their responses were and any participants scoring less than 133 were excluded recorded electronically. from the study [66]. Genetic DNA was obtained from each In a separate experimental session on the same testing subject using buccal swab of cheek cells and analyzed for day, 28 visual line drawings of objects from the Boston the APOE genotype at an offsite laboratory as described in Naming Test [71] were presented on a computer screen in [67]. Data from 40 of these participants have previously front of the subject. Duration of each stimulus was 200 msec been published [68]. with 30 sec ISIs. As in the olfactory identification task the subjects were asked to identify each picture via button Procedure press from a list of four written options on the computer San Diego Odor Identification Test (SDOIT) screen. Both olfactory and visual stimuli were presented The San Diego Odor Identification Test [22,57,69] con- via Compumedics STIM software. Order of experimental sists of 8 common household odors (e.g. chocolate, coffee) presentation, olfactory or visual, was randomized across presented in opaque jars. A set of 20 line drawings of the subjects so that some subjects received the visual experi- 8 odors and 14 distractors, presented in an array, were ment first, and some the olfactory experiment first. placed in front of each participant. Participants smelled the odors birhinically in random order and chose the odor ERP recording from the array of drawings. Verbalizing the name of the Olfactory and visual ERPs were obtained via Compume- odor or pointing to the picture of the odor were both dics™ 64-electode AG/AG/CL sintered Quick-Cap and Table 1 Means and Standard Deviations for demographic, behavioral and performance data for each age and ApoE group ApoE Negative ApoE Positive Young Middle Older Young Middle Older Age (years) 22.6 (2.0) 50.7 (1.7) 71.2 (3.6) 23.1 (2.3) 50.2 (4.5) 70.2 (2.9) Education (years) 14.7 (2.8) 14.9 (2.5) 16.1 (2.3) 14.9 (1.7) 15.2 (2.3) 14.8 (3.2) Dementia Rating Scale Score (144 max) 142.4 (2.0) 139.8 (4.8) 140.3 (2.9) 140.3 (5.0) 140.8 (4.1) 141.5 (2.1) Odor Threshold (dilution steps, 9 max) 7.4 (1.3) 6.7 (1.1) 6.3 (1.4) 7.3 (1.5) 6.8 (1.9) 4.4 (1.3) Odor Identification Test (6 max) 5.9 (0.3) 4.9 (1.2) 5.0 (1.3) 5.6 (0.5) 4.8 (1.4) 4.3 (1.2) OERP # Correctly Identified (28 max) 20.1 (4.3) 19.9 (6.1) 18.7 (4.2) 18.3 (3.9) 15.5 (3.7) 17.6 (4.0) VERP # Correctly Identified (28 max) 21.2 (7.8) 26.0 (2.1) 25.7 (2.8) 22.7 (4.0) 22.1 (6.5) 26.3 (2.2) Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 4 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Quick-Cell system, amplified via Synamps 2 amplifiers, correctly identified more odors than ε4+ participants. and recorded on computer hard disk via the Neuroscan The number of correctly identified odors did not differ software package. Electrode impedances were kept below significantly by ApoE status when each age group was 10 kΩ. At the time of recording the EEG data were digi- analyzed separately, (suggesting that this effect is small tized at 500 Hz through a 0.1 to 30 Hz bandpass filter. when the screening measures are applied). Analysis of Offline, the data were further filtered through a 0.1 to correctly identified pictures in the Picture Identification 6 Hz bandpass filter. Artifactual eyeblink activity was ERP task revealed a significant main effect of age group recorded and corrected offline via the Neuroscan soft- (F(2,54) = 3.60, p <.05, η = .12), such that older partici- ware utilizing the Occular Artifact Reduction method pants correctly identified more pictures than young par- within the software. ERP trials that included other types ticipants (p <.05). The effect of ApoE status was not of artifactual activity were excluded using both auto- significant for Picture Identification. mated exclusion (e.g. excluding all trials with voltage ranges larger than 50 μV) and by visually inspecting Topographical displays of ERP activity each trial prior to averaging . Ongoing EEG activity was Figure 1 illustrates topographical distributions of OERP recorded throughout the experiment and then trials amplitudes in μV over the post-stimulus time interval epoched offline to 500 msec pre-stimulus and 1500 msec from 700 ms through 1300 ms by age and ApoE groups. post-stimulus. Baseline corrected trials were then aver- For each of 19 electrodes (FP1, FP2, F7, F3, F2, F4, F8, aged. Peak amplitudes were measured from the pre- T7, C3, CZ, C4, T8, P7, P3, P2, P4, P8, O1, O2) ampli- stimulus baseline to maximum peak amplitude. Latency tudes were averaged over the 100 ms time intervals (e.g. windows from previous OERP studies [38,39] were used 700-800 ms) and input into graphing software in order as guidelines to identify peak components. Peaks were to visually display brain activity across the scalp for each picked blindly as to age, gender, and APOE status in age and APOE group. Given no significant ApoE effects order to avoid experimenter bias. in the visual modality only olfactory ERP topographies are shown. In the young group the OERP topographical Results maps show greater brain activation in the ε4+ partici- Demographics and screening measures pants compared to ε4- participants, over the left hemi- Table 1 summarizes demographic and screening mea- sphere electrodes, and particularly over parietal sures. Within each age group there were no significant electrodes, that decreases after 1100 ms. Middle age ε4+ differences in mean participant age between ApoE+ and and ε4- individuals demonstrated similar topographies, ApoE- participants (p >.05). Dementia Rating Scale however ε4+ participants showed somewhat more activ- scores did not differ significantly between ApoE groups ity over the right hemisphere electrodes compared to or age groups (p >.05) and all participants’ DRS scores left, in the 900-1100 ms range, whereas ε4- participants were in the range of normal cognitive functioning. Ana- showed more central electrode activity across the lysis of odor threshold test performance revealed that all recording epoch. The greatest differences can be participants scored in the normal range of olfactory observed in the older groups where ε4- participants functioning. While all participants were normosmic, the showed an increase in activation over left and central older participant group exhibited poorer olfactory electrode sites between 900-1100 ms, and ε4+ partici- threshold scores than the middle and young age groups pants showed relatively less overall activation during that (F(2,57) = 8.93, p <.001, η = .24), with no interaction of time period, but increasing activation over right frontal ApoE status. electrodes between 1000-1200 ms. Overall the topo- graphical maps clearly illustrate that brain activity Odor and picture identification related to olfactory processing differs not only by age, Table 1 shows identification scores by age and ApoE but more importantly by ApoE status, and the activity groups. Analysis of the San Diego Odor Identification differentially changes over the post-stimulus time period. Test revealed no significant main effects or interaction effects involving ApoE status (p >.05). It did demon- strate a significant main effect of age (F(2,57) = 6.04, Event Related Potentials (ERPs) p <.01, η = .18) with young participants correctly identi- Repeated measures multivariate analyses of variance fying more odors than both the middle and older age (MANOVAs) were performed for each ERP component groups (p <.05). (N1, P2, N2, P3) and olfactory and visual modalities Analysis of correctly identified number of odors from were analyzed separately for each peak amplitude and la- the Odor Identification ERP task revealed a main effect tency. Greenhouse-Geisser corrections were applied to of ApoE status collapsed across age groups (F(1,54) = all MANOVAs. Significant main effects and interactions 4.54, p <.05) η = .08), such that ε4- participants were further analyzed with post hoc Newman Keuls Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 5 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Figure 1 Topographical representation of OERP amplitudes in μV across 19 electrode sites by age and ApoE groups for 700-1300 ms post-stimulus time intervals. Multiple Range Tests (alpha 0.05). Significant visual and N2 amplitude demonstrated a significant main effect of olfactory ERP effects are summarized in Table 2. age (F(2,54) = 3.62, p <.05, η = .12) with older age parti- cipants producing significantly more negative N2 ampli- Picture identification ERPs tudes than middle age participants. Visual N1, P2, and N2 amplitudes demonstrated no sig- Figure 2 illustrates olfactory ERP peak latencies. nificant main or interaction effects (p >.05). Visual P3 Olfactory N1, P2, N2, and P3 latencies demonstrated amplitude demonstrated a significant main effect for significant interaction effects of Age x ApoE status 2 2 electrode site (F(2,108) = 4.28, p <.05, η = .07) such that (N1: F(2,54) = 4.73, p <.05, η = .15; P2: F(2,54) = 9.34, 2 2 the Cz and Pz electrode sites produced larger P3 ampli- p <.001, η = .26; N2: F(2,54) = 8.18, p <.01, η = .23; P3: tudes than the Fz site. F(2,54) = 14.11, p <.001, η = .34). Post hoc analyses of Figure 2 illustrates visual ERP peak latencies. Visual the interaction effects revealed that in the young group N1 and P2 latencies did not demonstrate significant those negative for the ε4 allele produced significantly 2 2 main or interaction effects (p >.05). Visual N2 latency longer N2 (η = .26), and P3 (η = .29), latencies. In the demonstrated a significant main effect of electrode site middle age group those positive for the ε4 allele pro- 2 2 (F(2,108) = 3.50, p <.05, η = .06) with the Pz electrode duced significantly longer N1 (η = .31), and P2 site producing shorter N2 latencies than the Fz electrode (η = .31) latencies. In the older group those positive for site. Visual P3 latency also revealed a significant main ef- the ε4 allele produced significantly longer latencies for 2 2 2 2 fect of electrode site (F(2,108) = 8.78, p <.01, η = .14) all components N1 (η = .50), P2 (η = .52), N2(η = .35), with the Cz and Pz electrode sites recording significantly and P3(η = .59). For N1 and P3 latencies, in both longer latencies than the Fz site (p <.01). Visual P3 la- ApoE groups, older participants produced significantly tency also showed a significant main effect of age group longer latencies than middle age participants and mid- (F(2,54) = 4.94, p <.05, η = .15) with older adults produ- dle age participants produced longer latencies than cing significantly longer visual P3 latencies than young young participants. For P2 and N2 latencies in ε4+ par- adults (p <.01). ticipants, this same pattern was observed, however in ε4- participants young adults did not differ significantly from middle age participants, but both young and mid- Odor identification ERPs dle age participants produced shorter latencies than Olfactory N1, P2, and P3 amplitudes demonstrated no older participants. significant main or interaction effects (p >.05). Olfactory Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 6 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Table 2 Summary of analyses performed and effect sizes for peak component amplitudes and latencies Peak measures Amplitude Latency N1 P2 N2 P3 N1 P2 N2 P3 Picture ID ERPs Age (A) - - - - - - - *(η=.15) ApoE Status (S) - - - - - - - - Electrode (E) - - - *(η=.07) - - *(η=.06) *(η=.14) AxS - - - - - --- AxE - - - - - --- SxE - - - - - --- AxSxE - - - - - --- Odor ID ERPs Age (A) - - *(η=.12) - ***(η=.70) ***(η=.68) ***(η=.64) ***(η=.76) ApoE Status (S) - - - - ***(η=.27) ***(η=.22) - - Electrode (E) - - - - - - - - Ax S - - - - *(η=.15) ***(η=.26) **(η=.23) ***(η=.34) AxE - - - - - --- SxE - - - - - --- AxSxE - - - - - --- * p <0.05. **p <0.01. ***p <0.001. Correlational analyses were performed between the the most significant single predictor in discriminating ERP odor ID performance and average (Fz, Cz, Pz) peak between ε4+ participants and ε4- participants (χ = 6.07, latencies (N1, P2, N2, P3). When all ages and ApoE p <.05) resulting in an overall correct classification rate groups were combined together odor ID performance of 70.0% (Sensitivity = 66.7%, Specificity = 73.3%). When marginally correlated with N1 latency (r = −.28, p <.05). P3 latency was also added to N1 amplitude in the model Correlational analyses were also performed for each (χ = 8.06, p <.01) overall correct classification rate age x ApoE group separately. The only significant correl- increased to 76.7% (Sensitivity = 80%, Specificity = ation between odor ID performance and latency was for 73.3%). Logistic regressions were also performed for N1 latency in the older Apoe+ group (r = −.77, p <.01). each age group separately in order to better understand the effects of ApoE status within each age group. In the Logistic regression analyses of OERP variables young participant group N2 amplitude was the most sig- In order to better understand the predictive value of the nificant predictor (χ = 7.79, p <.01) resulting in an over- ERP in differentiating ε4- and ε4+ participants, stepwise all classification rate of 65.0% (Sensitivity = 70.0%, logistic regression analysis was performed on olfactory Specificity = 60.0%). In the middle age group P2 latency N1, P2, N2, P3 amplitude and latency averaged over Fz, was the most significant single predictor (χ = 6.86, Cz, and Pz. Visual ERP variables were not included in p <.01) resulting in an overall classification rate of 80.0% logistic regression analysis because no significant ApoE (Sensitivity = 80.0%, Specificity = 80.0%). When P3 ampli- effects were present. A logistic regression is a type of re- tude and P3 latency were also added to the equation gression analysis used to predict the outcome of a binary with P2 latency (χ = 20.09, p <.001), the overall classifi- dependent variable (e.g. Apoe+ vs Apoe-) based on one cation rate for middle age participants increased to or more predictor variables (e.g. ERP amplitude and la- 90.0% (Sensitivity = 90.0%, Specificity = 90.0%). In the tency). The logistic regression analysis outputs predictive older age group P3 latency was the most significant sin- classification results including overall correct classifica- gle predictor (χ = 16.37, p <.001) resulting in an overall tion (total percentage of correctly classified individuals), classification rate of 90.0% (Sensitivity = 90.0%, Specifi- as well as sensitivity (e.g. APOE+ correctly classified as city = 90.0%). When N1 latency was also added to the APOE+) and specificity (e.g. APOE- correctly classified equation with P3 latency (χ = 27.73, p <.001), overall as APOE-). In the olfactory modality analysis of all age classification rate for older participants increased to groups combined revealed that olfactory N1 latency was 100.0% (Sensitivity = 100.0%, Specificity = 100.0%). Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 7 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Figure 2 Visual and olfactory average N1, P2, N2, and P3 latencies by age and ApoE groups. Error bars represent the standard error of the mean (SEM). Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 8 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Discussion activation changes across time over the post-stimulus This study demonstrated (1) robust odor identification interval of cognitive processing. This suggests that pro- ERP differences based on ApoE status and interactions cessing of olfactory stimuli is differentially affected by with age; (2) high correct ApoE classification rates utiliz- presence or absence of the ε4 allele. Additionally these ing the OERP that were different for each age group. effects change over the lifespan, such that individuals in A few previous studies have demonstrated ERP impair- different decades of life, even young adults, show varying ments in persons with a positive family history of AD, in patterns of brain activation. those diagnosed with early AD, and in individuals with In the present study, it is important to note that in mild cognitive impairment (MCI). MCI is commonly order to better understand the effects of the ApoE risk defined as subtle but measurable memory impairment factor at points before memory problems are present, without any other symptoms of dementia. Green et al. participants with dementia, early dementia, or mild cog- [72] demonstrated auditory ERP P3 latency increases in nitive impairment, as well as those with anosmia or se- pre-clinical groups of persons with a family history of vere hyposmia, were screened out of the study. Given AD and in those with a family history plus ε4+ status. this rigorous screening process, it is not surprising that They did not indicate, however, how many of the partici- no significant ApoE effects were found for the visual pic- pants demonstrated this latency difference, or how well ture identification task. Very robust effects of ApoE sta- this measure correctly classified participants into ε4+ or tus were demonstrated for the odor identification ERP ε4- groups. Olichney et al. [73] studied participants diag- task, as well as significant age by ApoE interaction nosed with MCI utilizing an N400/P600 semantic con- effects. This occurred despite no difference in perform- gruency task and then tracked those participants over ance on the Dementia Ratings Scale, odor threshold test- time. Participants with abnormal N400 or P600 effects ing, or the SDOIT by ApoE status. The present study had an 87 to 88% likelihood of progression to dementia strongly suggests that combining olfactory processing within 3 years. They suggest that these N400 abnormal- with cognitive processing [odor identification] may be ities in MCI may reflect subtle dysfunction of semantic sensitive enough to differentiate very early those with a memory processes. Utilizing this method, classification high likelihood from those with a low likelihood of of participants into diagnostic groups was high in sensi- developing AD, even as early as middle age. This to- tivity in MCI who converted to AD (81-94%) less so gether suggests the ability to identify odors and the when applied to all participants (58 to 65%). Chapman speed of odor identification is slowed in the presence of et al. [74] used a visual number-letter memory task to the ε4 allele. Picture identification remained intact in study ERPs in participants diagnosed as being in the ApoE+ participants, both for number of pictures cor- early stages of AD. Their results suggest that AD deficits rectly identified and speed with which the pictures were may include problems with storage in short-term mem- cognitively processed. ory, and that difficulties may lie in the cognitive proces- Of further note, the present study demonstrated good sing of stimuli that are relevant to the task in which the ApoE classification rates of 80% in the middle age group, participant is engaged. Using this method the authors with ε4+ participants producing significantly longer N1 were able to correctly classify 92% of participants into and P2 latencies than ε4- participants. It suggests that AD or control groups. While these studies are extremely ApoE-related olfactory functional decline is taking place helpful in understanding cognitive changes associated at much earlier ages than previously observed, further with early stages of dementia, even at the MCI stage, suggesting that early, pre-clinical, diagnosis of AD may they also raise the possibility of early diagnosis at even be a real possibility. Consistent with previous OERP earlier, pre-MCI, pre-clinical, stages of AD. A measure studies [62,63], older ε4+ participants produced signifi- that would aid diagnosis of AD many years before any cantly longer OERP peak latencies. In this group 100% classification rates were obtained suggesting a clear de- manifestation of other signs or symptoms would be ideal, especially once an effective medication for halting lineation in performance between ε4+ and ε4- partici- or altering the dementing process is developed. pants once they reach ages above 65 years old. Further research needs to examine the utility of vari- Illustrated on the ERP topographical maps, the current study demonstrated differing patterns of brain activity ous measures and tasks in the study of pre-clinical AD, recorded over the scalp, depending on ApoE status. in order to capture the pre-dementing processes at the earliest possible stages, and improve diagnostic ability. fMRI studies on activation have reported mixed results, with some showing increased activation in ε4 carriers Olfactory tasks involving cognitive processing, such as [30,75], and others demonstrating reduced activation in the OERP, appear to be very promising in this regard. ε4 carriers [76]. The current study demonstrates that Competing interest patterns of brain activation differ not only by ApoE sta- The authors report no biomedical financial interests or potential conflicts of tus, but across age groups, and that the pattern of interest. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 9 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Authors’ contributions 19. Bacon AW, Bondi MW, Salmon DP, Murphy C: Very early changes in CDM and CM designed the study and advised the research assistants olfactory functioning due to Alzheimer's disease and the role of through data collection and analysis, and interpreted the data. CDM apolipoprotein E in olfaction. Ann N Y Acad Sci 1998, 855:723–731. constructed the olfactometer. CDM and CM wrote and approved the final 20. Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, Welsh-Bohmer K: version of the manuscript. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer's disease. Neurobiol Aging 2002, 23(3):397–404. 21. Gilbert PE, Murphy C: Differences between recognition memory and Acknowledgments remote memory for olfactory and visual stimuli in nondemented elderly Supported by NIH Grant DC002064 to Claire Murphy. The authors would like individuals genetically at risk for Alzheimer's disease. Exp Gerontol 2004, to thank the late Dr. Leon Thal and the UCSD ADRC (P50AG005131-28) for 39(3):433–441. genotyping, Dr. John Polich, Krystin Corby, Joel Kowalewski, Jessica 22. Morgan CD, Nordin S, Murphy C: Odor Identification as an Early Marker Bartholow, and Roberto Zamora for research assistance. for Alzheimers-Disease - Impact of Lexical Functioning and Detection Sensitivity. J Clin Exp Neuropsychol 1995, 17(5):793–803. Author details 23. Olofsson JK, Nordin S, Wiens S, Hedner M, Nilsson LG, Larsson M: Odor Department of Psychology, San Diego State University, San Diego, CA identification impairment in carriers of ApoE-varepsilon4 is independent 92120, USA. University of California San Diego Medical Center, San Diego, of clinical dementia. Neurobiol Aging 2010, 31(4):567–577. CA 92120, USA. SDSU/UCSD Joint Doctoral Program, 6363 Alvarado Ct., 24. Calhoun-Haney R, Murphy C: Apolipoprotein epsilon 4 is associated with Suite 101, San Diego, CA 92120-4913, USA. more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores. Brain Cogn 2005, 58(2):178–182. Received: 22 January 2012 Accepted: 15 June 2012 25. Murphy C, Jernigan TL, Fennema-Notestine C: Left hippocampal volume loss Published: 31 July 2012 in Alzheimer's disease is reflected in performance on odor identification: a structural MRI study. J Int Neuropsychol Soc 2003, 9(3):459–471. References 26. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA: 1. American Psychiatric Association: Diagnostic and statistical manual of mental Olfactory Impairment in Presymptomatic Alzheimer's Disease. Ann N Y disorders, Revised 4th ed. Washington, DC: American Psychiatric Press; 2000. Aca Sci 2009, 1170(1):730–735(736). 2. Blacker D: The genetics of Alzheimer's disease: progress, possibilities, and 27. Backman L, Andersson JL, Lyberg L, Winblad B, Nordberg A, Almkvist O: pitfalls. Harv Rev Psychiatry 1997, 5(4):234–237. Brain regions associated with episodic retrieval in normal aging and 3. Combarros O, Alvarez-Arcaya A, Sanchez-Guerra M, Infante J, Berciano J: Alzheimer's disease. Neurology 1999, 52(9):1861–1870. Candidate gene association studies in sporadic Alzheimer's disease. 28. Becker JT, Mintun MA, Aleva K, Wiseman MB, Nichols T, DeKosky ST: Dement Geriatr Cogn Disord 2002, 14(1):41–54. Compensatory reallocation of brain resources supporting verbal episodic 4. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small memory in Alzheimer's disease. Neurology 1996, 46(3):692–700. GW, Roses AD, Haines JL, Pericakvance MA: Gene dose of apolipoprotein E 29. Bondi MW, Houston WS, Eyler LT, Brown GG: fMRI evidence of type 4 allele and the risk of Alzheimer's disease in late onset families. compensatory mechanisms in older adults at genetic risk for Alzheimer Science 1993, 261(5123):921–923. disease. Neurology 2005, 64(3):501–508. 5. Teter B, Raber J, Nathan B, Crutcher KA: The presence of apoE4, not the 30. Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, absence of apoE3, contributes to AD pathology. J Alzheimers Dis 2002, Mazziotta JC, Small GW: Patterns of brain activation in people at risk for 4:155–163. Alzheimer's disease. N Engl J Med 2000, 343(7):450–456. 6. Bertram L, Tanzi RE: The genetic epidemiology of neurodegenerative 31. Grady CL, McIntosh AR, Beig S, Keightley ML, Burian H, Black SE: Evidence disease. J Clin Invest 2005, 115(6):1449–1457. from functional neuroimaging of a compensatory prefrontal network in 7. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Alzheimer's disease. J Neurosci 2003, 23(3):986–993. Pericakvance MA, Risch N, vanDuijn CM: Effects of age, sex, and ethnicity 32. Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, on the association between apolipoprotein E genotype and Alzheimer O’Jile JR, Riordan HJ, Santulli RB, Smith CA, Weaver JB: Neuroanatomic disease - A meta-analysis. JAMA 1997, 278(16):1349–1356. substrates of semantic memory impairment in Alzheimer's disease: 8. Burke W, Pinsky LE, Press NA: Categorizing genetic tests to identify patterns of functional MRI activation. J Int Neuropscyhol Soc 1999, their ethical, legal, and social implications. Am J Med Genet 2001, 5(5):377–392. 106(3):233–240. 33. Woodard JL, Grafton ST, Votaw JR, Green RC, Dobraski ME, Hoffman JM: 9. Murphy C: Loss of olfactory function in dementing disease. Physiol Behav Compensatory recruitment of neural resources during overt rehearsal of 1999, 66(2):177–182. word lists in Alzheimer's disease. Neuropsychology 1998, 12(4):491–504. 10. Averback P: 2 new lesions in Alzheimers-disease. Lancet 1983, 34. Seidenberg M, Guidotti L, Nielson KA, Woodard JL, Durgerian S, Antuono P, 2(8360):1203. Zhang Q, Rao SM: Semantic memory activation in individuals at risk for 11. Braak H, Braak E: Frequency of stages of Alzheimer-related lesions in developing Alzheimer disease. Neurology 2009, 73(8):612–620. different age categories. Neurobiol Aging 1997, 18:351–357. 35. Rombouts SA, Barkhof F, van Meel CS, Scheltens P: Alterations in brain 12. Christen-Zaech S, Kraftsik R, Pillevuit O, Kiraly M, Martins R, Khalili K, Miklossy activation during cholinergic enhancement with rivastigmine in J: Early olfactory involvement in Alzheimer's disease. Can J Neurol Sci Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002, 73(6):665–671. 2003, 30(1):20–25. 36. Covington JW, Geisler MW, Polich J, Murphy C: Normal aging and odor 13. Esiri MM, Wilcock GK: The Olfactory bulbs in Alzheimers-disease. J Neurol intensity effects on the olfactory event-related potential. Int J Neurosurg Psychiatry 1984, 47(1):56–60. Psychophysiol 1999, 32(3):205–214. 14. Ohm TG, Braak H: Olfactory-Bulb Changes in Alzheimers-Disease. Acta 37. Evans WJ, Cui L, Starr A: Olfactory event-related potentials in normal Neuropathol 1987, 73(4):365–369. human subjects: effects of age and gender. Electroencephalogr Clin 15. Reyes PF, Golden GT, Fariello RG, Fagel L, Zalewska M: Olfactory pathways Neurophysiol 1995, 95(4):293–301. in Alzheimer's disease (AD): Neuropathological studies [abstract]. Society 38. Morgan CD, Covington JW, Geisler MW, Polich J, Murphy C: Olfactory for Neuroscience 1985, 11:168. event-related potentials: older males demonstrate the greatest deficits. 16. Van Hoesen GW, Solodkin A: Cellular and systems neuroanatomical Electroencephalogr Clin Neurophysiol 1997, 104(4):351–358. changes in Alzheimer's disease. In: Calcium hypothesis of aging and 39. Morgan CD, Geisler MW, Covington JW, Polich J, Murphy C: Olfactory P3 in dementia. Disterhoft JF, Khachaturian ZS (eds). Proc NY Acad Sci (USA) young and older adults. Psychophysiology 1999, 36(3):281–287. 1994, 747:12–35. 40. Morgan CD, Murphy C: Differential effects of active attention and age on 17. den Heijer T, Oudkerk M, Launer LJ, Van Duijn CM, Hofman A, Breteler MM: event-related potentials to visual and olfactory stimuli. Int J Psychophysiol Hippocampal, amygdalar, and global brain atrophy in different 2010, 78(2):190–199. apolipoprotein E genotypes. Neurology 2002, 59:746–748. 18. Murphy C, Bacon AW, Bondi MW, Salmon DP: Apolipoprotein E status is 41. Murphy C, Morgan CD, Geisler MW, Wetter S, Covington JW, Madowitz MD, associated with odor identification deficits in nondemented older Nordin S, Polich JM: Olfactory event-related potentials and aging: persons. Ann N Y Acad Sci 1998, 855:744–750. normative data. Int J Psychophysiol 2000, 36(2):133–145. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 10 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 42. Nordin S, Quinonez C, Morgan CD, Geisler MW, Polich J, Murphy C: 67. Sundermann EE, Gilbert PE, Murphy C: Apolipoprotein E epsilon 4 Olfactory event-related potentials in young and elderly adults: genotype and gender: Effects on memory. Am J Geriatr Psychiatry 2007, evaluation of tracking task versus eyes open/closed recording. Chem 15(10):869–878. Senses 1999, 24(4):459–464. 68. Zamora R, Bartholow J, Green E, Morgan CD, Murphy C: Adiposity 43. Thesen T, Wetter S, Murphy C: Olfactory event-related potential detects measures predict olfactory processing speed in older adult carriers of age-related changes in olfactory processing with velopharyngeal closure the apolipoprotein E4 allele. Clin Neurophysiol 2011, doi:10.1016/j. and normal breathing. Psychophysiology 2000, 37:S97. clinph.2011.09.001. 44. Wetter S, Murphy C: Individuals with Down's syndrome demonstrate 69. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM: abnormal olfactory event-related potentials. Clin Neurophysiol 1999, Prevalence of olfactory impairment in older adults. JAMA 2002, 110(9):1563–1569. 288(18):2307–2312. 45. Wetter S, Peavy G, Jacobson M, Hamilton J, Salmon D, Murphy C: Olfactory 70. Thesen T, Murphy C: Age-related changes in olfactory processing and auditory event-related potentials in Huntington's disease. detected with olfactory event-related brain potentials using Neuropsychology 2005, 19(4):428–436. velopharyngeal closure and natural breathing. Int J Psychophysiol 2001, 40(2):119–127. 46. Kobal G: Elektrophysiologische Untersuchungen des menschlichen Geruchsinns. 71. Kaplan E, Goodglass H, Weintrab S: The Boston Naming Test. Philadelphia: Stuttgart: Thieme; 1981. Lea and Febiger; 1983. 47. Lorig TS, Elmes DG, Zald DH, Pardo JV: A computer-controlled 72. Green J, Levey AI: Event-related potential changes in groups at increased olfactometer for fMRI and electrophysiological studies of olfaction. Behav risk for Alzheimer disease. Arch Neurol 1999, 56(11):1398–1403. Res Methods Instrum Comput 1999, 31(2):370–375. 73. Olichney JM, Taylor JR, Gatherwright J, Salmon DP, Bressler AJ, Kutas M, Iragui- 48. Lorig TS: The application of electroencephalographic techniques to the Madoz VJ: Patients with MCI and N400 or P600 abnormalities are at very study of human olfaction: a review and tutorial. Int J Psychophysiol 2000, high risk for conversion to dementia. Neurology 2008, 70(19):1763–1770. 36(2):91–104. 74. Chapman RM, Nowlis GH, McCrary JW, Chapman JA, Sandoval TC, Guillily 49. Murphy C, Nordin S, de Wijk RA, Cain WS, Polich J: Olfactory-evoked MD, Gardner MN, Reilly LA: Brain event-related potentials: diagnosing potentials: assessment of young and elderly, and comparison to early-stage Alzheimer's disease. Neurobiol Aging 2007, 28(2):194–201. psychophysical threshold. Chem Senses 1994, 19(1):47–56. 75. Han SD, Houston WS, Jak AJ, Eyler LT, Nagel BJ, Fleisher AS, Brown GG, 50. Overbosch P, de Wijk R, de Jonge TJ, Koster EP: Temporal integration and Cory-Bloom J, Salmon D, Thal LJ, Bondi MW: Verbal paired-associate reaction times in human smell. Physiol Behav 1989, 45(3):615–626. learning by APOE genotype in non-demented older adults: fMRI 51. Ekman GB, Berglund U, Berglund B, Lindwall T: Perceived intensity of odor: evidence of a right hemispheric compensatory response. Neurobiol Aging a function of time of adaptation. Scan J Psychol 1967, 8:177–186. 2007, 28(2):238–247. 52. Wilson DA, Linster C: Neurobiology of simple memory. J Neurophysiol 76. Lind J, Persson J, Ingvar M, Larsson A, Cruts M, Van Broeckhoven C, 2008, 100:2–7. Adolfsson R, Backman L, Nilsson LG, Petersson KM, Nyberg L: Reduced 53. Polich J: P300, probability, and inter-stimulus interval. Psychophysiology functional brain activity response in cognitively intact apolipoprotein E 1990, 27:396–403. epsilon 4 carriers. Brain 2006, 129:1240–1248. 54. Polich J: Probability and inter-stimulus interval effects on the P300 from auditory stimuli. Int J Psychophysiol 1990, 10:163–170. doi:10.1186/1744-9081-8-37 55. Polich J: P300 in clinical applications: meaning, method, and Cite this article as: Morgan and Murphy: Individuals at risk for measurement.In Electroencephalography: Basic Principles, Clinical Alzheimer’s disease show differential patterns of ERP brain activation Applications, and Related Fields. 3rd edition. Edited by Niedermeyer E, Lopes during odor identification. Behavioral and Brain Functions 2012 8:37. da Silva F. Baltimore, MD: Williams and Wilkins; 1993:1005–1018. 56. Moore PA: A model of the role of adaptation and disadaptation in olfactory receptor neurons: implications for the coding of temporal and intensity patterns in odor signals. Chem Senses 1994, 19(1):17–86. 57. Murphy C, Morgan CD: Olfactory Function and Event-Related Potentials in Alzheimers Disease.In Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics. Edited by Iqbal K, Sisodia SS, Winblad B. Chichester, UK: John Wiley and Sons, Ltd; 2001:237–251. 58. Donchin E, Heffley E, Hillyard SA, Loveless N, Maltzman I, Ohman A, Rosler F, Ruchkin D, Siddle D: Cognition and event-related potentials. II. The orienting reflex and P300. Ann N Y Acad Sci 1984, 425:39–57. 59. Polich J, Hoffman LD: P300 and handedness: on the possible contribution of corpus callosal size to ERPs. Psychophysiology 1993, 35(5):497–507. 60. Geisler MW, Morgan CD, Covington JW, Murphy C: Neuropsychological performance and cognitive olfactory event-related brain potentials in young and elderly adults. J Clin Exp Neuropsychol 1999, 21(1):108–126. 61. Morgan CD, Murphy C: Olfactory event-related potentials in Alzheimer's disease. J Int Neuropsychol Soc 2002, 8(6):753–763. 62. Wetter S, Murphy C: Apolipoprotein E epsilon 4 positive individuals demonstrate delayed olfactory event-related potentials. Neurobiol Aging 2001, 22(3):439–447. Submit your next manuscript to BioMed Central 63. Murphy C, Solomon ES, Haase L, Wang M, Morgan CD: Olfaction in aging and take full advantage of: and Alzheimer's disease: event-related potentials to a cross-modal odor- recognition memory task discriminate ApoE epsilon4+ and ApoE epsilon • Convenient online submission 4- individuals. Ann N Y Acad Sci 2009, 1170:647–657. • Thorough peer review 64. Cain WS, Gent J, Catalanotto FA, Goodspeed RB: Clinical evaluation of olfaction. Am J Otolaryngol 1983, 4(4):252–256. • No space constraints or color figure charges 65. Murphy C, Gilmore MM, Seery CS, Salmon DP, Lasker BR: Olfactory • Immediate publication on acceptance thresholds are associated with degree of dementia in Alzheimer's disease. Neurobiol Aging 1990, 11(4):465–469. • Inclusion in PubMed, CAS, Scopus and Google Scholar 66. Mattis S: Mental status examination for organic mental syndrome in the • Research which is freely available for redistribution elderly patient.In Geriatric psychiatry: A handbook for psychiatrists and primary care physicians. Edited by Bellak L, Katasu TB. New York: Grune and Submit your manuscript at Statton; 1976:77–121. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Individuals at risk for Alzheimer’s disease show differential patterns of ERP brain activation during odor identification

Download PDF
10 pages

Loading next page...
 
/lp/springer-journals/individuals-at-risk-for-alzheimer-s-disease-show-differential-patterns-LvgLEQszBz

References (152)

Publisher
Springer Journals
Copyright
Copyright © 2012 by Morgan and Murphy; licensee BioMed Central Ltd.
Subject
Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
eISSN
1744-9081
DOI
10.1186/1744-9081-8-37
pmid
22849610
Publisher site
See Article on Publisher Site

Abstract

Background: Studies suggest that older adults at risk of developing Alzheimer’s disease may show olfactory processing deficits before other signs of dementia appear. Methods: We studied 60 healthy non-demented individuals, half of whom were positive for the genetic risk factor the Apolipoprotein E ε4 allele, in three different age groups. Event-related potentials to visual and olfactory identification tasks were recorded and analyzed for latency and amplitude differences, and plotted via topographical maps. Results: Varying patterns of brain activation were observed over the post-stimulus epoch for ε4- versus ε4+ individuals on topographical maps. Individuals with the ε4 allele demonstrated different ERP peak latencies during identification of olfactory but not visual stimuli. High correct ApoE classification rates were obtained utilizing the olfactory ERP. Conclusions: Olfactory ERPs demonstrate functional decline in individuals at risk for Alzheimer’s disease at much earlier ages than previously observed, suggesting the potential for pre-clinical detection of AD at very early stages. Keywords: Alzheimer’s disease, Apolipoprotein E, Olfactory event-related potentials, Age, Smell impairment, Olfaction [6,7]. Presence of the ε4 allele increases the risk but does Alzheimer’s disease is a neurologic disorder accompan- ied by progressive memory loss, cognition loss and func- not guarantee future development of AD [8]. tional decline [1]. The cause or causes of AD are not yet Studies have found olfactory dysfunction in AD in- cluding impairment in olfactory threshold sensitivity, known and definitive diagnosis can only be made via postmortem autopsy or, while living, a brain biopsy. The odor identification, odor recognition memory, remote greatest risk factor for development of AD is advancing memory for odors, and odor fluency for review see [9]. Regions of the brain involved in the processing of olfac- age. Genetic research has confirmed that the ε4 allele of the apolipoprotein E (ApoE) gene is the strongest gen- tory information, such as the entorhinal cortex, prepiri- etic risk factor for AD [2-5]. Inheritance of a single form cortex, and the anterior olfactory nucleus show increased neuritic plaques and neurofibrillary tangles in ApoE ε4 variant increases a persons risk of developing AD by a factor of three in men and four in women, and AD, as well as cell loss, granulovacuolar degeneration having two copies of the ε4 allele increases risk up to and tangles in the olfactory bulb [4,10-15]. The neuro- 15-fold compared to persons without the ε4 variant pathological changes associated with AD have been shown to affect the primary regions of the brain involved in olfaction but have less effect on other primary sensory * Correspondence: cmurphy@sciences.sdsu.edu areas [16]. Greater hippocampal atrophy has been Department of Psychology, San Diego State University, San Diego, CA 92120, USA reported in non-demented ε4+ individuals compared to University of California San Diego Medical Center, San Diego, CA 92120, ε4- controls [17]. Studies of persons with the ε4 allele USA have also demonstrated olfactory deficits in odor Full list of author information is available at the end of the article © 2012 Morgan and Murphy; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 2 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 identification [18], odor detection [19] and odor memory 900 ms [50]. Neuronal recovery time of the olfactory [20], as well as odor recognition memory [21]. Odor system is much longer than other sensory systems identification appears to be particularly sensitive to cog- [38,51,52]. Auditory and visual stimuli can be presented nitive changes associated with dementia. Correct classifi- every 2–3 seconds in ERP research without significant cation rates of 100% have been obtained between adaptation [53-55] while in the olfactory system inter- persons at risk for AD from controls utilizing an odor stimulus intervals of 30–45 seconds are required. This identification test [22]. ε4+ individuals demonstrate sig- slower neuronal recovery is partially due to olfactory re- nificantly poorer odor identification than ε4- nondemen- ceptor cells that rapidly adapt and slowly recover [56] ted older adults [18,23]. Odor identification abilities and partially due to habituation [52]. Given longer inter- declined more rapidly in ε4+ persons than ε4- persons stimulus intervals in olfactory stimulation, fewer trials over a four year time period while during the same time are presented than in other systems in order to reduce period there was no significant change in odor threshold, potential subject fatigue and loss of vigilance. A nar- picture identification, or DRS scores [24]. Odor identifi- rower filter is also applied when processing the ERP data cation has been shown to be directly related to left hip- to compensate for the smaller number of trials. pocampal volume and to AD pathology in the brain The early components of the OERP, the N1, P2, and [25,26]. Given that areas of the brain that process olfac- N2 are considered exogenous sensory components that tory information are some of the earliest affected in AD have been associated with odor threshold and odor iden- and those at risk for AD, olfactory changes may be some tification [38,49,57]. The P3 component in general repre- of the earliest signs of the disease in the preclinical sents endogenous processing of a stimulus, reflecting phase. both stimulus classification speed and the ability to at- Neuroimaging studies have suggested a functional re- tend to and evaluate a stimulus [58,59]. OERP P3 latency cruitment hypothesis of age-related compensatory correlates with neuropsychological tests that measure changes where those with AD and those at risk for AD memory and cognitive processing speed [60]. Several utilize additional cognitive resources to bring memory- studies have demonstrated increased OERP peak laten- related performance to normal levels [27-33]. Persons cies associated with aging [36,38,39,41,60]. Older males with a positive family history (FH) of AD and those with produced significantly smaller OERP peak amplitudes both FH and the ε4 allele had greater activation predom- than older females when utilizing relatively short inter- inantly in the bilateral posterior cingulate/precuneus, bi- stimulus intervals, suggesting greater olfactory impair- lateral temporoparietal junction, and bilateral prefrontal ments in males [38]. Studies of the OERP have further cortex [34]. ApoE+ individuals produced greater brain documented olfactory deficits in AD [61], specifically activation in the bilateral fusiform gyri, right superior longer P2 and P3 latencies in AD patients compared to parietal cortex, left pyramis/uvula, left middle frontal controls. These latency measures also correlate signifi- gyrus, and medial frontal gyrus [29]. Similarly, partici- cantly with dementia status as measured by the Demen- pants diagnosed with Mild Cognitive Impairment or AD tia Rating Scale (DRS). Importantly, studies utilizing the demonstrate greater activation in the frontal areas of the OERP with persons at risk for AD, due to the ApoE ε4 al- brain [35]. These studies suggest the potential for detec- lele, have also demonstrated differences. ε4+ non- tion of AD and early preclinical stages using measures of demented older adults produced significantly longer brain response. OERP latencies than age-matched ε4- individuals [62]. Brain activity can be measured from the surface of the Additionally, high sensitivity and specificity was obtained scalp via the electroencephalogram and more specifically in classifying ε4+ and ε4- individuals based on OERP la- the event-related potential (ERP), a measure that is ex- tency alone. Utilizing a cross-modal odor recognition quisitely sensitive to the timing of the brain’s response. memory task differential brain activity was observed be- tween ApoE groups, such that ε4- participants differed Olfactory event-related potentials (OERPs) recorded in relation to olfactory stimulation has demonstrated sensi- from ε4+ participants in activation of the frontal elec- tivity to subtle changes in olfactory functioning asso- trode sites, supporting the compensatory hypothesis [63]. ciated with aging, disease, and ApoE status [36-45]. This study examines OERPs in an odor identification OERPs require odor stimulation via specially built olfact- task compared to a picture identification task in three ometers which control the exact timing of stimulus separate age groups and in persons positive and negative onset while avoiding simultaneous stimulation of other for the ε4 allele. We hypothesized that ε4+ individuals sensory modalities such as stimulation of the trigeminal would demonstrate differing topographical patterns of system [39,46-49]. These olfactometers also warm and brain activation compared to ε4- individuals as mea- humidify the air stream in order to prevent somatosen- sured by the ERP. As in previous studies we also sory cues. Reaction times to odors vary based on the hypothesized that ε4+ older adults would produce longer stimulus and subject characteristics but range from 800- OERP peak latencies than ε4- participants and that this Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 3 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 difference would be greater than differences measured acceptable ways of responding. Total number correct of the with an odor threshold test and a traditional odor identi- 6 most commonly identified odors was used for analysis. fication test (San Diego Odor Identification Test). ERP stimulus presentation Methods and materials Olfactory stimulation was performed via computer con- Participants trolled olfactometer incorporating designs of previous Participants were 60 adults divided into three age groups, olfactometers [39,46-49]. Odors were presented utilizing a Young Adults (10 M, 10F, Mean age = 22.8 years), Middle single stimulus paradigm for 200 msec and an interstimu- Age Adults (10 M, 10F, Mean Age = 50.5), and Older lus interval (ISI) of 30 sec. Participants employed Velo- Adults (10 M, 10F, Mean age = 70.7). Half of each group pharyngeal closure to restrict breathing to the mouth and were positive for the ε4 allele. Table 1 presents demo- thereby maintain a constant odorant flow rate [46,48,70]. graphic variables by age and ApoE groups. Participants Fourteen separate odors (banana, rose, cinnamon, peanut were recruited from the general community, from San butter, baby powder, mustard, chocolate, pine, lemon, or- Diego State University, and from an ongoing subject pool ange, vanilla, coffee, leather, wintergreen) were presented at the Lifespan Human Senses Laboratory. The research twice each in pseudo-randomized order. Six of these odors was approved by IRBs at San Diego State University and were chosen in order to replicate the most identifiable the University of California, San Diego and subjects gave odors from the San Diego Odor Identification Test informed consent. All participants were screened for odor [22,57,69]. All odorants were undiluted and two drops of sensitivity via odor threshold test and odor identification each odorant were placed into the olfactometer before test and any participants with threshold scores lower than each subject session. After each odor presentation the par- 4, or odor identification scores less than 3, were excluded ticipants were asked to identify the odor via button press from the study [22,64,65]. Participants were screened for from a list of four written options presented on the com- cognitive impairment using the Dementia Rating Scale, puter screen in front of them and their responses were and any participants scoring less than 133 were excluded recorded electronically. from the study [66]. Genetic DNA was obtained from each In a separate experimental session on the same testing subject using buccal swab of cheek cells and analyzed for day, 28 visual line drawings of objects from the Boston the APOE genotype at an offsite laboratory as described in Naming Test [71] were presented on a computer screen in [67]. Data from 40 of these participants have previously front of the subject. Duration of each stimulus was 200 msec been published [68]. with 30 sec ISIs. As in the olfactory identification task the subjects were asked to identify each picture via button Procedure press from a list of four written options on the computer San Diego Odor Identification Test (SDOIT) screen. Both olfactory and visual stimuli were presented The San Diego Odor Identification Test [22,57,69] con- via Compumedics STIM software. Order of experimental sists of 8 common household odors (e.g. chocolate, coffee) presentation, olfactory or visual, was randomized across presented in opaque jars. A set of 20 line drawings of the subjects so that some subjects received the visual experi- 8 odors and 14 distractors, presented in an array, were ment first, and some the olfactory experiment first. placed in front of each participant. Participants smelled the odors birhinically in random order and chose the odor ERP recording from the array of drawings. Verbalizing the name of the Olfactory and visual ERPs were obtained via Compume- odor or pointing to the picture of the odor were both dics™ 64-electode AG/AG/CL sintered Quick-Cap and Table 1 Means and Standard Deviations for demographic, behavioral and performance data for each age and ApoE group ApoE Negative ApoE Positive Young Middle Older Young Middle Older Age (years) 22.6 (2.0) 50.7 (1.7) 71.2 (3.6) 23.1 (2.3) 50.2 (4.5) 70.2 (2.9) Education (years) 14.7 (2.8) 14.9 (2.5) 16.1 (2.3) 14.9 (1.7) 15.2 (2.3) 14.8 (3.2) Dementia Rating Scale Score (144 max) 142.4 (2.0) 139.8 (4.8) 140.3 (2.9) 140.3 (5.0) 140.8 (4.1) 141.5 (2.1) Odor Threshold (dilution steps, 9 max) 7.4 (1.3) 6.7 (1.1) 6.3 (1.4) 7.3 (1.5) 6.8 (1.9) 4.4 (1.3) Odor Identification Test (6 max) 5.9 (0.3) 4.9 (1.2) 5.0 (1.3) 5.6 (0.5) 4.8 (1.4) 4.3 (1.2) OERP # Correctly Identified (28 max) 20.1 (4.3) 19.9 (6.1) 18.7 (4.2) 18.3 (3.9) 15.5 (3.7) 17.6 (4.0) VERP # Correctly Identified (28 max) 21.2 (7.8) 26.0 (2.1) 25.7 (2.8) 22.7 (4.0) 22.1 (6.5) 26.3 (2.2) Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 4 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Quick-Cell system, amplified via Synamps 2 amplifiers, correctly identified more odors than ε4+ participants. and recorded on computer hard disk via the Neuroscan The number of correctly identified odors did not differ software package. Electrode impedances were kept below significantly by ApoE status when each age group was 10 kΩ. At the time of recording the EEG data were digi- analyzed separately, (suggesting that this effect is small tized at 500 Hz through a 0.1 to 30 Hz bandpass filter. when the screening measures are applied). Analysis of Offline, the data were further filtered through a 0.1 to correctly identified pictures in the Picture Identification 6 Hz bandpass filter. Artifactual eyeblink activity was ERP task revealed a significant main effect of age group recorded and corrected offline via the Neuroscan soft- (F(2,54) = 3.60, p <.05, η = .12), such that older partici- ware utilizing the Occular Artifact Reduction method pants correctly identified more pictures than young par- within the software. ERP trials that included other types ticipants (p <.05). The effect of ApoE status was not of artifactual activity were excluded using both auto- significant for Picture Identification. mated exclusion (e.g. excluding all trials with voltage ranges larger than 50 μV) and by visually inspecting Topographical displays of ERP activity each trial prior to averaging . Ongoing EEG activity was Figure 1 illustrates topographical distributions of OERP recorded throughout the experiment and then trials amplitudes in μV over the post-stimulus time interval epoched offline to 500 msec pre-stimulus and 1500 msec from 700 ms through 1300 ms by age and ApoE groups. post-stimulus. Baseline corrected trials were then aver- For each of 19 electrodes (FP1, FP2, F7, F3, F2, F4, F8, aged. Peak amplitudes were measured from the pre- T7, C3, CZ, C4, T8, P7, P3, P2, P4, P8, O1, O2) ampli- stimulus baseline to maximum peak amplitude. Latency tudes were averaged over the 100 ms time intervals (e.g. windows from previous OERP studies [38,39] were used 700-800 ms) and input into graphing software in order as guidelines to identify peak components. Peaks were to visually display brain activity across the scalp for each picked blindly as to age, gender, and APOE status in age and APOE group. Given no significant ApoE effects order to avoid experimenter bias. in the visual modality only olfactory ERP topographies are shown. In the young group the OERP topographical Results maps show greater brain activation in the ε4+ partici- Demographics and screening measures pants compared to ε4- participants, over the left hemi- Table 1 summarizes demographic and screening mea- sphere electrodes, and particularly over parietal sures. Within each age group there were no significant electrodes, that decreases after 1100 ms. Middle age ε4+ differences in mean participant age between ApoE+ and and ε4- individuals demonstrated similar topographies, ApoE- participants (p >.05). Dementia Rating Scale however ε4+ participants showed somewhat more activ- scores did not differ significantly between ApoE groups ity over the right hemisphere electrodes compared to or age groups (p >.05) and all participants’ DRS scores left, in the 900-1100 ms range, whereas ε4- participants were in the range of normal cognitive functioning. Ana- showed more central electrode activity across the lysis of odor threshold test performance revealed that all recording epoch. The greatest differences can be participants scored in the normal range of olfactory observed in the older groups where ε4- participants functioning. While all participants were normosmic, the showed an increase in activation over left and central older participant group exhibited poorer olfactory electrode sites between 900-1100 ms, and ε4+ partici- threshold scores than the middle and young age groups pants showed relatively less overall activation during that (F(2,57) = 8.93, p <.001, η = .24), with no interaction of time period, but increasing activation over right frontal ApoE status. electrodes between 1000-1200 ms. Overall the topo- graphical maps clearly illustrate that brain activity Odor and picture identification related to olfactory processing differs not only by age, Table 1 shows identification scores by age and ApoE but more importantly by ApoE status, and the activity groups. Analysis of the San Diego Odor Identification differentially changes over the post-stimulus time period. Test revealed no significant main effects or interaction effects involving ApoE status (p >.05). It did demon- strate a significant main effect of age (F(2,57) = 6.04, Event Related Potentials (ERPs) p <.01, η = .18) with young participants correctly identi- Repeated measures multivariate analyses of variance fying more odors than both the middle and older age (MANOVAs) were performed for each ERP component groups (p <.05). (N1, P2, N2, P3) and olfactory and visual modalities Analysis of correctly identified number of odors from were analyzed separately for each peak amplitude and la- the Odor Identification ERP task revealed a main effect tency. Greenhouse-Geisser corrections were applied to of ApoE status collapsed across age groups (F(1,54) = all MANOVAs. Significant main effects and interactions 4.54, p <.05) η = .08), such that ε4- participants were further analyzed with post hoc Newman Keuls Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 5 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Figure 1 Topographical representation of OERP amplitudes in μV across 19 electrode sites by age and ApoE groups for 700-1300 ms post-stimulus time intervals. Multiple Range Tests (alpha 0.05). Significant visual and N2 amplitude demonstrated a significant main effect of olfactory ERP effects are summarized in Table 2. age (F(2,54) = 3.62, p <.05, η = .12) with older age parti- cipants producing significantly more negative N2 ampli- Picture identification ERPs tudes than middle age participants. Visual N1, P2, and N2 amplitudes demonstrated no sig- Figure 2 illustrates olfactory ERP peak latencies. nificant main or interaction effects (p >.05). Visual P3 Olfactory N1, P2, N2, and P3 latencies demonstrated amplitude demonstrated a significant main effect for significant interaction effects of Age x ApoE status 2 2 electrode site (F(2,108) = 4.28, p <.05, η = .07) such that (N1: F(2,54) = 4.73, p <.05, η = .15; P2: F(2,54) = 9.34, 2 2 the Cz and Pz electrode sites produced larger P3 ampli- p <.001, η = .26; N2: F(2,54) = 8.18, p <.01, η = .23; P3: tudes than the Fz site. F(2,54) = 14.11, p <.001, η = .34). Post hoc analyses of Figure 2 illustrates visual ERP peak latencies. Visual the interaction effects revealed that in the young group N1 and P2 latencies did not demonstrate significant those negative for the ε4 allele produced significantly 2 2 main or interaction effects (p >.05). Visual N2 latency longer N2 (η = .26), and P3 (η = .29), latencies. In the demonstrated a significant main effect of electrode site middle age group those positive for the ε4 allele pro- 2 2 (F(2,108) = 3.50, p <.05, η = .06) with the Pz electrode duced significantly longer N1 (η = .31), and P2 site producing shorter N2 latencies than the Fz electrode (η = .31) latencies. In the older group those positive for site. Visual P3 latency also revealed a significant main ef- the ε4 allele produced significantly longer latencies for 2 2 2 2 fect of electrode site (F(2,108) = 8.78, p <.01, η = .14) all components N1 (η = .50), P2 (η = .52), N2(η = .35), with the Cz and Pz electrode sites recording significantly and P3(η = .59). For N1 and P3 latencies, in both longer latencies than the Fz site (p <.01). Visual P3 la- ApoE groups, older participants produced significantly tency also showed a significant main effect of age group longer latencies than middle age participants and mid- (F(2,54) = 4.94, p <.05, η = .15) with older adults produ- dle age participants produced longer latencies than cing significantly longer visual P3 latencies than young young participants. For P2 and N2 latencies in ε4+ par- adults (p <.01). ticipants, this same pattern was observed, however in ε4- participants young adults did not differ significantly from middle age participants, but both young and mid- Odor identification ERPs dle age participants produced shorter latencies than Olfactory N1, P2, and P3 amplitudes demonstrated no older participants. significant main or interaction effects (p >.05). Olfactory Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 6 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Table 2 Summary of analyses performed and effect sizes for peak component amplitudes and latencies Peak measures Amplitude Latency N1 P2 N2 P3 N1 P2 N2 P3 Picture ID ERPs Age (A) - - - - - - - *(η=.15) ApoE Status (S) - - - - - - - - Electrode (E) - - - *(η=.07) - - *(η=.06) *(η=.14) AxS - - - - - --- AxE - - - - - --- SxE - - - - - --- AxSxE - - - - - --- Odor ID ERPs Age (A) - - *(η=.12) - ***(η=.70) ***(η=.68) ***(η=.64) ***(η=.76) ApoE Status (S) - - - - ***(η=.27) ***(η=.22) - - Electrode (E) - - - - - - - - Ax S - - - - *(η=.15) ***(η=.26) **(η=.23) ***(η=.34) AxE - - - - - --- SxE - - - - - --- AxSxE - - - - - --- * p <0.05. **p <0.01. ***p <0.001. Correlational analyses were performed between the the most significant single predictor in discriminating ERP odor ID performance and average (Fz, Cz, Pz) peak between ε4+ participants and ε4- participants (χ = 6.07, latencies (N1, P2, N2, P3). When all ages and ApoE p <.05) resulting in an overall correct classification rate groups were combined together odor ID performance of 70.0% (Sensitivity = 66.7%, Specificity = 73.3%). When marginally correlated with N1 latency (r = −.28, p <.05). P3 latency was also added to N1 amplitude in the model Correlational analyses were also performed for each (χ = 8.06, p <.01) overall correct classification rate age x ApoE group separately. The only significant correl- increased to 76.7% (Sensitivity = 80%, Specificity = ation between odor ID performance and latency was for 73.3%). Logistic regressions were also performed for N1 latency in the older Apoe+ group (r = −.77, p <.01). each age group separately in order to better understand the effects of ApoE status within each age group. In the Logistic regression analyses of OERP variables young participant group N2 amplitude was the most sig- In order to better understand the predictive value of the nificant predictor (χ = 7.79, p <.01) resulting in an over- ERP in differentiating ε4- and ε4+ participants, stepwise all classification rate of 65.0% (Sensitivity = 70.0%, logistic regression analysis was performed on olfactory Specificity = 60.0%). In the middle age group P2 latency N1, P2, N2, P3 amplitude and latency averaged over Fz, was the most significant single predictor (χ = 6.86, Cz, and Pz. Visual ERP variables were not included in p <.01) resulting in an overall classification rate of 80.0% logistic regression analysis because no significant ApoE (Sensitivity = 80.0%, Specificity = 80.0%). When P3 ampli- effects were present. A logistic regression is a type of re- tude and P3 latency were also added to the equation gression analysis used to predict the outcome of a binary with P2 latency (χ = 20.09, p <.001), the overall classifi- dependent variable (e.g. Apoe+ vs Apoe-) based on one cation rate for middle age participants increased to or more predictor variables (e.g. ERP amplitude and la- 90.0% (Sensitivity = 90.0%, Specificity = 90.0%). In the tency). The logistic regression analysis outputs predictive older age group P3 latency was the most significant sin- classification results including overall correct classifica- gle predictor (χ = 16.37, p <.001) resulting in an overall tion (total percentage of correctly classified individuals), classification rate of 90.0% (Sensitivity = 90.0%, Specifi- as well as sensitivity (e.g. APOE+ correctly classified as city = 90.0%). When N1 latency was also added to the APOE+) and specificity (e.g. APOE- correctly classified equation with P3 latency (χ = 27.73, p <.001), overall as APOE-). In the olfactory modality analysis of all age classification rate for older participants increased to groups combined revealed that olfactory N1 latency was 100.0% (Sensitivity = 100.0%, Specificity = 100.0%). Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 7 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Figure 2 Visual and olfactory average N1, P2, N2, and P3 latencies by age and ApoE groups. Error bars represent the standard error of the mean (SEM). Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 8 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Discussion activation changes across time over the post-stimulus This study demonstrated (1) robust odor identification interval of cognitive processing. This suggests that pro- ERP differences based on ApoE status and interactions cessing of olfactory stimuli is differentially affected by with age; (2) high correct ApoE classification rates utiliz- presence or absence of the ε4 allele. Additionally these ing the OERP that were different for each age group. effects change over the lifespan, such that individuals in A few previous studies have demonstrated ERP impair- different decades of life, even young adults, show varying ments in persons with a positive family history of AD, in patterns of brain activation. those diagnosed with early AD, and in individuals with In the present study, it is important to note that in mild cognitive impairment (MCI). MCI is commonly order to better understand the effects of the ApoE risk defined as subtle but measurable memory impairment factor at points before memory problems are present, without any other symptoms of dementia. Green et al. participants with dementia, early dementia, or mild cog- [72] demonstrated auditory ERP P3 latency increases in nitive impairment, as well as those with anosmia or se- pre-clinical groups of persons with a family history of vere hyposmia, were screened out of the study. Given AD and in those with a family history plus ε4+ status. this rigorous screening process, it is not surprising that They did not indicate, however, how many of the partici- no significant ApoE effects were found for the visual pic- pants demonstrated this latency difference, or how well ture identification task. Very robust effects of ApoE sta- this measure correctly classified participants into ε4+ or tus were demonstrated for the odor identification ERP ε4- groups. Olichney et al. [73] studied participants diag- task, as well as significant age by ApoE interaction nosed with MCI utilizing an N400/P600 semantic con- effects. This occurred despite no difference in perform- gruency task and then tracked those participants over ance on the Dementia Ratings Scale, odor threshold test- time. Participants with abnormal N400 or P600 effects ing, or the SDOIT by ApoE status. The present study had an 87 to 88% likelihood of progression to dementia strongly suggests that combining olfactory processing within 3 years. They suggest that these N400 abnormal- with cognitive processing [odor identification] may be ities in MCI may reflect subtle dysfunction of semantic sensitive enough to differentiate very early those with a memory processes. Utilizing this method, classification high likelihood from those with a low likelihood of of participants into diagnostic groups was high in sensi- developing AD, even as early as middle age. This to- tivity in MCI who converted to AD (81-94%) less so gether suggests the ability to identify odors and the when applied to all participants (58 to 65%). Chapman speed of odor identification is slowed in the presence of et al. [74] used a visual number-letter memory task to the ε4 allele. Picture identification remained intact in study ERPs in participants diagnosed as being in the ApoE+ participants, both for number of pictures cor- early stages of AD. Their results suggest that AD deficits rectly identified and speed with which the pictures were may include problems with storage in short-term mem- cognitively processed. ory, and that difficulties may lie in the cognitive proces- Of further note, the present study demonstrated good sing of stimuli that are relevant to the task in which the ApoE classification rates of 80% in the middle age group, participant is engaged. Using this method the authors with ε4+ participants producing significantly longer N1 were able to correctly classify 92% of participants into and P2 latencies than ε4- participants. It suggests that AD or control groups. While these studies are extremely ApoE-related olfactory functional decline is taking place helpful in understanding cognitive changes associated at much earlier ages than previously observed, further with early stages of dementia, even at the MCI stage, suggesting that early, pre-clinical, diagnosis of AD may they also raise the possibility of early diagnosis at even be a real possibility. Consistent with previous OERP earlier, pre-MCI, pre-clinical, stages of AD. A measure studies [62,63], older ε4+ participants produced signifi- that would aid diagnosis of AD many years before any cantly longer OERP peak latencies. In this group 100% classification rates were obtained suggesting a clear de- manifestation of other signs or symptoms would be ideal, especially once an effective medication for halting lineation in performance between ε4+ and ε4- partici- or altering the dementing process is developed. pants once they reach ages above 65 years old. Further research needs to examine the utility of vari- Illustrated on the ERP topographical maps, the current study demonstrated differing patterns of brain activity ous measures and tasks in the study of pre-clinical AD, recorded over the scalp, depending on ApoE status. in order to capture the pre-dementing processes at the earliest possible stages, and improve diagnostic ability. fMRI studies on activation have reported mixed results, with some showing increased activation in ε4 carriers Olfactory tasks involving cognitive processing, such as [30,75], and others demonstrating reduced activation in the OERP, appear to be very promising in this regard. ε4 carriers [76]. The current study demonstrates that Competing interest patterns of brain activation differ not only by ApoE sta- The authors report no biomedical financial interests or potential conflicts of tus, but across age groups, and that the pattern of interest. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 9 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 Authors’ contributions 19. Bacon AW, Bondi MW, Salmon DP, Murphy C: Very early changes in CDM and CM designed the study and advised the research assistants olfactory functioning due to Alzheimer's disease and the role of through data collection and analysis, and interpreted the data. CDM apolipoprotein E in olfaction. Ann N Y Acad Sci 1998, 855:723–731. constructed the olfactometer. CDM and CM wrote and approved the final 20. Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, Welsh-Bohmer K: version of the manuscript. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer's disease. Neurobiol Aging 2002, 23(3):397–404. 21. Gilbert PE, Murphy C: Differences between recognition memory and Acknowledgments remote memory for olfactory and visual stimuli in nondemented elderly Supported by NIH Grant DC002064 to Claire Murphy. The authors would like individuals genetically at risk for Alzheimer's disease. Exp Gerontol 2004, to thank the late Dr. Leon Thal and the UCSD ADRC (P50AG005131-28) for 39(3):433–441. genotyping, Dr. John Polich, Krystin Corby, Joel Kowalewski, Jessica 22. Morgan CD, Nordin S, Murphy C: Odor Identification as an Early Marker Bartholow, and Roberto Zamora for research assistance. for Alzheimers-Disease - Impact of Lexical Functioning and Detection Sensitivity. J Clin Exp Neuropsychol 1995, 17(5):793–803. Author details 23. Olofsson JK, Nordin S, Wiens S, Hedner M, Nilsson LG, Larsson M: Odor Department of Psychology, San Diego State University, San Diego, CA identification impairment in carriers of ApoE-varepsilon4 is independent 92120, USA. University of California San Diego Medical Center, San Diego, of clinical dementia. Neurobiol Aging 2010, 31(4):567–577. CA 92120, USA. SDSU/UCSD Joint Doctoral Program, 6363 Alvarado Ct., 24. Calhoun-Haney R, Murphy C: Apolipoprotein epsilon 4 is associated with Suite 101, San Diego, CA 92120-4913, USA. more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores. Brain Cogn 2005, 58(2):178–182. Received: 22 January 2012 Accepted: 15 June 2012 25. Murphy C, Jernigan TL, Fennema-Notestine C: Left hippocampal volume loss Published: 31 July 2012 in Alzheimer's disease is reflected in performance on odor identification: a structural MRI study. J Int Neuropsychol Soc 2003, 9(3):459–471. References 26. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA: 1. American Psychiatric Association: Diagnostic and statistical manual of mental Olfactory Impairment in Presymptomatic Alzheimer's Disease. Ann N Y disorders, Revised 4th ed. Washington, DC: American Psychiatric Press; 2000. Aca Sci 2009, 1170(1):730–735(736). 2. Blacker D: The genetics of Alzheimer's disease: progress, possibilities, and 27. Backman L, Andersson JL, Lyberg L, Winblad B, Nordberg A, Almkvist O: pitfalls. Harv Rev Psychiatry 1997, 5(4):234–237. Brain regions associated with episodic retrieval in normal aging and 3. Combarros O, Alvarez-Arcaya A, Sanchez-Guerra M, Infante J, Berciano J: Alzheimer's disease. Neurology 1999, 52(9):1861–1870. Candidate gene association studies in sporadic Alzheimer's disease. 28. Becker JT, Mintun MA, Aleva K, Wiseman MB, Nichols T, DeKosky ST: Dement Geriatr Cogn Disord 2002, 14(1):41–54. Compensatory reallocation of brain resources supporting verbal episodic 4. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small memory in Alzheimer's disease. Neurology 1996, 46(3):692–700. GW, Roses AD, Haines JL, Pericakvance MA: Gene dose of apolipoprotein E 29. Bondi MW, Houston WS, Eyler LT, Brown GG: fMRI evidence of type 4 allele and the risk of Alzheimer's disease in late onset families. compensatory mechanisms in older adults at genetic risk for Alzheimer Science 1993, 261(5123):921–923. disease. Neurology 2005, 64(3):501–508. 5. Teter B, Raber J, Nathan B, Crutcher KA: The presence of apoE4, not the 30. Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, absence of apoE3, contributes to AD pathology. J Alzheimers Dis 2002, Mazziotta JC, Small GW: Patterns of brain activation in people at risk for 4:155–163. Alzheimer's disease. N Engl J Med 2000, 343(7):450–456. 6. Bertram L, Tanzi RE: The genetic epidemiology of neurodegenerative 31. Grady CL, McIntosh AR, Beig S, Keightley ML, Burian H, Black SE: Evidence disease. J Clin Invest 2005, 115(6):1449–1457. from functional neuroimaging of a compensatory prefrontal network in 7. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Alzheimer's disease. J Neurosci 2003, 23(3):986–993. Pericakvance MA, Risch N, vanDuijn CM: Effects of age, sex, and ethnicity 32. Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, on the association between apolipoprotein E genotype and Alzheimer O’Jile JR, Riordan HJ, Santulli RB, Smith CA, Weaver JB: Neuroanatomic disease - A meta-analysis. JAMA 1997, 278(16):1349–1356. substrates of semantic memory impairment in Alzheimer's disease: 8. Burke W, Pinsky LE, Press NA: Categorizing genetic tests to identify patterns of functional MRI activation. J Int Neuropscyhol Soc 1999, their ethical, legal, and social implications. Am J Med Genet 2001, 5(5):377–392. 106(3):233–240. 33. Woodard JL, Grafton ST, Votaw JR, Green RC, Dobraski ME, Hoffman JM: 9. Murphy C: Loss of olfactory function in dementing disease. Physiol Behav Compensatory recruitment of neural resources during overt rehearsal of 1999, 66(2):177–182. word lists in Alzheimer's disease. Neuropsychology 1998, 12(4):491–504. 10. Averback P: 2 new lesions in Alzheimers-disease. Lancet 1983, 34. Seidenberg M, Guidotti L, Nielson KA, Woodard JL, Durgerian S, Antuono P, 2(8360):1203. Zhang Q, Rao SM: Semantic memory activation in individuals at risk for 11. Braak H, Braak E: Frequency of stages of Alzheimer-related lesions in developing Alzheimer disease. Neurology 2009, 73(8):612–620. different age categories. Neurobiol Aging 1997, 18:351–357. 35. Rombouts SA, Barkhof F, van Meel CS, Scheltens P: Alterations in brain 12. Christen-Zaech S, Kraftsik R, Pillevuit O, Kiraly M, Martins R, Khalili K, Miklossy activation during cholinergic enhancement with rivastigmine in J: Early olfactory involvement in Alzheimer's disease. Can J Neurol Sci Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002, 73(6):665–671. 2003, 30(1):20–25. 36. Covington JW, Geisler MW, Polich J, Murphy C: Normal aging and odor 13. Esiri MM, Wilcock GK: The Olfactory bulbs in Alzheimers-disease. J Neurol intensity effects on the olfactory event-related potential. Int J Neurosurg Psychiatry 1984, 47(1):56–60. Psychophysiol 1999, 32(3):205–214. 14. Ohm TG, Braak H: Olfactory-Bulb Changes in Alzheimers-Disease. Acta 37. Evans WJ, Cui L, Starr A: Olfactory event-related potentials in normal Neuropathol 1987, 73(4):365–369. human subjects: effects of age and gender. Electroencephalogr Clin 15. Reyes PF, Golden GT, Fariello RG, Fagel L, Zalewska M: Olfactory pathways Neurophysiol 1995, 95(4):293–301. in Alzheimer's disease (AD): Neuropathological studies [abstract]. Society 38. Morgan CD, Covington JW, Geisler MW, Polich J, Murphy C: Olfactory for Neuroscience 1985, 11:168. event-related potentials: older males demonstrate the greatest deficits. 16. Van Hoesen GW, Solodkin A: Cellular and systems neuroanatomical Electroencephalogr Clin Neurophysiol 1997, 104(4):351–358. changes in Alzheimer's disease. In: Calcium hypothesis of aging and 39. Morgan CD, Geisler MW, Covington JW, Polich J, Murphy C: Olfactory P3 in dementia. Disterhoft JF, Khachaturian ZS (eds). Proc NY Acad Sci (USA) young and older adults. Psychophysiology 1999, 36(3):281–287. 1994, 747:12–35. 40. Morgan CD, Murphy C: Differential effects of active attention and age on 17. den Heijer T, Oudkerk M, Launer LJ, Van Duijn CM, Hofman A, Breteler MM: event-related potentials to visual and olfactory stimuli. Int J Psychophysiol Hippocampal, amygdalar, and global brain atrophy in different 2010, 78(2):190–199. apolipoprotein E genotypes. Neurology 2002, 59:746–748. 18. Murphy C, Bacon AW, Bondi MW, Salmon DP: Apolipoprotein E status is 41. Murphy C, Morgan CD, Geisler MW, Wetter S, Covington JW, Madowitz MD, associated with odor identification deficits in nondemented older Nordin S, Polich JM: Olfactory event-related potentials and aging: persons. Ann N Y Acad Sci 1998, 855:744–750. normative data. Int J Psychophysiol 2000, 36(2):133–145. Morgan and Murphy Behavioral and Brain Functions 2012, 8:37 Page 10 of 10 http://www.behavioralandbrainfunctions.com/content/8/1/37 42. Nordin S, Quinonez C, Morgan CD, Geisler MW, Polich J, Murphy C: 67. Sundermann EE, Gilbert PE, Murphy C: Apolipoprotein E epsilon 4 Olfactory event-related potentials in young and elderly adults: genotype and gender: Effects on memory. Am J Geriatr Psychiatry 2007, evaluation of tracking task versus eyes open/closed recording. Chem 15(10):869–878. Senses 1999, 24(4):459–464. 68. Zamora R, Bartholow J, Green E, Morgan CD, Murphy C: Adiposity 43. Thesen T, Wetter S, Murphy C: Olfactory event-related potential detects measures predict olfactory processing speed in older adult carriers of age-related changes in olfactory processing with velopharyngeal closure the apolipoprotein E4 allele. Clin Neurophysiol 2011, doi:10.1016/j. and normal breathing. Psychophysiology 2000, 37:S97. clinph.2011.09.001. 44. Wetter S, Murphy C: Individuals with Down's syndrome demonstrate 69. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM: abnormal olfactory event-related potentials. Clin Neurophysiol 1999, Prevalence of olfactory impairment in older adults. JAMA 2002, 110(9):1563–1569. 288(18):2307–2312. 45. Wetter S, Peavy G, Jacobson M, Hamilton J, Salmon D, Murphy C: Olfactory 70. Thesen T, Murphy C: Age-related changes in olfactory processing and auditory event-related potentials in Huntington's disease. detected with olfactory event-related brain potentials using Neuropsychology 2005, 19(4):428–436. velopharyngeal closure and natural breathing. Int J Psychophysiol 2001, 40(2):119–127. 46. Kobal G: Elektrophysiologische Untersuchungen des menschlichen Geruchsinns. 71. Kaplan E, Goodglass H, Weintrab S: The Boston Naming Test. Philadelphia: Stuttgart: Thieme; 1981. Lea and Febiger; 1983. 47. Lorig TS, Elmes DG, Zald DH, Pardo JV: A computer-controlled 72. Green J, Levey AI: Event-related potential changes in groups at increased olfactometer for fMRI and electrophysiological studies of olfaction. Behav risk for Alzheimer disease. Arch Neurol 1999, 56(11):1398–1403. Res Methods Instrum Comput 1999, 31(2):370–375. 73. Olichney JM, Taylor JR, Gatherwright J, Salmon DP, Bressler AJ, Kutas M, Iragui- 48. Lorig TS: The application of electroencephalographic techniques to the Madoz VJ: Patients with MCI and N400 or P600 abnormalities are at very study of human olfaction: a review and tutorial. Int J Psychophysiol 2000, high risk for conversion to dementia. Neurology 2008, 70(19):1763–1770. 36(2):91–104. 74. Chapman RM, Nowlis GH, McCrary JW, Chapman JA, Sandoval TC, Guillily 49. Murphy C, Nordin S, de Wijk RA, Cain WS, Polich J: Olfactory-evoked MD, Gardner MN, Reilly LA: Brain event-related potentials: diagnosing potentials: assessment of young and elderly, and comparison to early-stage Alzheimer's disease. Neurobiol Aging 2007, 28(2):194–201. psychophysical threshold. Chem Senses 1994, 19(1):47–56. 75. Han SD, Houston WS, Jak AJ, Eyler LT, Nagel BJ, Fleisher AS, Brown GG, 50. Overbosch P, de Wijk R, de Jonge TJ, Koster EP: Temporal integration and Cory-Bloom J, Salmon D, Thal LJ, Bondi MW: Verbal paired-associate reaction times in human smell. Physiol Behav 1989, 45(3):615–626. learning by APOE genotype in non-demented older adults: fMRI 51. Ekman GB, Berglund U, Berglund B, Lindwall T: Perceived intensity of odor: evidence of a right hemispheric compensatory response. Neurobiol Aging a function of time of adaptation. Scan J Psychol 1967, 8:177–186. 2007, 28(2):238–247. 52. Wilson DA, Linster C: Neurobiology of simple memory. J Neurophysiol 76. Lind J, Persson J, Ingvar M, Larsson A, Cruts M, Van Broeckhoven C, 2008, 100:2–7. Adolfsson R, Backman L, Nilsson LG, Petersson KM, Nyberg L: Reduced 53. Polich J: P300, probability, and inter-stimulus interval. Psychophysiology functional brain activity response in cognitively intact apolipoprotein E 1990, 27:396–403. epsilon 4 carriers. Brain 2006, 129:1240–1248. 54. Polich J: Probability and inter-stimulus interval effects on the P300 from auditory stimuli. Int J Psychophysiol 1990, 10:163–170. doi:10.1186/1744-9081-8-37 55. Polich J: P300 in clinical applications: meaning, method, and Cite this article as: Morgan and Murphy: Individuals at risk for measurement.In Electroencephalography: Basic Principles, Clinical Alzheimer’s disease show differential patterns of ERP brain activation Applications, and Related Fields. 3rd edition. Edited by Niedermeyer E, Lopes during odor identification. Behavioral and Brain Functions 2012 8:37. da Silva F. Baltimore, MD: Williams and Wilkins; 1993:1005–1018. 56. Moore PA: A model of the role of adaptation and disadaptation in olfactory receptor neurons: implications for the coding of temporal and intensity patterns in odor signals. Chem Senses 1994, 19(1):17–86. 57. Murphy C, Morgan CD: Olfactory Function and Event-Related Potentials in Alzheimers Disease.In Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics. Edited by Iqbal K, Sisodia SS, Winblad B. Chichester, UK: John Wiley and Sons, Ltd; 2001:237–251. 58. Donchin E, Heffley E, Hillyard SA, Loveless N, Maltzman I, Ohman A, Rosler F, Ruchkin D, Siddle D: Cognition and event-related potentials. II. The orienting reflex and P300. Ann N Y Acad Sci 1984, 425:39–57. 59. Polich J, Hoffman LD: P300 and handedness: on the possible contribution of corpus callosal size to ERPs. Psychophysiology 1993, 35(5):497–507. 60. Geisler MW, Morgan CD, Covington JW, Murphy C: Neuropsychological performance and cognitive olfactory event-related brain potentials in young and elderly adults. J Clin Exp Neuropsychol 1999, 21(1):108–126. 61. Morgan CD, Murphy C: Olfactory event-related potentials in Alzheimer's disease. J Int Neuropsychol Soc 2002, 8(6):753–763. 62. Wetter S, Murphy C: Apolipoprotein E epsilon 4 positive individuals demonstrate delayed olfactory event-related potentials. Neurobiol Aging 2001, 22(3):439–447. Submit your next manuscript to BioMed Central 63. Murphy C, Solomon ES, Haase L, Wang M, Morgan CD: Olfaction in aging and take full advantage of: and Alzheimer's disease: event-related potentials to a cross-modal odor- recognition memory task discriminate ApoE epsilon4+ and ApoE epsilon • Convenient online submission 4- individuals. Ann N Y Acad Sci 2009, 1170:647–657. • Thorough peer review 64. Cain WS, Gent J, Catalanotto FA, Goodspeed RB: Clinical evaluation of olfaction. Am J Otolaryngol 1983, 4(4):252–256. • No space constraints or color figure charges 65. Murphy C, Gilmore MM, Seery CS, Salmon DP, Lasker BR: Olfactory • Immediate publication on acceptance thresholds are associated with degree of dementia in Alzheimer's disease. Neurobiol Aging 1990, 11(4):465–469. • Inclusion in PubMed, CAS, Scopus and Google Scholar 66. Mattis S: Mental status examination for organic mental syndrome in the • Research which is freely available for redistribution elderly patient.In Geriatric psychiatry: A handbook for psychiatrists and primary care physicians. Edited by Bellak L, Katasu TB. New York: Grune and Submit your manuscript at Statton; 1976:77–121. www.biomedcentral.com/submit

Journal

Behavioral and Brain Functions – Springer Journals

Published: Jul 31, 2012

There are no references for this article.