This paper reports several important results concerning early post-stimulus processing in normal aging and AD. First, C145 revealed a task relevancy effect manifested differently in normal elderly and AD groups such that the normal Control group showed the largest effect in the occipital brain region while the AD group showed more anterior involvement in the early post-stimulus processing of stimuli. Second, dividing the AD group into subgroups by performance accuracy on the Number-Letter task indicated that the AD subgroup who achieved higher accuracy may be compensating by recruiting additional central brain areas to process task relevancy.
Examining task relevancy effects has been useful in developing ERP markers for AD [5
]. For the Controls, there was a significant difference between C145 under relevant and irrelevant task conditions in occipital regions. AD subjects’ mean C145 waveforms for relevant and irrelevant stimuli show no difference in the occipital region. It should be noted that the raw ERP waveform recorded at OZ () appears to show a difference between task relevancies in the AD group; however, this difference was due to other ERP components that overlap
with C145 (especially CNV [5
], which relates to stimulus expectancies). We used differing experimental conditions that manipulate varying components, including CNV, in conjunction with PCA to untangle overlapping components [25
In the central region, the AD group as a whole showed a significant task relevancy effect whereas the Control group showed no relevancy effect. This suggests an interesting idea about brain plasticity that is contrary to the general and perhaps outdated view that AD causes diminished brain activity. Our results agree with Transcranial Magnetic Stimulation (TMS) findings [46
] in that in early-stage AD hyperexcitability in the brain may lead to functional compensation. The AD group demonstrated a different spatial pattern of brain activity for this short-latency component. Even at this early stage of post-stimulus processing, there were remarkable differences between individuals with mild AD and normal elderly. This mirrors previous findings that AD does not always result in smaller component score amplitudes [5
] and that neuronal loss may be compensated through reorganizing neural circuits [46
Compensatory mechanisms may maintain or restore behavior when underlying neurological mechanisms are damaged or less efficient [18
]. Dividing the AD group into two subgroups based on their performance on the Number-Letter task () indicated that those AD individuals capable of achieving more accurate performance may process early post-stimulus relevancy differently than those AD subjects who have lower performance (). The difference in task relevancy processing between the AD-high and AD-low group was striking, where the AD-low group showed essentially no early processing of task relevancy while the AD-high group recruited more neural resources, particularly at anterior locations.
Examining task effects between the occipital region and the central region revealed where and to what extent each group performed task relevancy and stimulus type processing (). The Control group had a significant task relevancy effect in the occipital region that neither the AD-high nor the AD-low group showed. Also, the occipital region showed an interesting processing trend. C145 amplitudes in the occipital region became smaller from Control to AD-high to AD-low groups. AD subjects failed to differentially process relevant and irrelevant stimuli; however, the AD-high performance group showed an overall larger occipital response, one that more closely matched that of Controls, than the AD-low group.
At central areas (), the amplitudes for the Control, AD-high, and AD-low groups were more similar to each other than in the occipital region. All three groups presented a significant stimulus type effect (numbers, letters). However, the AD-high subgroup was the only group to present a significant task relevancy effect (relevant, irrelevant). It seems, therefore, that the AD-high group recruited additional more anterior neural resources to perform early identification of relevant stimuli.
We examined the correlational links between Number-Letter task performance and C145 amplitudes under task conditions (). Indeed, we found C145 amplitudes for relevant and irrelevant conditions in the occipital region were significantly negatively correlated with accuracy, indicating larger negative amplitudes positively impacted resultant performance. Including the Control group in a correlation analysis for the central region was not logical given the hypothesis that this region was involved in compensation due to disease impairment. Therefore, we studied the correlation between C145 amplitudes and accuracy using only the AD subjects and found a significant positive correlation (r = 0.34) between accuracy and C145 amplitude difference scores (relevant – irrelevant). It was the differential processing at the central region that improved some AD subjects’ performance. Also, there was a negative correlation (r = -0.28) between C145 irrelevant scores in the central region and accuracy, implying that perhaps the AD-low subgroup focuses to a larger extent on irrelevant stimuli than the AD-high subgroup, which might have in turn negatively impacted the AD-low group's ability to complete the task successfully.
These results suggest that the AD-high group achieved better performance through a combination of larger, more Control-like activity in occipital areas and compensation through recruiting more anterior areas in processing task relevancy. Clément and Belleville [51
] found support for such a hypothesis using fMRI and word-pair recognition tasks in cognitively high-performing and low-performing groups of subjects with Mild Cognitive Impairment (MCI). We suggest the deficits of AD cannot simply be explained as a reduction of activity in key neurological areas. Compensation, also, is not simply involvement of additional brain areas. How these additional areas are used in early information processing as related to task dimensions (e.g., stimulus type for AD-low, relevancy for AD-high) is crucial to compensating for AD-related impairment.
Although the AD-low group did not show a task relevancy effect for this short-latency component, they did demonstrate a stimulus type effect (differentiating between numbers and letters) at both the occipital and central regions (). This indicates the AD-low group was processing some aspect of the Number-Letter task at this early stage, even if it was not differentiating between relevant and irrelevant stimuli. It is possible the AD-low group was only processing stimulus type but not adequately identifying whether the numbers or letters were relevant to task, which was crucial to successful performance.
Our results could perhaps be explained by the AD-low group simply being further advanced in the disease than the AD-high group, which would account for their poorer performance on the Number-Letter task. We do not have sufficient biomarker or imaging data that would allow us to differentiate the degree of neurodegeneration between the two groups. However, there was no significant difference in Mini-Mental State Examination score [28
] between the AD-high and AD-low groups, indicating the severity of dementia was comparable (). Furthermore, these subjects were all clinically diagnosed with early-stage AD by memory-disorder physicians. It is also possible that the individuals in the AD-high group would have outperformed the individuals in the AD-low group regardless of the disease. Education speaks to this issue, and the two AD subgroups were similar in this regard. The AD subgroups also showed comparable intelligence as measured by the American National Adult Reading Test (AMNART) [52
(1,35) = 2.36, p
= 0.13). Finally, comorbid depression can affect cognitive ability, but testing with the GDS [30
] showed no significant difference between the AD-high and AD-low subgroups (F(1,35) = 0.03, p
It should be noted that C145 is a very short-latency ERP component for the visual system, with other components that follow it also impacted by AD [5
]. It is not reasonable to assume compensation observed during this early component completely explains Number-Letter task performance, nor is it reasonable to state that the AD-low subgroup fails entirely to discriminate between stimuli relevant to the task and those that were not. It was remarkable, however, that this early, short-latency component did have such a strong influence on cognitive performance for this task (as seen by the significant correlations between C145 amplitudes and accuracy). How the AD-high group achieves higher performance must be furthered studied with subsequent ERP components; this report establishes that this pattern of short-latency brain activity differentiates between AD subjects who maintain better cognitive performance from those who do not. Further work to examine C145 task effects in individuals with MCI (some of whom later develop AD) might also elucidate when and where AD-related damage begins to impact early information processing.
Compensatory mechanisms that maintain function have been described in AD for non-cognitive tasks, including motor function [46
]. Babiloni et al. [53
] studied desynchronization/synchronization of alpha and beta electroencephalographic (EEG) rhythms related to finger movements and found some different topographic features in mild AD patients not found in normal old subjects. Ferreri et al. [46
] used different techniques for studying compensatory mechanisms in motor function. Cortical motor output to upper limbs was elicited by TMS, and mild AD patients showed increased motor cortex excitability that indicated a frontal and medial shift in excitable scalp sites compared with Controls. Their findings fit nicely with the frontal shift of EEG rhythms in early AD patients [53
] as well as with our frontal shift of ERP measures of C145 in early AD reported here, although they did not occur in precisely the same brain locations.
In addition, others have discussed compensatory mechanisms in aging and AD related to cognitive tasks [19
]. Riis et al. [23
] examined compensation in normal elderly and young adults and found that a longer-latency ERP component (P300) indexed appropriation of greater neural resources. They found significant stimulus effects in short-latency components, but these effects did not modulate among their groups. We have found with the Number-Letter paradigm that task effects that relate to performance do occur differently between AD and Control subjects in a short-latency component. fMRI studies have indicated AD and pre-clinical AD subjects recruit more anterior brain areas, including parietal and temporal areas, to successfully complete cognitive tasks, including memory encoding and retrieval [51
]. EEG and ERPs provide much higher temporal resolution than fMRI, PET, and other neuroimaging techniques and thus allow examination of short-latency neural activity that may represent task-related cognitive processing before memory encoding occurs.
Many studies of compensation in AD focus on higher-level, longer-latency cognitive aspects. Our results suggest that compensation may begin very early in the information processing stream (145 ms post-stimulus), and this may help explain why some individuals with AD have greater cognitive efficiency than others, even if they present the same level of cognitive impairment through clinical assessment. While this study focused on group differences to elucidate possible compensation, C145 has been shown to be useful in identifying AD individuals [5
] and with further study could possibly suggest further means to measure compensatory activity at the individual level. Studying C145 and other ERP components related to compensation might reveal basic anatomical and functional differences that are blurred at the level of behavioral analysis which could yield improved methods to diagnose and predict individual clinical outcomes. If researchers grasp a better understanding of brain plasticity and how the brain compensates for the damage caused by AD, it may lead to more timely and efficient treatments.