Absent event-related potential (ERP) word repetition effects in mild Alzheimer's disease

Department of Neurosciences, University of California, San Diego, CA 92161, USA.
Clinical Neurophysiology (Impact Factor: 3.1). 07/2006; 117(6):1319-30. DOI: 10.1016/j.clinph.2006.02.022
Source: PubMed


We hypothesized that an ERP word repetition paradigm, which reliably elicits and modulates the P600 and N400 components, would be particularly sensitive to the memory deficits and altered synaptic plasticity in mild Alzheimer's disease (AD). The P600 (a late positive component, or 'LPC'), and the N400, are sensitive indices of memory encoding and semantic processing, respectively.
We studied 11 patients with mild AD (mean MMSE=22.9) and 11 elderly (mean age=77.1) normal controls (NC) on a paradigm in which semantically 'congruous' category statement/exemplar pairs (50%) and 'incongruous' category statement/non-exemplar pairs (50%) repeat at 10-140 s intervals. A minimum of 19 channels ERP data were recorded and submitted to split-plot ANOVAs.
Normal ERP data showed: (1) a significant word repetition effect for congruous words, with a wide-spread late positivity between approximately 300 and 800 ms post-stimulus (P600) that is larger for New than Old words; (2) a significant N400 repetition effect for incongruous words, with a right posterior negativity that is reduced for Old relative to New words. By contrast, neither of these word repetition effects was reliably present in the mild AD group. Good group discrimination was achieved by requiring that both these repetition effects were > or = the 10th percentile, with 100% sensitivity and 82% specificity.
We found significant abnormalities of the N400 and P600 in mild AD, with both potentials showing markedly reduced sensitivity to word repetition.
The absence of normal N400 and LPC/P600 word repetition effects suggests impaired functioning of their neural generators, several of which are located in medial temporal lobe predilection sites (e.g. anterior fusiform, parahippocampal gyrus, hippocampus) for AD/tau pathology.

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    • "Verbal memory and language processes in FXTAS also have been probed via an ERP word repetition paradigm/category judgment task, in which semantically congruous (50%) and incongruous words are repeated after an interval of between 10 and 140 seconds. This word repetition paradigm was employed in the first published ERP study of FXTAS [42], in which it was demonstrated that FXTAS patients had a significantly reduced N400 word repetition effect (new-old incongruous words), an electrophysiological marker of semantic processing load and implicit memory previously shown to be sensitive to early Alzheimer’s disease (AD) [43,44]. Unlike persons with AD, however, FXTAS patients displayed a preserved P600 word repetition effect (new-old congruous words) that has been linked to episodic/declarative memory. "
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    ABSTRACT: The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.
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    • "In the first ERP study in FXTAS, Olichney et al. (2010) demonstrated that male-predominant FXTAS individuals have a significantly reduced N400 word repetition effect – an electrophysiological index of semantic processing and implicit memory – which has also been shown highly sensitive to early-stage Alzheimer's disease (AD; Olichney et al. 2006, 2008). On the other hand, unlike AD, FXTAS patients had relatively normal verbal memory scores and the associated P600 word repetition effects (Olichney et al. 2010). "
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    ABSTRACT: FXTAS, a neurodegenerative disorder, affects Fragile X (FMR1) gene premutation carriers in late-life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory, and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. 61 females (34 FXTAS Mage = 62.7, 27 controls Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated ~10-140s later. N400 and P600 amplitude data were submitted to ANCOVA. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. ERP analyses revealed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.
    Genes Brain and Behavior 12/2013; 13(2). DOI:10.1111/gbb.12114 · 3.66 Impact Factor
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    • "Using the ERP word repetition paradigm, we have found that the P600 repetition effect is reduced or absent in mild AD (Olichney et al., 2006). Furthermore, in patients with mild cognitive impairment (MCI), reductions in either the P600 or N400 word repetition effect are associated with greater likelihood of subsequent transition to AD dementia (Olichney et al., 2008). "
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