Early event-related potential changes during working memory activation predict rapid decline in mild cognitive impairment.

BACKGROUND: The conversion of mild cognitive impairment (MCI) to Alzheimer's disease is associated with substantial compromise of neocortical circuits subserving rapid cognitive functions such as working memory. Event-related potential (ERP) analysis is a powerful tool to identify early impairment of these circuits, yet research for an electrophysiological marker of cognitive deterioration in MCI is scarce. Using a "2-back" activation paradigm, we recently described an electrophysiological correlate of working memory activation (positive-negative working memory [PN(wm)] component) over parietal electrodes. METHODS: Ours was a longitudinal study of 24 MCI patients with ERP analysis at inclusion and neuropsychological follow-up after 1 year. We used ERP waveform subtraction analysis between the n-back and control tasks. Analysis of variance (ANOVA) was used to compare electroencephalograph latencies between progressive MCI (PMCI) and stable MCI (SMCI), and univariate regression was used to assess the relationship between neuropsychological measures at baseline and clinical outcome. RESULTS: Thirteen (54%) MCI patients showed PMCI, and 11 (46%) remained stable (SMCI). In SMCI, a PN(wm) component with significantly larger density compared to baseline was identified when subtracting the detection task for both the 1- and 2-back tasks. In contrast, in PMCI, the PN(wm) component was absent in both 1-back and 2-back conditions. Neuropsychological variables and n-back test performance at inclusion did not predict cognitive deterioration 1 year later. CONCLUSIONS: In conjunction with recent functional imaging data, the present results support the notion of an early dysfunction of neural generators within the parietal cortex in MCI. They also reveal that the absence of the PN(wm) component may provide an easily applicable qualitative predictive marker of rapid cognitive deterioration in MCI.

Memory evaluation with a new cued recall test in patients with mild cognitive impairment and Alzheimer's disease.

Free delayed recall is considered the memory measure with the greatest sensitivity for the early diagnosis of dementia. However, its specificity for dementia could be lower, as deficits other than those of pure memory might account for poor performance in this difficult and effortful task. Cued recall is supposed to allow a better distinction between poor memory due to concurrent factors and impairments related to the neurodegenerative process. The available cued recall tests suffer from a ceiling effect. This is a prospective, longitudinal study aiming to assess the utility of a new memory test based on cued recall that avoids the ceiling effect in the early diagnosis of Alzheimer's disease (AD). Twenty-five patients with mild cognitive impairment (MCI), 22 probable AD patients (NINCDS-ADRDA) at a mild stage, 22 elderly patients with subjective memory complaints (SMC) and 38 normal age-matched controls took part in the study. The patients underwent a thorough cognitive evaluation and the recommended screening procedure for the diagnosis of dementia. All patients were re-examined 12-18 months later. A newly devised delayed cued recall test using semantic cues (The RI48 Test) was compared with three established memory tests: the Ten Word-List Recall from CERAD, the "Doors" and the "Shapes" Tests from "The Doors and People Test Battery". Forty-four % of the MCI patients fulfilled criteria for probable AD at follow-up. The RI48 Test classified correctly 88% of the MCI and SMC participants and was the best predictor of the status of MCI and mild AD as well as the outcome of the MCI patients. Poor visual memory was the second best predictor of those MCI patients who evolved to AD. A cued recall test which avoids the ceiling effect is at least as good as the delayed free recall tests in the early detection of AD.

Mechanism of disorientation in Alzheimer's disease.

In nondemented amnesics, disorientation mostly reflects a failure to select memories that pertain to ongoing reality (increased temporal context confusion; TCC), a failure strongly associated with orbitofrontal damage. In the present study, we used the same paradigm--2 runs of a continuous recognition task--in 23 patients with mild to moderate Alzheimer's disease (AD) (Clinical Dementia Rating Scale score of 1-2). We found that disorientation was frequent in this sample (52%). However, although it correlated moderately well with general measures of dementia severity, verbal episodic memory and executive functioning, there was no significant correlation with TCC. Thus, disorientation in AD appears to reflect general cognitive decline rather than a specific cognitive failure such as increased TCC. This finding is compatible with the different distribution of degeneration in AD and the orbitofrontal damage typically present in severely disoriented amnesics.

Improving screening accuracy for dementia in a community sample by augmenting cognitive testing with informant report.

This study sought to determine whether the augmentation of cognitive testing with an informant report questionnaire could improve accuracy in screening for dementia in a community setting. The sample consisted of 646 subjects aged 70-93 years. Cognitive state was assessed using the Mini-Mental State Examination (MMSE). Informants completed the 16-item short form of the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE). Dementia was diagnosed according to DSM-III-R criteria. Combination of the IQCODE with the MMSE resulted in more accurate prediction of caseness than either test alone. Receiver Operating Characteristic analysis demonstrated the superior screening performance of a logical "or" rule and a weighted sum of scores on the two tests over other methods of combination, replicating previous clinically based research. The findings also suggest that the appropriate combination of existing tests may be a fruitful method of improving screening accuracy in a variety of situations.

Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.

Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone.