P300 energy loss in aging and Alzheimer's disease

The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer's disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an "oddball" task in 14 young normal individuals (YN: 21-41 years), 11 elderly normal individuals (EN: 61-80 years), and 23 probable AD patients (AD: 63-93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD.     

老年抑郁症和阿尔茨海默症的听觉P300比较研究

目的比较老年抑郁症(SD)患者和阿尔茨海默症(AD)患者的听觉P300的特点。方法对36例SD患者、32例AD患者以及40名健康老人对照(NC组)进行P300检测。结果 SD组、AD组和NC组在靶潜伏期Cz脑区N2以及在靶波幅Cz脑区P3和非靶波幅Cz脑区P2上均有显著统计学差异(P<0.01)。AD主成份N2表现为延迟,与NC组和SD组有极显著统计学差异(P<0.01)。SD组和AD组靶波幅P3和非靶波幅P2均见降低,与NC组比较也有显著统计学差异(P<0.05或P<0.01)。结论作为反映SD和AD患者认知功能障碍的客观生理指标,P300有可能作为SD和AD辅助诊断的一个脑电波标志。     

Auditory P300 response in the assessment of Alzheimer's disease in Down's syndrome: a 2-year follow-up study

ABSTRACT. Sixty-five subjects with Down's syndrome were followed up and retested 2 years after the initial recording ni auditory P300 (P3) event-related potential described in a companion paper (Blackwood et al. , 1988). The number of subjects showing clinical evidence for Alzheimer's type dementia had increased by a further 14%. In subjects showing clinical deterioration over a period of 2 years, 78% (7/9) had an increase in P3 latency which was three standard deviations or greater than the group mean. None of the 20 fragile-X group retested showed significant change after 2 years. The results suggest that P3 change may be a sensitive index of the onset of Alzheimer's type dementia in Down's syndrome.     

Diagnostic value of event-related evoked potentials N200 and P300 subcomponents in early diagnosis of Alzheimer's disease and mild cognitive impairment.

Event-related potentials (ERPs) have a large application in the evaluation of cognitive processes, particularly in Alzheimer's disease (AD). The aim of the present study was to evaluate the clinical relevance of event-related evoked potentials (N2 and P3 subcomponents) in early diagnosis of AD and mild cognitive impairment (MCI). We prospectively studied 60 subjects. They all underwent the following investigations: neurologic and neuropsychological examination; functional evaluation, i.e., ERPs; cerebral imagery (morphologic and functional). Subjects were classified into 3 groups: group 1: 30 dementia of Alzheimer type (NINCDS-ADRDA, DSM-IV criteria); group 2: 20 MCI; and group 3: 10 control subjects. ERPs were significantly different between the groups (AD, MCI, control subjects), with a marked increase of P3 latencies, particularly when compared with N2 latencies (P < 0.0001). Furthermore, sensitivity was 87% to 95% for the differentiation of AD patients from MCI and control subjects, using prolonged P3 latencies (specificity, 90% to 95%), whereas using N2 prolonged latencies, sensitivity was 70% to 75% (specificity, 70% to 90%). Moreover, in the MCI group, N2 latencies strongly discriminated MCI from control subjects, with 90% sensitivity and 70% specificity and correctly categorized 80% of MCI subjects against 73% for P3. The abnormalities of N2 and P3 components may be linked, in AD and MCI, to an alteration of automatic and controlled attention processing.     

Alzheimer's disease and P300: review and evaluation of task and modality

Early stage Alzheimer disease patients and matched elderly unaffected controls (n = 16/group) were evaluated with the P300 event-related brain potential (ERP). All subjects performed four oddball tasks that varied systematically in task difficulty and were each presented in the auditory and visual modalities. P300 amplitude was smaller and peak latency longer for the Alzheimer patients compared to elderly control subjects across tasks and modalities. P300 differences between Alzheimer patients and controls were largest for the relatively easy tasks, with little influence of stimulus modality observed. The results suggest that the P300 brain potential is sensitive to Alzheimer's disease processes during its early stages, and that easily performed stimulus discrimination tasks are the clinically most useful. Theoretical and practical implications are reviewed.     

Cognitive evoked potentials (P300) in early Huntington's disease

The P3 component of both auditory-event- and visual-event-related potentials of 13 patients with Huntington's disease was studied and compared with the P3 component of normal patients. The latencies of the patients' P3 components were compared with the latency-age regression lines generated by the normal population in both modalities. A P3 latency was considered abnormal if it fell above the 2-SE limit for the latency-age regression line. The incidence of normal or abnormal P3 latencies in the two modalities was compared with the results of computed tomography, electroencephalography, and neuropsychological testing. Nine patients had abnormal P3 latencies and ten patients had abnormal visual P3 latencies, with seven having abnormal latencies on both tests and 12 having abnormal latencies on one of the two tests. An abnormal P3 latency in one modality did not imply an abnormal P3 latency in the other. An abnormality of the P3 latency did not correlate with an abnormality in results from computed tomography, electroencephalography, or neuropsychological testing.     

阿尔茨海默病和血管性痴呆听觉事件相关电位P300比较研究

目的 探讨阿尔茨海默病（AD）和血管性痴呆（VD）在听觉事件相关电位P300检测中的不同特点。方法 收集符合ICD-10诊断标准的30例AD和36例VD患者,并以35例健康老人作对照组（NC）。使用丹麦仪器以及“听觉靶-非靶刺激序列”为诱发事件,完成P300检测。结果 （1）3组在靶潜伏期Cz脑区N2以及在靶波幅Cz脑区P2、P3和非靶波幅Cz脑区P2上均有显著差异（P〈0．01）。（2）AD主成分N2表现为延迟,与NC组和VD组有极显著性差异（P〈0．01）。（3）AD组和VD组靶波幅P3和非靶波幅P2均见降低,与NC组比较也有显著性差异（P〈0．05-〈0．01）。结论 提示作为反映AD和VD认知功能障碍的客观生理指标,P300有可能作为AD和VD辅助诊断的一个脑电生理学标志。P300检查可作为老年神经精神科的必查项目。     

Normal latency of the P300 event-related potential in mild-to-moderate Alzheimer's disease and depression

A two-tone-discrimination task was used to elicit the P300 component of event-related (brain) potentials (ERPs) from patients with presumed Alzheimer's dementia of mild or moderate severity, depressed patients of older age, and cognitively normal individuals. Although the average P300 latency of the Alzheimer patients was greater than that of the depressed patients, which in turn was greater than that of older aged normals, none of the group differences in latency were statistically significant. Moreover, when latency was examined on an individual basis, less than one-quarter of the Alzheimer patients had an abnormally delayed P300 for their age. Reaction times and the percentage of correct behavioral responses to the tones did distinguish the Alzheimer from the normal group; on both measures the patients' scores were significantly worse. It was concluded that the performance of a simple tone discrimination task requiring a button-press response does not sufficiently tax those cognitive functions impaired in the earlier stages of Alzheimer's dementia to result in abnormally slowed cognitive processing of the kind reflected in P300 latency.     

Executive dysfunction in early Alzheimer's disease.

Twenty five patients with probable mild Alzheimer''s disease were assessed for deficits in executive functioning and the impact of these deficits on performance in other neuropsychological domains. The Wisconsin card sorting test, the release from proactive interference paradigm, the verbal fluency test, and the Stroop test were adopted to classify patients with (AD+) and without (AD-) executive deficits. Seven of the patients showed an impairment in executive function (AD+), defined as a performance below the cut off score in at least two of these tests. There were no significant differences in clinical assessments, demographic features, or other cognitive functions between patients. Executive dysfunction may be an early additional feature in a subgroup of patients with mild Alzheimer''s disease. Impairment on frontal lobe tests does not seem to be related to the severity or duration of disease, or to a different pattern of impairment in other cognitive domains.     

Long-term effects of donepezil on P300 auditory event-related potentials in patients with Alzheimer's disease

The P300, one of the cognitive event-related potentials (ERPs) of the cerebral cortex, reflects the functioning of the neurochemical system involved in cognitive processes. We investigated clinical significance of the components of auditory P300 ERPs, in comparison with neuropsychologic tests including the Mini-Mental State Examination and the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog), for evaluating of the effect of donepezil (DPZ) (5 mg daily for 6 months), an acetylcholinesterase inhibitor, in patients with Alzheimer's disease (AD). Reduction of P300 latency associated with a parallel improvement of ADAS-J cog scores was observed after administration of 5 mg/day of DPZ in patients with AD. P300 latency gives very useful information on the progression of AD, especially in the longitudinal follow-up of patients with AD during treatment with DPZ acting on cholinergic pathways.     

Diagnosis of early Alzheimer's disease

Current criteria for the diagnosis of Alzheimer's disease require that the patient also fulfils the criteria for dementia. This means inevitably that the disease is well-established. As treatments become available there is an important need for early diagnosis. There are two components to diagnosis; the recognition that cognitive performance is below that which would be anticipated for the individual and secondly to relate this to a specific disease process. Research studies need to identify the very earliest changes i.e. before symptoms commence. Such studies have focused on at risk populations either by virtue of age or a positive family history. Both groups have demonstrated that memory is the salient early feature, particularly verbal memory, impairment of which may precede overt symptoms by many years. The other major approach has been that of neuroimaging. Group studies of at risk individuals, for example for those who carry an apoE4 allele, have shown relative biparietal, bitemporal hypometabolism in the at risk group. Similarly, structural neuroimaging may show hippocampal atrophy at an early stage. Serial studies to determine rate of change, may be more valuable than single cross-sectional studies. Recent techniques of positional matching and registration allow precise quantitation of rates of cerebral atrophy which may be useful in early diagnosis.     

The effects of donepezil on the P300 auditory and visual cognitive evoked potentials of patients with Alzheimer's disease.

Donepezil is a cholinesterase inhibitor used for the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The purpose of this study was to determine the effect of treatment with donepezil 5 mg qd on cognitive evoked potentials (EPs) of patients with AD. Although treatment with donepezil did not normalize EP latencies, treatment was associated with a significant decrease in the auditory P300 latency (mean latency pretreatment=401. 5 msec; posttreatment=392.7 msec.; P=0.04), and the visual P300 latency (mean latency pretreatment=605.7 msec; posttreatment=580.3 msec; P=0.04). Treatment with donepezil had no discernible effect on auditory or visual P300 EP amplitudes.     

P38 MAP kinase is activated at early stages in Alzheimer's disease brain

The regional, cellular, and subcellular localization of phosphorylated p38 MAPK (pp38) was examined by immunocytochemistry, immuofluorescent multiple labeling, and immunoblotting of extracts as well as immunoprecipitates of human postmortem tissue from control and Alzheimer's disease (AD) cases at different Braak stages. "Early AD" cases (Braak stages IV-V) and a subset of Braak stage VI cases have high levels of pp38 immunoreactivity, with the most dense immunoreactivity located in CA2 and subiculum followed by CA1 in the hippocampus. On the contrary, very little pp38 was detected in age-matched controls (Braak stages 0-II). More importantly, as revealed by various multiple labeling experiments, pp38 immunoreactivity is mainly located in neurons bearing early neurofibrillary pathology, but not in typically fibrillar tangles that are densely stained by thioflavin-S. Most pp38-positive neurons only contain a small amount of phospho-tau. Additionally, pp38 immunoreactivity was not associated with senile plaques. At the subcellular level, pp38-immunoreactive granules are usually larger than the granules stained with the lysosomal marker cathepsin D. Immunoblotting with different extraction buffers and immunoprecipitation indicate that pp38 does not or only loosely binds to phospho-tau. Taken together, this study demonstrates that p38 MAPK is activated at early stages of neurofibrillary degeneration in AD hippocampus. The p38 activation may also be linked to neurodegeneration through mechanisms other than neurofibrillary tangle formation.     

Quantitative assessment of ALZ-50 immunoreactivity in Alzheimer's disease.

A quantitative assay for ALZ-50 immunoreactivity was evaluated in samples of superior temporal gyrus taken at autopsy from 13 Alzheimer patients and 11 controls. The assayable immunoreactivity appears to be stable for at least 24 hours postmortem but was lost with formalin fixation. The mean value of the Alzheimer patients was tenfold higher than that of the controls (P less than .002). The values of four Alzheimer samples overlapped with the low levels seen in controls, but no controls had elevated levels. In this sample population, therefore, the assay had a sensitivity of 69% and specificity of 100%.     

EEG detection of early Alzheimer's disease using psychophysical tasks.

In this study, we hypothesized that a quantitative EEG (qEEG) method for measuring EEG variability combined with specific psychophysical tasks could improve the classification accuracy of subjects with normal aging vs. mild cognitive impairment (MCI) or mild dementia due to Alzheimer's Disease and Related Disorders (ADRD). The cross-sectional sample consisted of 48 subjects (32 normal aging and 16 ADRD: n = 3 mild dementia, n = 13 MCI FAST stage 3). During EEG recording, subjects performed two visual, delayed recognition memory tasks as well as a task that tested their ability to perceive structure-from-motion (SFM). These EEG data were used to compute qEEG measures of the (normalized) variance of posterior cortical activity during the first 150 milliseconds (ms) after stimulus onset and the variance of anterior cortical activity during the second 150 ms epoch. The ratio, anterior/posterior cerebral qEEG value, was then computed for each subject, and the optimal cutoff value identified to discriminate normal from impaired subjects. An optimal qEEG cutoff value for the delayed recognition memory tasks correctly discriminated 30 of the 32 normal aging subjects (94% specificity) and 14 of 16 MCI-to-mild ADRD subjects (88% sensitivity). On the other hand, the application of this qEEG measure to EEG data recorded while subjects performed a SFM task did not distinguish between ADRD and normal aging any better than chance. In conclusion, this qEEG measure is specific to the psychophysical task being performed by the subject. When it was combined with delayed recognition memory tasks, it yielded results that are comparable to the accuracies reported by PET scan studies of normal aging vs. AD with mild cognitive impairment. These results warrant further evaluation.     

Repeated pain assessment in Alzheimer's disease

In previous studies, patients with probable Alzheimer's disease (AD) have indicated that they experienced less pain intensity and affect from their painful conditions than nondemented elderly persons. However, in those studies, pain assessment occurred only once. Therefore, it may be possible that pain which had occurred, for example, a day earlier, could have been forgotten. Therefore, in the present study, AD patients' pain was assessed daily, i.e. once a day and even three times a day, during a longer period. The results parallel those of earlier studies, i.e. compared to elderly persons without dementia, AD patients appear to perceive less pain intensity and pain affect. These findings support the hypothesis that AD is characterized by an alteration in pain experience.