Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.

BACKGROUND: The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles. OBJECTIVE: To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. SETTING: Alzheimer's Disease Research Center. SUBJECTS: One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline. MEASUREMENTS: The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale. DESIGN: The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures. RESULTS: The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results. CONCLUSIONS: The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.

Nonsteroidal anti-inflammatory drugs in Alzheimer's disease.

We reviewed the records of 210 patients in the Johns Hopkins Alzheimer's Disease Research Center to evaluate the role of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical features and progression of the disease. We compared patients taking NSAIDs or aspirin on a daily basis (N = 32) to non-NSAID patients (N = 177) on clinical, cognitive, and psychiatric measures. The NSAID group had a significantly shorter duration of illness at study entry. Even after controlling for this difference, the NSAID group performed better on the Mini-Mental State Examination, Boston Naming Test, and the delayed condition of the Benton Visual Retention Test. Furthermore, analysis of longitudinal changes over 1 year revealed less decline among NSAID patients than among non-NSAID patients on measures of verbal fluency, spatial recognition, and orientation. These findings support other recent studies suggesting that NSAIDs may serve a protective role in Alzheimer's disease.

Intertarget interval does not affect P300 within oddball series.

Increasing interstimulus interval or decreasing target probability of an oddball series increases P300 amplitude. These findings serve as one of the key underpinnings for the context updating hypothesis of P300. This hypothesis argues that by increasing the average amount of time elapsing between targets, decay of the neural model occurs and there is greater need for updating the model's accuracy. The amount of updating is reflected by increased P300 amplitude. To date, most comparisons have been made between P300 elicited by targets in different oddball series which vary in their mean intertarget interval. The current study examined P300 responses to within-series targets grouped according to how much time had elapsed since the previous target. No differences were found between P300 responses elicited by targets occurring 5-20 s since the previous target. This indicates that P300 amplitude does not vary with the amount of time passing between targets. Therefore, the context updating hypothesis may require some revision.

Changes in visual fixation and saccadic eye movements in Alzheimer's disease.

Visual fixation and saccadic eye movements were assessed in 31 mild to moderately demented patients with probable Alzheimer's disease (AD) and 31 age- and education-matched nondemented elderly control subjects. Seventeen AD and 17 matched control subjects were reassessed after a 9-month interval. On a fixation task, duration of fixation and number of intrusive saccades were not different between groups at baseline or follow-up. Both AD patients and control subjects showed more intrusive saccades at follow-up than at baseline. AD patients showed increased latency to initiation of saccades at baseline and on follow-up. Amplitude and velocity of saccades were not different between groups at any visit. Changes in measures of fixation, but no saccade measure, correlated with changes in MMSE scores over testing sessions. These data suggest that fixation is more sensitive than are saccades to the progession of AD.

Stability of performance on the Hopkins Verbal Learning Test.

Stability of performance on the Hopkins Verbal Learning Test (HVLT) was assessed in 45 healthy elderly subjects over a 9-month period. Stability coefficients were moderate but statistically significant for total recall (r = 0.50), true-positive recognitions (r = 0.66), and false-positive errors (r = 0.42). These correlations are comparable to test-retest correlations reported for other clinical tests of verbal memory (e.g., Logical Memory subtest of the Wechsler Memory Scale-Revised, California Verbal Learning Test) and are sufficient for its clinical use.

Head injury as a risk factor in Alzheimer's disease.

Several case-control studies have reported head injury to be more common among patients with Alzheimer's disease (AD) than healthy elderly controls. The present study sought to determine whether milder head injury is also a risk factor for AD. Furthermore, it was hypothesized that head injury would be more common among AD patients without a genetic risk for the disease. History of head injury in 68 consecutive cases of probable or definite AD and 34 non-demented control subjects was ascertained from their spouses. Head injury was reported in 20 of the AD patients (29%), and in only one control subject (2.9%) (odds ratio = 13.75). Twenty per cent of the familial and 43.5% of the sporadic AD cases reportedly had a premorbid head injury (odds ratio = 3.08). Head injury had no effect on age of dementia onset. The results indicate that head trauma may be a predisposing factor to AD, particularly in the absence of a clear genetic contribution.

Predicting rate of cognitive decline in probable Alzheimer's disease.

Recent attempts to identify predictors of rate of decline in Alzheimer's disease (AD) have been extremely variable in choice of outcome variables, predictor variables tested, timing of assessments, and statistical approaches. In this study, a random effects regression model was applied to seek predictors of decline on the Mini-Mental State Exam in 132 patients with probable AD reassessed every 6 months for up to 7.5 years. Potential predictor variables at baseline were of three types: patients characteristics, clinical variables, and cognitive performances. The final multivariate analysis indicated that the following characteristics predicted more rapid cognitive decline: more education, history of dementia in a first degree relative, non-right handedness, better performances of Boston Naming Test, Gollin Incomplete Figures Test, and Benton Visual Retention Test-Delay, and worse performances on Responsive Naming Test, WAIS-R Block Design, and Benton Visual Retention Test-Copy.

Apo-E genotype and verbal deficits in Alzheimer's disease.

Apo-E genotype was not significantly related to cognitive performance in 157 Alzheimer's disease patients. However, patients homozygous for the epsilon 4 allele appeared most impaired on global cognition but least impaired on language measures. Further study with larger samples may reveal that Apo-E genotype accounts for some of the variability in cognitive deficits observed in Alzheimer's disease.

Accuracy of clinical diagnosis of Alzheimer disease and clinical features of patients with non-Alzheimer disease neuropathology.

Neuropathological examination confirmed the clinical diagnosis of possible or probable Alzheimer disease (AD) in 90 of the first 100 patients who came to autopsy at the Johns Hopkins Alzheimer's Disease Research Center. In 10 cases, postmortem brain examination did not confirm AD but revealed variable patterns of neuronal loss in neocortex and limbic structures without amyloid deposits. The most common pattern of degeneration was relatively isolated hippocampal sclerosis (HS). Despite the finding that the 10 patients with non-AD neuropathology were ill for less time and were less cognitively impaired at study entry than those patients with definite AD, they had shorter survival times and showed equal behavioral disturbance at study entry (on a standardized measure). The clinical case reports included here suggest early and progressive prominent behavioral disturbance and other indexes of rapid illness progression in three of the four HS patients and two other non-AD patients. We conclude that the criteria of the National Institute of Neurological Disorders and Stroke/Alzheimer Disease and Related Disorders Association for possible or probable AD are highly accurate and that misdiagnosis is most likely to occur early in the course of illness and in patients with prominent behavioral disturbance or other atypical features.

CT measurement of suprasellar cistern predicts rate of cognitive decline in Alzheimer's disease.

Previous studies reveal significant relationships between some quantitative computed tomography (CT) measures and level of cognitive functioning in patients with Alzheimer's disease (AD). This study was designed to determine whether measurements from CT scans of AD patients could predict future rates of decline in cognitive function. Subjects were 8 men and 19 women diagnosed with probable AD. CT measures included bifrontal ratio, bicaudate ratio, and areas of lateral ventricles, third ventricle, and suprasellar cistern (SSC). Measures of cognitive and adaptive functioning were obtained at the time of the scan and on follow-up. Of the CT measures, the SSCR (SSC corrected for intracranial area) was the most highly correlated with Mini-Mental State Exam (MMSE) score and other cognitive measures at the time of the scan. Follow-up data were obtained for those 20 individuals who were mildly to moderately demented at the time of the scan (MMSE > or = 10). Rate of change was calculated for each neuropsychological measure. The SSCR correlated significantly with rate of change for MMSE and other measures of cognitive and adaptive functioning. This study demonstrates that CT measurement of the SSC can predict the subsequent rate of neurocognitive decline in AD patients.