We investigated the relationship between APOE genotype and rate of disease progression and survival in 99 patients with probable Alzheimer's disease (AD) who were followed biannually for up to 6 years. Patients were stratified into two groups, those with and without at least one APOE epsilon4 allele. The rate of decline in modified Mini-Mental State Examination scores was slower, the presence of extrapyramidal signs was decreased, and the development of myoclonus occurred later among patients with APOE epsilon4 alleles compared with patients with other genotypes. Compared with patients without an APOE epsilon4 allele, the risk of mortality was also decreased in patients with at least one epsilon4 allele (RR = 0.38; CI = 0.17-0.84, p < 0.02). Because the decline in mental ability as well as the development of myoclonus and extrapyramidal signs are consistent manifestations of disease progression, our results imply that APOE epsilon4 is associated with a less aggressive form of AD.

Objective. —To develop and validate an approach that uses clinical features that can be determined in a standard patient visit to estimate the length of time before an individual patient with Alzheimer disease (AD) requires care equivalent to nursing home placement or dies. Design. —Prospective cohort study of 236 patients, followed up semiannually for up to 7 years. A second validation cohort of 105 patients was also followed. Setting. —Three AD research centers. Patients. —All patients met National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and had mild dementia at the initial visit. Intervention. —Predictive features, ascertained at the initial visit, were sex, duration of illness, age at onset, modified Mini-Mental State Examination (mMMS) score, and the presence or absence of extrapyramidal signs or psychotic features. Main Outcome Measures. —(1) Requiring the equivalent of nursing home placement and (2) death. Results. —Prediction algorithms were constructed for the 2 outcomes based on Cox proportional hazard models. For each algorithm, a predictor index is calculated based on the status of each predictive feature at the initial visit. A table that specifies the number of months in which 25%, 50%, and 75% of patients with any specific predictor index value are likely to reach the end point is then consulted.Survival curves for time to need for care equivalent to nursing home placement and for time to death derived from the algorithms for selected predictor indexes fell within the 95% confidence bands of actual survival curves for patients.When the predictor variables from the initial visit for the validation cohort patients were entered into the algorithm, the predicted survival curves for time to death fell within the 95% confidence bands of actual survival curves for the patients. Conclusions. —The prediction algorithms are a first but promising step toward providing specific prognoses to patients, families, and practitioners. This approach also has clear implications for the design and interpretation of clinical trials in patients with AD.

BACKGROUND Studies using clinical measures to track AD progression often assume linear declines over the entire course of the disease, which may not be justified. The objective of this study was to model change in measures of the clinical severity of Alzheimer's disease (AD) over time. METHODS We developed a method to apply growth curve models to prospective data and characterize AD patients' functional change over time. Data from the modified Mini-Mental State Examination (mMMSE) and measures of basic and instrumental ADL, administered semiannually for up to 5 years to 236 patients with probable AD, were modeled. RESULTS The rate of decline in mMMS scores per 6-month interval gradually increased as scores dropped from the maximum of 57 to 20. The rate of decline then decreased as scores approached 0, resulting in an inverse "S" curve. The rate of increase in instrumental ADL scores per interval attenuated as the scores increased, while that for basic ADL scores across intervals was constant. CONCLUSIONS Differences in the pattern of progression of the three measures is in part a function of their psychometric properties. The progression curves may also reflect content-specific features of the instruments. Superimposition of the modeled decline in these three content areas suggests a hypothetical model of the relative timing of cognitive and functional changes in AD.

Objective: To determine how the advent of extrapyramidal signs influences the progression of Alzheimer disease as measured by standard clinical measures. Design: We applied growth curve models to prospective data to characterize patients' cognitive and functional changes over time. To detect changes in disease course related to extrapyramidal signs, their onset was treated as a time-dependent covariate. Setting: Three research medical centers. Participants: Patients (n=217) with probable Alzheimer disease. Intervention: Patients were followed up semiannually for 5 years. Main Outcome Measures: Scores on the modified Mini-Mental State Examination and measures of basic and instrumental activities of daily living from the Blessed Dementia Rating Scale. Results: For basic and instrumental activities of daily living, disease course was more rapid once extrapyramidal signs developed. Decline in the modified Mini-Mental State Examination score was greater at the time the signs developed, but not at subsequent visits. Conclusions: The point at which extrapyramidal signs emerge is associated with measurable acceleration in the progression of Alzheimer disease. This may in part explain why extrapyramidal signs are associated with a poorer prognosis. The differential influence of extrapyramidal signs on cognitive and functional measures suggests that the pathological changes underlying these disease features may vary.

OBJECTIVE: To measure behaviors indicative of quality of life (QOL) in patients with Alzheimer's disease and to examine correlates of patient QOL.DESIGN: Cross-sectional investigation.SETTING: Multi-center study.PARTICIPANTS: Sample of 130 diagnosed patients.PRINCIPAL OUTCOME MEASURES: Proxy ratings of (1) the frequency, opportunity, and enjoyment of 15 non-ADL activities potentially within the capacity of a demented person, and (2) the frequency of a series of positive and negative affects, evident in clearly demarcated facial and bodily expressions.RESULTS: QOL ratings were reliably elicited. Family and institutional caregivers differed only in reports of opportunity for patient activity. Frequency of activities declined with increasing severity of dementia. The frequency of negative affects increased and positive affects declined with increasing severity of dementia, but correlations were weak. High QOL, defined by frequent activity and positive affect, was evident in a quarter of the sample. In multivariate models, functional and cognitive status independently predicted QOL among community-resident older adults; only absence of antipsychotics was related to QOL among older people in nursing homes. Patient education, a marker of premorbid state, independently predicted some activity patterns.CONCLUSIONS: Although the subjective world of the demented patient is not directly accessible, readily observable behaviors offer a basis for assessing QOL.

Objective: Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease. Method: A prospective, double-blind; placebo-controlled study of high-dose d-alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha-tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms. Results: Treatment with d-alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder. Conclusions: Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.

Objective: To examine whether either extrapyramidal signs or psychotic features are associated with more rapid progression of Alzheimer's disease. Background: It has been unclear whether extrapyramidal signs and psychosis are predictors of faster course or are simply late signs. Methods: Two hundred thirty-six patients with mild Alzheimer's disease were recruited in three cities and followed semiannually. Results: Using Cox proportional hazards models that adjusted for age, sex, disease severity, and estimated duration of illness at study entry, the presence of extrapyramidal signs at entry was associated with higher relative risk (RR) of reaching moderate cognitive (RR = 2.35, 95% CI = 1.12 to 4.92) or functional (RR = 2.31, 95% CI = 1.37 to 3.90) severity, nursing home entry (RR = 2.51, 95% CI = 1.32 to 4.76), or death (RR = 3.04, 95% CI = 1.31 to 7.05). Psychosis predicted only the functional end point (RR = 1.85, 95% CI = 1.18 to 2.90). Using regression models, modified Mini-Mental State scores declined 1.30 points (95% CI = 0.16 to 2.44) per 6-month interval, more among patients with than those without extrapyramidal signs; patients with psychosis declined 1.15 (95% CI = 0.52 to 1.77) more mMMS points per interval. Conclusions: This study confirms extrapyramidal signs and psychosis as robust predictors of disease end points and rapid progression in Alzheimer's disease.

We examined the pattern of cognitive impairment and rate of cognitive and functional decline as a function of age at symptom onset in 127 patients with probable Alzheimer's disease (AD). At baseline, early-onset (before age 65) and late-onset groups were mildly and comparably impaired on the modified Mini-Mental State Examination (mMMS) and the Blessed Dementia Rating Scale-Part 1 (BDRS). Repeated-measures analysis of variance revealed significantly more rapid decline in early-onset subjects over a 2-year follow-up period. Multivariate linear regression analyses indicated that age at symptom onset strongly predicted rate of decline on the mMMS and the BDRS, even after controlling for symptom duration, gender, family history of dementia, and baseline mMMS and BDRS scores. Early- and late-onset AD subjects also differed in terms of pattern of performance on the mMMS. Early-onset subjects scored significantly lower than late-onset subjects on attentional items of the mMMS at baseline and follow-up. Conversely, late-onset subjects scored significantly lower than early-onset subjects on memory and naming items at baseline, and the two groups were comparable on these tasks at follow-up. Results provide longitudinal evidence of more rapid cognitive and functional decline in subjects with early-onset AD and suggest that early-onset AD may be characterized by predominant impairment of attentional skills.

The "Predictors Study" is a prospective cohort study of the natural history of Alzheimer disease (AD), the aim of which is to identify milestones in disease progression and to develop a model to predict disease course in individual patients. The empirical background to this study is based on previous reports that the presence of extrapyramidal signs (EPS), myoclonus, and psychosis in AD may signify greater disease severity at any given stage and a more rapid course of the disease over time. The present analyses were conducted to determine whether these independent "predictor" variables were associated with greater disease severity at baseline within a new cohort of 224 mild AD patients recruited from three different medical centers (in New York, Baltimore, and Boston). Measures of disease severity were provided by the modified Mini-Mental State Examination (mMMSE) and the Blessed Dementia Rating Scale (BDRS), which measures functional capacity. Independent variables were EPS, delusions, and slowing of the posterior dominant EEG rhythm. The frequency of myoclonus and hallucinations was too low to permit adequate statistical assessment of their effects at this time. EPS and EEG slowing were associated with low mMMSE scores, whereas delusions were primarily associated with impaired functional capacity. These effects were independent of the influence of age and disease duration. These results indicate that the effects of these independent variables can be detected at mild stages of AD and that these effects can be generalized across different geographical regions.

Clinicians should be able to provide the patient with Alzheimer disease (AD) and the family with an accurate prediction of what to expect, but the variability in the rate of disease progression precludes this. In several previous studies, specific clinical signs such as muscular rigidity, myoclonus, and hallucinations or delusions were associated with rapid progression to a more severe stage of dementia or death. The “Predictors Study,” a longitudinal study at three independent sites, was designed to develop a predictor model of the natural history of Alzheimer disease. The study was conducted at three study sites, New York, Baltimore, and Boston in a cohort of 224 patients with early probable AD. This article describes the design and implementation of the Predictors Study, and compares features of the study cohort at baseline across sites. Patients were all at the mild stage of disease at entry and were relatively comparable across sites. Extrapyramidal signs and delusions were common, but myoclonus was rarely observed.

Magnetic resonance imaging and a comprehensive cognitive evaluation were carried out in a series of 29 patients with mild to moderate Huntington's disease (HD). A factor analysis of the neuropsychological test scores provided three factors: a memory/speed-of-processing factor, a "frontal" factor, and a response inhibition factor. The memory/speed factor correlated significantly with measures of caudate atrophy, frontal atrophy, and atrophy of the left (but not the right) sylvian cistern. There were no significant correlations between the "frontal" or response inhibition factors and measures of cortical or subcortical brain atrophy. Our findings confirm that subcortical atrophy is significantly correlated with specific cognitive deficits in HD, and demonstrate that cortical atrophy also has important association with the cognitive deficits of patients with HD.

We compared covert shift of visual attention in patients with schizophrenia or bipolar disorder, both in states of remission, to normal controls to examine the persistence of lateralized attentional deficits into nonpsychotic states. Although patients were slower in all conditions than normals, there was no difference in pattern of attentional shift among the groups. This suggests that the left-hemisphere deficit in shift of covert attention in schizophrenia may be limited to periods of florid illness.

H-reflex recovery functions and homosynaptic depression curves were studied in unmedicated hyperkinetic and control children in the presence and absence of the Jendrassik manoeuvre. The Jendrassik manoeuvre failed to affect recovery function reflex amplitude across or within groups, but reflex amplitude was augmented in the homosynaptic depression procedure for hyperkinetic children who failed to show recovery function facilitation. The absence of Jendrassik-associated reflex facilitation in children during the recovery function and during selective homosynaptic depression rates may reflect developmental influences on processes underlying this phenomenon. However, reflex augmentation in non-facilitating hyperkinetic subjects suggests that these processes are present in children and can be revealed under conditions of decreased motoneuronal excitability. These findings suggest that reduced gamma-efferent drive may contribute to decreased motoneuronal excitability observed in hyperkinetic children, but the possible role of other Jendrassik-activated influences, such as coactivation of alpha and gamma motoneurons or selective activation of alpha motoneurons by processes independent of increased gamma-efferent drive, cannot be excluded.