Neurology

In a large, well-characterized population of community-dwelling persons with Alzheimer's disease (AD), we investigated the emergence of behavioral symptomatology and its association with changes in cognitive, global-clinical, and functional status. Behavioral Rating Scale for Dementia (BRSD) item responses from 235 AD patients with varying levels of dementia severity and without significant behavioral disturbance were taken from the baseline and 12-month visits in a study of cognitive and behavioral instruments. Item-level analysis revealed new symptoms at every dementia severity level. The symptoms that emerged in the greatest proportion of patients were change in weight, change in appetite, diurnal confusion, uncooperativeness, restlessness, clingy behavior, loss of initiative, and change in sleeping pattern. Changes in cognitive status over the 12 months were associated with changes in functional status and not with the emergence of behavioral symptomatology; however, change in the latter two domains tended to be associated. The findings support the hypothesis that increasing behavioral disturbance is not strongly associated with decreasing cognitive status and that, except for psychotic symptoms, a previously observed association between dementia severity and behavioral status may have been mediated partly by changes in functional abilities.

To estimate the prevalence of, and develop norms for, significant agitation in community-dwelling persons with Alzheimer's disease (AD), the authors applied three different criteria to persons with AD (n=235) and normal elderly control subjects (NEC; n=64). The criteria were used to identify the minimum total score on the Cohen-Mansfield Agitation Inventory (CMAI) that represents significant or "excessive" agitation and to estimate its prevalence. The "ultraliberal" criterion resulted in 99.1% of persons with AD and 56.6% of NEC being classified as "excessively" disturbed. The "liberal" and "conservative" criteria classified 66.7% and 68.2% of persons with AD, and no NEC, as "excessively" disturbed. The authors conclude that the best estimate of prevalence of excessive agitation in this population is 67.5%, and that individuals with CMAI scores of 0 to 14 probably should not be considered to have excessive agitation.

d-Ala-Peptide T-amide (DAPTA), the first viral entry inhibitor, blocks chemokine (CCR5) receptors, not CD4. Early investigators could not “replicate” DAPTAs potent in vitro antiviral effect using the lab-adapted, X4, peptide T-insensitive strain, IIIB, delaying clinical virological studies. We now report that DAPTA, administered to eleven long-term infected (mean=17 years) patients with stable persistent plasma “virus” for up to 32 weeks did not change this level. Infectious virus could not be isolated from their plasma suggesting HIV RNA was devoid of replicative capacity. Progressively less actual virus (P<0.01) could be isolated from white blood cells (PBMCs). DAPTA flushed the monocyte reservoir to undetectable viral levels in most patients. Five of eleven had a mean CD4 increase of 33%. Immune benefits also included a four-fold increase in γ-interferon-secreting T-cells (antiviral cytotoxic T-cells) in the absence of drug-related toxicity. All five CD4 responders had increases in antiviral T cells and decreases in infected monocytes, an argument for initiating further studies promptly.

In the course of a 4-month study of interventions for behavioral disturbances in 148 Alzheimer's disease (AD) patients, the following assessment instruments were examined for validity: the clinical global impression of change (CGIC; L. S. Schneider et al., 1997), Cohen-Mansfield agitation inventory (CMAI; J. Cohen-Mansfield, 1986)); consortium to establish a registry for Alzheimer's disease (CERAD) behavioral rating scale for dementia (BRSD; P. N. Tariot et al., 1995), revised memory and behavioral problems checklist (RMBPC; I. Teri et al., 1992) and the agitated behavior in dementia scale (ABID; R. Logsdon et al., submitted). The 4 specific behavioral/agitation scales had excellent cross-sectional and longitudinal correlations with each other, suggesting high validity, but changes as indicated by CGIC scores did not correlate well with change scores on the other instruments. It is concluded that specific behavioral instruments are preferable to the more general CGIC for detecting and quantifying behavioral disturbances in AD patients.

We explored the applicability of the standard scoring of the Cohen-Mansfield Agitation Inventory (CMAI), a widely used nursing-home derived instrument, to community-dwelling persons with Alzheimer's disease (AD). Item responses to the CMAI were gathered from participants in two large clinical studies, one of which specifically included patients with behavioral disturbances. Confirmatory factor analysis in these two groups of well-characterized AD patients suggested that conventional CMAI subscoring did not adequately describe the responses of these two groups. Exploratory factor analysis indicated that the four CMAI subscores, based on a verbal-physical and aggressive-non-aggressive conceptualization of behavioral disturbance, did not fit community dwelling persons with AD. Based on cross-sectional and longitudinal analyses, there was suggestive evidence for three behavioral clusters, but these clusters did not achieve statistical significance Overall, the CMAI seemed best suited to describe the overall level rather than the specific subtypes of behavioral dyscontrol in community-dwelling persons with AD.

We retrospectively analyzed sleep time and sleep disturbance symptoms in 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer's disease (AD). Our primary objective was to determine differences in subjective sleep disturbance between these samples. Secondary objectives were to determine if subjects with time in bed (TIB) < or =6 h per night reported more sleep disturbance and whether sleep complaints were associated with more severe cognitive and/or functional impairment. The prevalence of 'sleep problems' (a single item) was significantly lower in NDE (18.3%) than AD (27.6%), and the proportions of each cohort reporting TIB < or =6 h per night were very low (NDE: 6.0%; AD: 3.5%) and not significantly different. Less TIB was correlated with better cognitive function for AD (P < 0.01), and cognition and function were significantly worse for AD subjects with estimates of >6 h of TIB compared with those with estimates of < or =6 h (P < 0.05). Greater sleep disturbance was correlated with greater functional impairment in both cohorts; but only in AD did greater estimated TIB also correlate with greater functional impairment (all P < 0.05). In general, estimated TIB was not associated with mood in either cohort; however, in both cohorts depression was significantly associated with sleep disturbance symptoms and was significantly worse in those who reported having 'sleep problems'. There was no association between subjective perception of 'sleep problems', the number and frequency of sleep disturbance symptoms, and estimated TIB in either group.

The Clinical Dementia Rating (CDR) is a widely used semiobjective instrument for staging dementia severity. A global CDR score is reported that is derived from individual scores in six domains. In this study, we examined both agreement and disagreement, among raters and with a gold standard, to identify domain-specific and global dementia severity level ratings that would most benefit from further training or greater emphasis in future training. We found that raters-in-training experienced the most difficulty with rating normal and questionable dementia. They also had the most trouble scoring the memory domain. When they disagreed with the gold standard, they nearly always gave higher ratings. A third, extremely experienced group of raters were uniform in their high levels of agreement on each domain and the global CDR and tended to give lower ratings if they disagreed with the gold standard. Analysis of the agreement and disagreement patterns suggested that greater emphasis on the memory, home and hobbies, and orientation domains during CDR training, and increasing the information provided for the judgment and problem solving domain on the standardized CDR worksheets, could improve the consistency of raters and increase the efficiency with which they are trained to use the CDR.

PURPOSE: To assess attitudes toward complementary and alternative medicine (CAM) and its place in the medical school curriculum and medical practice among preclinical students at Georgetown University School of Medicine (GUSOM), Washington, DC.

METHOD: Two-hundred sixty-six first-year (n=111) and second-year (n=155) medical students rated their attitudes toward CAM and 15 CAM modalities in terms of personal use, inclusion in the curriculum, and use/utility in clinical practice.

RESULTS: Nearly all (91%) students agreed that "CAM includes ideas and methods from which Western medicine could benefit"; more than 85% agreed that "knowledge about CAM is important to me as a student/future practicing health professional"; and more than 75% felt that CAM should be included in the curriculum. Among all students, the most frequently indicated level of desired training was "sufficient to advise patients about use," for 11 of the 15 modalities. The greatest level of training was wanted for acupuncture, chiropractic, herbal medicine, and nutritional supplements. The descriptions of CAM in future clinical practice that occurred most frequently were endorsement, referral, or provision of acupuncture, biofeedback, chiropractic, herbal medicine, massage, nutritional supplements, prayer, and meditation.

CONCLUSIONS: Interest in and enthusiasm about CAM modalities was high in this sample; personal experience was much less prevalent. Students were in favor of CAM training in the curriculum to the extent that they could provide advice to patients; the largest proportions of the sample planned to endorse, refer patients for, or provide 8 of the 15 modalities surveyed in their future practice.

This study describes two well-characterized groups of Alzheimer's disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference-whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized 'diversity of behaviors' and 'frequency' with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.

Reading-related skills were tested in normally-reading, reading-disabled, and deaf adults, who did not differ on average Performance IQ. The latter two groups demonstrated similar levels of phonological awareness - both much lower than controls - but only the disabled readers also exhibited deficits in other skills, including verbal short-term memory, morphological awareness, speeded written naming, and reading comprehension. The average reading level of these deaf readers was significantly higher than that of the disabled readers. Three controls also demonstrated limited phonological awareness and no other deficits in a pilot study, performing similarly to the deaf readers. The results support other studies suggesting that it may be processes dependent on memory, and not solely the degree to which phonological awareness is possessed, which determine reading achievement.

BACKGROUND: This research examines student evaluations of their experience and attitudes in an 11 week mind-body skills course for first year medical students.

AIMS: The aim is to understand the impact of this course on students' self-awareness, self-reflection, and self-care as part of their medical education experience.

METHODS: This study uses a qualitative content analysis approach to data analysis. The data are 492 verbatim responses from 82 students to six open-ended questions about the students' experiences and attitudes after a mind-body skills course. These questions queried students' attitudes about mind-body medicine, complementary medicine, and their future as physicians using these approaches.

RESULTS: The data revealed five central themes in students' responses: connections, self discovery, stress relief, learning, and medical education.

CONCLUSIONS: Mind-body skills groups represent an experiential approach to teaching mind-body techniques that can enable students to achieve self-awareness and self-reflection in order to engage in self-care and to gain exposure to mind-body medicine while in medical school.

The authors sought to define "abnormal" levels for total scores on the CERAD Behavioral Rating Scale for Dementia (BRSD) and for 37 BRSD items by comparing 242 patients with Alzheimer's disease (AD) and 64 normal elderly control subjects (NEC). BRSD total scores for NEC ranged as high as 52 (out of a maximum 167), and although item prevalence rates were higher for AD patients, not all of these differences were significant. Many symptoms were observed in < or = 10% of AD subjects. Lower Mini-Mental State Examination scores were not consistently associated with lower or higher levels of endorsement across all items. Over 6 and 12 months, endorsement rates were relatively stable for both groups. The authors conclude that assessment of behavior in long-term studies will be needed to quantify "abnormal" levels, and that item-level BRSD information could be important in clinical trials.

OBJECTIVES: To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease.

DESIGN:A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.

SETTING:Private homes and long-term care facilities.

PARTICIPANTS:157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.

MEASUREMENTS: Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.

RESULTS:No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.

CONCLUSIONS:Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease. objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.

The authors' main objective was to investigate the relationship between changes in psychopathological, cognitive and activity of daily living (ADL) instrument scores over 12 months in community-dwelling persons with Alzheimer's disease (AD). A secondary objective was to evaluate the validity of dividing the Clinical Dementia Rating (CDR), a global dementia staging instrument into cognitive and functional subscores. Changes in measures of psychopathology, cognition and function between the baseline and 12-month visits were entered into these post hoc analyses of data from a one-year clinical trial to evaluate behavioral, cognitive and functional assessment instruments for use in clinical trials with AD patients. Exploratory factor analysis was used to determine whether there was independence between changes in any of these three domains of interest for this disease population; participants were a cohort of 187 well-characterized, community-dwelling persons with AD. One-year change in the behavioral symptoms of this cohort of persons with AD was statistically independent from changes in scores on cognitive and functional measures. Some evidence of independence of 12 month changes in cognitive and functional measures was found. Cognitive and functional subscores for the CDR were supported. These findings suggest that changes in behavior and cognition in dementia may have distinct pathophysiologies.

In this post hoc analysis of baseline responses to the CERAD Behavior Rating Scale for Dementia in a clinical trial of interventions for agitation in Alzheimer's disease (AD), the authors investigated the distribution of, and relationships between, agitation, depression, and psychosis in 148 individuals with AD. Prevalence of depressive symptoms was highest (78.4%), followed by agitation (77.6%) and psychotic symptoms (69.3%); 51.1% of the sample had symptoms in all 3 domains. Cross-sectionally, psychotic symptoms were most closely associated with Mini-Mental State Examination (MMSE) scores, while agitation was less so. Depressive symptoms were relatively consistently prevalent across MMSE levels. After controlling for the presence of agitated symptoms, psychosis and depression were significantly associated, but neither symptoms of psychosis nor of depression were associated with agitation when depression or psychosis, respectively, was controlled for. Significant psychopathological comorbidity should be considered in the design of clinical trials targeting particular psychopathology in this disease population.

We retrospectively analyzed sleep disturbance symptoms and estimated time in bed from the intake interviews of 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer's disease (AD). Our primary objective was to identify what symptoms might underlie an individual's perception of 'sleep problems' and to determine if these were consistent within, and across, our two cohorts. We stratified each cohort according to whether or not they (or their caregiver) indicated that they had a 'sleep problem', and compared the frequency and endorsement rates of each of 21 sleep disturbance symptoms across those who did or did not endorse 'sleep problem'. For less than half of the symptoms in persons with AD, and a quarter of those in NDE, endorsement rates were significantly different depending on whether the reporter (or their sleep partner) did or did not report a sleep problem. Differences in mean frequency ratings between individuals reporting sleep problems relative to those not reporting were observed on 10 symptoms in both cohorts; six of these were the same symptom for both cohorts. When persons with subjective sleep problems in the AD and NDE cohorts were compared, only four of 21 symptoms were endorsed in one and not the other; two symptoms were significantly more frequent in one cohort than the other. Thus, within cohorts, the differences between persons with and without 'sleep problems' were relatively pronounced while the main differences in specific sleep-related symptoms between AD and NDE were not. Observed between-cohort differences appear to be driven by who is reporting, and the high prevalence of daytime sleeping in AD. Within-cohort differences reflect a clear distinction between persons with and without sleep problems, regardless of the reporter.

CONTEXT: The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer's Disease Cooperative Study (ADCS).

OBJECTIVE: To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets.

DESIGN: Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm.

SETTING: The ratings were assigned during a single, 3-hour session in a closed room.

PARTICIPANTS: Two clinical monitors and one project director/clinical monitor supervisor.

MAIN OUTCOME MEASURES: Percent agreement, Kendall's tau-b, and Cohen's kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects.

RESULTS:Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (kappa = 0.66, orientation and judgment & problem solving boxes) to excellent (kappa = 0.83, global CDR) agreement.

CONCLUSIONS: The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.

These retrospective analyses represent a pilot study of a potential new outcome, expected emergence. The Behavior Rating Scale for Dementia (BRSD) was administered at the baseline and 12-month visits of a multicenter study. The authors computed the rates at which each BRSD symptom emerged over 12 months in normal elderly control subjects (n=64). These normal rates were then applied as the expected emergent rate (EER) to a population of individuals with Alzheimer's disease (n=235). The comparison of expected emergence to observed emergence in Alzheimer's disease showed interpretable differences. EER assesses whether treatments limit emergence in the target, relative to the standard, population. The ratio of expected to observed emergence provides an intuitively appealing quantification of treatment efficacy and can be used with any instrument that uses categorical or frequency ratings.

It has been established that triiodothyronine (T3) and thyroxine (T4) measurements by tandem mass spectrometry (MS/MS) are more specific and are significantly different from immunoassay (IA) measurements (all p< or =0.05) throughout pregnancy. In this study, we examined the clinical implications of these discrepancies.

METHODS:Kappa statistics were used to determine the degree to which IA and MS/MS agreed in their identification of out-of-reference interval observations of circulating T4 and T3 from 52 normal, iodine-sufficient women during each trimester of pregnancy.

RESULTS: After taking chance agreement into account, the two methods had poor agreement on classification of T3 values at the first (kappa=0.185) and second (kappa=0.183) trimesters, with extremely poor agreement for the third trimester and 1-year postpartum. Agreement on T4 was poor only for the third trimester (kappa=0.183). The two methods agreed on out-of-range values in only 0-25% of T3 cases and 25-66.7% of T4 cases.

CONCLUSIONS: The areas of disagreement suggest that women at risk (i.e., with analyte values outside of the 5-95% range) will not be detected using IA. Based on this cohort, our preliminary estimates are that 25-100% of such women would be missed if IA were used to assay the analyte.

BACKGROUND: Executive dysfunction (EDF) is common in Alzheimer disease (AD); however, its relationship to other symptoms is difficult to assess in patients with AD.

OBJECTIVES: To determine the prevalence of EDF and study its relationship to cognitive, functional, and neuropsychiatric symptoms in patients with AD.

DESIGN, SETTING, AND PATIENTS: A retrospective analysis of data from participants in the English Instruments Protocol of the Alzheimer's Disease Cooperative Study. Subjects were drawn from a sample of patients evaluated at tertiary referral centers.

RESULTS: A total of 64% of AD patients were classified as having EDF. Patients with EDF performed worse on tests of cognition (P <.001), dementia severity (P <.001), and activities of daily living (P =.01) and had more frequent symptoms of psychosis (P =.03) with greater emergence during the 12-month interval (P =.03) compared with patients with normal executive function. Less than 30% of the variance in executive function performance was explained by cognitive measures.

CONCLUSION: These findings support the assessment of executive function in persons with AD and the importance of frontal lobe dysfunction in AD.A