Publications

Three pairs of twins, each with proved monozygosity, were shown to be discordant for dementia of the Alzheimer's type and to have remained discordant for periods of 8 to 11 years. Dementia of the Alzheimer's type was demonstrated by history; serial clinical examinations; serial measurements of cerebral glucose utilization using positron emission tomography and of cerebral ventricular volumes and of rates of change of volumes using quantitative computed tomography; and by serial neuropsychological tests. The results of each of these measures showed no evidence of clinical abnormality in any unaffected twin. DNA markers from the proximal long arm of chromosome 21 did not distinguish between the affected and the unaffected member of any pair of identical twins. Family pedigrees were negative for Alzheimer's disease. The results suggest that environmental or other nongenetic factors contribute to Alzheimer's disease in discordant monozygotic twins, or that some cases arise by a postzygotic somatic mutation.

OBJECTIVE

(1) To establish the range of cerebral atrophy across the adult age spectrum in optimally healthy, rigorously evaluated individuals. (2) To determine, across the age spectrum, the relation of gender and cerebral atrophy (as measured by ventricular enlargement) to cognitive function.

DESIGN

Cross-sectional comparison by age and gender.

SETTING

Ambulatory research unit.

PARTICIPANTS

Sixty-four healthy men (mean age +/- SD = 49 +/- 18 yr) and 43 healthy women (51 +/- 18 yr) volunteers enrolled in a longitudinal study of healthy aging. The population was selected for optimal health; all were rigorously screened to exclude medical and psychiatric illness.

MAIN OUTCOME MEASURES

Brain atrophy by CT scan and cognitive function by standardized neuropsychological testing.

RESULTS

After correction for inter-subject variability in cranial volume, women had smaller lateral, but not third, ventricles. For both genders, there were significant differences with age in ventricular volume. After an approximately constant 20% increase in ventricular volume per decade in both genders, a precipitous increase in volume was found beginning in the fifth decade in men and in the sixth decade in women. In men and women, there was a significant negative correlation between ventricular volume and the sum of performance scale scores on the Wechsler Adult Intelligence Scale (WPSS) but not in the sum of the verbal scale scores (WVSS). However, after controlling for age, ventricular volume no longer significantly contributed to the relation between age and WPSS.

CONCLUSIONS

In unequivocally healthy individuals, gender plays an important role in age-associated central cerebral atrophy as measured by progressive ventricular enlargement. Increase in ventricle volume independent of age, does not explain normal age-related declines seen in WPSS scores.

In infants, vaccines consisting of a carrier protein conjugated to the bacterial capsular polysaccharide (PRP) are far more protective against Hemophilus influenzae type b (Hib) disease than unconjugated PRP. To determine the tolerability and immunogenicity of Hib conjugate vaccines in the elderly, we vaccinated 30 volunteers, aged 69-84 years, with either PRP conjugated to an outer membrane protein complex (PRP-OMP), or PRP oligomers conjugated to CRM197, a nontoxic, mutant diphtheria toxin (HbOC). Prior to vaccination, 40% of subjects had serum anti-PRP antibody levels < 1.0 microgram ml-1. Four weeks following vaccination, all subjects had concentrations > 1.0 microgram ml-1, a level generally considered to be protective. The post-vaccination geometric mean concentrations were 35.5 and 50.1 micrograms ml-1 for the PRP-OMP and HbOC groups, respectively (0.05 < P < 0.10). Subjects in the HbOC group, but not the PRP-OMP group, showed, on average, ten fold increases in IgG antibody to diphtheria toxoid after conjugate vaccination. Side-effects of vaccination were mild except in one subject given HbOC, who developed extensive erythema and swelling of the injected arm.

A variety of modifications of the living environment have been proposed as beneficial for minimizing the psychological and behavioral symptoms of dementia, as well as promoting maximal functional independence. Potential modifications include physical design elements such as wandering pathways, electronically controlled exits, and secured outdoor courtyards as well as alterations of other environmental components such as bright light exposure, ambient noise, music, and color. Interventions targeted at normalizing the circadian abnormalities found in dementia patients include modification of activity timing, exercise, light exposure, nocturnal darkness, and ambient temperature adjustment.

BACKGROUND

Medicare claims as the basis for health condition adjustments is becoming a method of choice in capitation reimbursement. A recent study has found that claims-based beneficiary classification for Alzheimer's disease produces lower prevalence estimates and higher average costs than previous healthcare cost studies in this population. These sets of studies differ in data sources, period length, and in their specification of dementia.

OBJECTIVES

Participants in the Medicare Alzheimer's Disease Demonstration (MADDE) provide a sample of persons known to have some form of dementia. This group is used to test the adequacy of claims data for identifying eligible cases and any bias in expenditure differences between those flagged or not flagged by a claim in a given period.

DESIGN

A prospective cohort design using up to 36 months of claims data.

SETTING

The demonstration enrolled 4166 participants in treatment, and 3942 in a control group in eight communities across the US. Cases were combined in this analysis.

PARTICIPANTS

Persons with available Medicare Part A & B claims data: those receiving care under fee for service reimbursement were used in the analysis. A total of 5379 MADDE cases received fee for service care during 1991 and 1992, the period of primary interest in the analysis.

MEASUREMENT

Client health and functional status interviews and Medicare Part A & B claims.

RESULTS

Less than 20% of MADDE participants were classified with Dementia of the Alzheimer type (DAT) from a single year of claims although 68% had a DAT diagnosis from a referring physician. Annualized expenditures were 1.7 times higher among those with DAT from claims compared with those known otherwise to have dementia but who had not been identified with this condition from Medicare claims.

CONCLUSION

Underclassification of dementia from claims records can be partially remedied by increasing the period during which claims are compiled, but additional diagnostic sources will likely be needed to increase prevalence counts closer to 100% of true cases. Risk adjustment based on a single year of reported claims expenditures may overpay providers, at least in the short term, because payment incentives will likely increase prevalence reporting.

BACKGROUND

Agitation includes wandering, crying out, abusive vocalization, and assaultive behavior and occurs in up to 70% of patients with dementia. Although the neuroleptic haloperidol has been used for decades to control disruptive behavior in psychotic and demented patients, the effectiveness of this drug for agitated dementia remains in question. The first meta-analysis on the effectiveness of haloperidol for agitated dementia, published in 1990, was limited in scope and was unable to provide clear guidelines for the use of haloperidol for demented patients who are agitated. Meta-analyses in 1998 and 2000 examined haloperidol compared with other neuroleptics as well as with placebo and omitted a number of databases, including non-English language publications. To determine the effect of haloperidol, compared with placebo, in the control of agitated dementia and to make recommendations for future research in this area a more widely based, yet more highly focussed review was carried out.

OBJECTIVES

The main objective was to determine whether evidence supports the use of haloperidol to treat agitation in demented patients.

SEARCH STRATEGY

The CDCIG Specialized Register was searched to identify all available reports on haloperidol treatment of agitated dementia.

SELECTION CRITERIA

We examined randomized, placebo-controlled trials, with concealed allocation, where subjects' dementia and agitation were assessed. Trials involving treatment of less than one week were not included.

DATA COLLECTION AND ANALYSIS

1. Two reviewers extracted data from included trials. 2. Data were pooled, where possible, and analysed using appropriate statistical methods. 3. Odds ratios or average differences were calculated. 4. Only 'intention to treat' data were included. Where a cross-over design was employed (Devanand, 1998), only the initial phase of the study was used to compare haloperidol versus placebo. 5. Sensitivity analysis was applied to heterogeneity of results and to gauge the effect of the included studies of small sample size. 6. In addition to the overall meta-analysis, individual analyses of the reports were carried out to examine the effect of degree of dementia, dose of haloperidol, and duration of therapy on agitated dementia. Analysis included the following groups: All patients treated with haloperidol compared with placebo.

MAIN RESULTS

There were five included trials. All studies stated "intention to treat" analysis of their results. Three studies were from the United States, and two studies were from Europe. Two studies examined patients with various forms of dementia, and three studies included only patients with diagnosed Alzheimer's dementia. 1. Overall meta-analysis of the response of agitated patients to haloperidol, compared with controls, showed no improvement in agitation. There is some evidence that haloperidol helps to control aggression. Adverse reactions and dropouts were more frequent among haloperidol treated patients, compared with controls. This meta-analysis provided no information about the relationship between the degree of dementia, the kind of agitation manifested, or the dosage and duration of therapy with haloperidol and response to treatment of demented patients with agitation. 2. The results of this meta-analysis were too broad to permit specific recommendations for treatment of agitated dementia with haloperidol. 3. Higher dose haloperidol, or prolonged haloperidol (12 weeks compared with 3 - 6 weeks) was associated with increased side effects, largely related to Parkinsonian symptoms of rigidity and bradykinesia.

REVIEWER'S CONCLUSIONS

1. Haloperidol appeared to provide no improvement in agitation among demented patients compared with placebo, but side effects were frequent. 2. Dropout rates were higher for haloperidol compared with placebo treated patients, suggesting that side effects led to discontinuation of treatment in some patients. 3. Because of the wide focus of this meta-analysis, not enough information was provided to permit recommendations linking haloperidol treatment of agitated dementia to degree of dementia, manifestations of agitation, or dosage and duration of treatment of haloperidol. 4. Individual analysis of reports indicated that higher dose haloperidol (more than 2 mg per day) may have been more effective than lower dose haloperidol (less than 2 mg per day) in controlling aggression, but not other manifestations of agitation, among patients with mild to moderate dementia. 5. Similar analysis suggested that prolonged therapy with haloperidol (more than 3 - 6 wks) or higher dosage (more than 2 mg per day) was more likely to result in side effects than were short term therapy (3 weeks) or lower dose haloperidol (less than 2 mg per day). 6. The reports provided too little information to permit interpretation of the effect of degree or type of dementia on response to haloperidol. Except for a favorable response of aggression to haloperidol, no other manifestations of agitated dementia were found to have improved following therapy with haloperidol, compared with controls.