Publications

Quantitative CT demonstrated increased CSF and 3rd ventricular volumes, and decreased gray matter and white matter volume, in older (greater than 45 years) Down's syndrome (DS) adults with dementia as compared with younger DS adults. Serial CT studies repeated after periods of up to 2 years demonstrated significant progressive cerebral atrophy. Older DS adults without dementia, but with cognitive decline, did not show cerebral atrophy as compared with young DS subjects. These results suggest brain atrophy must be present to accompany dementia in older DS subjects, despite the presence of Alzheimer's disease neuropathology in all older subjects. The Alzheimer's disease process in DS may occur in 2 stages, the 1st with neuropathology and cognitive decline, the 2nd with additional cerebral atrophy and dementia.

Abnormalities in calcium homeostasis have been reported in Alzheimer's disease (AD) and in the neurofibrillary tangle disorders of amyotrophic lateral sclerosis and parkinsonism-dementia occurring in the Pacific. In order to more fully evaluate calcium physiology in AD, we analyzed the size of pineal and choroid plexus calcifications, using X-ray computed tomography, in 23 patients with probable AD and 18 healthy age-matched control subjects. The area occupied by calcification was measured from hard copies of the data by two independent observers who were blind to the diagnosis. There were no differences in the areas occupied by pineal or choroid plexus calcifications between the two groups. These data suggest that AD is not accompanied by alternations in intracranial calcium deposition in pineal gland or choroid plexus.

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.