CSF and serum concentrations of albumin and IgG in Alzheimer's disease.

Cerebrospinal fluid (CSF) and serum concentrations of albumin and immunoglobulin G (IgG) were measured in 31 patients with presumptive Alzheimer's disease (AD) and in 14 healthy control subjects. The albumin and IgG quotients, and IgG index were calculated to evaluate the permeability of the blood-brain barrier and the intrathecal production of immunoglobulins. X-ray computerized tomography (CT) of the head was performed to investigate the relation between cerebral atrophy and CSF protein concentrations. The albumin and IgG quotients, and the IgG index did not differ significantly between the AD and control groups. Cerebral atrophy, as measured by CSF volume, was not related to CSF protein concentrations in either group. The results do not support the hypothesized roles of blood-brain barrier disruption or of immunologically-mediated injury of the central nervous system in the pathogenesis of AD.

Neuroanatomical abnormalities in obsessive-compulsive disorder detected with quantitative X-ray computed tomography.

New brain imaging techniques may provide evidence for a biological basis for severe psychiatric disorders. The authors used quantitative X-ray computed tomography (CT) to analyze the brain volume of 10 male patients with severe primary obsessive-compulsive disorder and 10 healthy male control subjects. Caudate nucleus volume in the patients with obsessive-compulsive disorder was significantly less than that of control subjects, but lenticular nuclei, third ventricle, and lateral ventricle volumes did not differ between these two groups, and no abnormal asymmetry of bilateral structures was detected. These findings support other evidence of involvement of the caudate nucleus in obsessive-compulsive disorder.

Anatomic, metabolic, neuropsychological, and molecular genetic studies of three pairs of identical twins discordant for dementia of the Alzheimer's type.

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.

Rate of ventricular enlargement in dementia of the Alzheimer type correlates with rate of neuropsychological deterioration.

We studied twelve men and six women with dementia of the Alzheimer type (DAT) and twelve healthy men at intervals of 6 months to 5 years. In the male DAT patients, mean CT rates of enlargement of third ventricle and of total lateral ventricular volumes differed significantly from zero and exceeded respective control values (p less than 0.05). The rate of neuropsychological decline correlated with rates of enlargement of the third ventricle or right lateral ventricle. Women with DAT also had significant rates of enlargement of the third and total lateral ventricles. The rate of lateral ventricular dilatation discriminated DAT patients from controls.

Serial quantitative CT analysis of brain morphometrics in adult Down's syndrome at different ages.

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.

Cerebrospinal fluid monoamine markers are decreased in dementia of the Alzheimer type with extrapyramidal features.

We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls. Compared with concentrations in DAT and controls, the concentrations of homovanillic acid (HVA) and biopterin were significantly decreased in DAT with extrapyramidal signs (EDAT). CSF 3-methoxy-4-hydroxy-phenethyleneglycol and 5-hydroxyindoleacetic acid did not differ significantly among these groups. Age at onset of dementia was positively correlated with CSF HVA (r = 0.49, p less than 0.05). The two dementia groups did not differ significantly in the extent of ventricular dilation as measured by quantitative CT, but EDAT patients had lower Mini-Mental State Examination scores than did DAT patients. When patients were matched for age and dementia severity, CSF HVA and biopterin concentrations remained significantly lower in EDAT than in DAT patients. These results indicate that EDAT patients form a distinct subgroup of DAT with evidence of central monoamine dysfunction.

Digital and palmar dermatoglyphics in dementia of the Alzheimer type.

Digital and palmar dermatoglyphics were examined in 29 men and 27 women with dementia of the Alzheimer type (DAT) and 112 age-, sex-, and racial group-matched controls. Female patients had significantly (p less than 0.05) more accessory triradii and complete Sydney creases than controls; no dermatoglyphic differences were detected in the males. Separating the patients by age of onset prior to or after age 65 years did not help differentiate patients from controls by dermatoglyphic profile. This study failed to confirm either the previously reported dermatoglyphic differences between DAT patients and controls or the reported similarity of the dermatoglyphic pattern of DAT to that of Down syndrome patients.

The significance of age-related enlargement of the cerebral ventricles in healthy men and women measured by quantitative computed X-ray tomography.

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.

Misclassification and selection bias when identifying Alzheimer's disease solely from Medicare claims records.

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.

Quantitative X-ray computed tomography (CT) in dementia of the Alzheimer type (DAT).

Dementia of the Alzheimer type (DAT) has proven to be difficult to diagnose using computerized X-ray tomography (CT). To improve the identification of DAT with CT, several different quantitative approaches have been tried. Brain parenchymal density measurements and a variety of linear indices of ventricular size have failed to reliably separate DAT patients from age matched controls. Measures of ventricular volume improve discrimination, but overlap with controls persists. The inadequacy of a single CT study to diagnose DAT is clearly related to the overlap of brain atrophy in DAT and healthy aging, a finding which has also been noted in post-mortem studies. Estimating the rate of ventricular enlargement from quantitative measurements of ventricular size on successive CT scans may allow the physician to take advantage of the progressive nature of DAT, improving separation of DAT patients from healthy controls.

Cognitive impairment on a rehabilitation service.

Many techniques of rehabilitation require that the patient have intact cognition. This study determined the frequency of impaired cognition among the predominantly elderly patients on a community teaching hospital acute rehabilitation ward. The Cognitive Capacity Screening Examination (CCSE) was administered to 81 patients (ages 44 to 99, means 77, male:female 29:52). That 52 patients (64%) scored below 20 on the CCSE suggests significant cognitive impairment. The cognitively impaired patients were older than those with normal CCSE scores (p less than 0.05) and 19 patients had a prior history of chronic dementia. The physicians of 12 of the cognitively impaired patients (15% of all patients screened) were unaware of the impairment prior to their CCSE. Cognitively impaired patients scored similarly irrespective of a prior history of similar impairment (CCSE scores 10.2 +/- 1 for those without a prior history of dementia, 7.3 +/- 1.4 for those with prior dementia, p greater than 0.05). Physicians were more likely to be aware of a patient's current cognitive problems if the patient had a prior history of dementia (19/19 vs 21/33, p less than 0.01). The utility of employing a routinely administered CCSE to all patients accepted by a rehabilitation ward is emphasized. The time, cost, and effort of routinely performing such tests are negligible, and the potential benefits are considerable.

A quantitative study of intracranial calcification in dementia of the Alzheimer type.

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.

Phase I study of the immunogenicity and safety of conjugated Hemophilus influenzae type b vaccines in the elderly.

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.

Cerebral metabolism, anatomy, and cognition in monozygotic twins discordant for dementia of the Alzheimer type.

One pair of monozygotic twins discordant for dementia of the Alzheimer type (DAT) was studied using neuropsychological testing, quantitative x-ray computed tomography (QCT) and magnetic resonance imaging (MRI) of the brain. Cerebral glucose metabolism was measured using positron emission tomography (PET) and 2-[18-F]fluoro-2-deoxy-D-glucose (FDG). The affected twin had a seven year history of progressive cognitive impairment and was severely demented. Neuropsychological testing of the affected twin demonstrated marked deficits in all areas of cognitive function. The asymptomatic twin showed some impairment on tests of perceptual organisation and delayed recall. The affected twin had loss of gray matter and ventricular enlargement on QCT and MRI compared with healthy controls (p less than 0.05). He also had frontal and parietal lobe hypometabolism and increased asymmetry of metabolism on PET compared to both his twin and healthy age-matched controls (p less than 0.05). PET, QCT, and MRI distinguished changes in the twin with DAT compared with his brother and healthy controls. Although the subtle neuropsychological abnormalities of the asymptomatic twin may be signs of early DAT, they were not accompanied by any changes in regional cerebral metabolism or brain structure.