Postmortem examination was performed on 137 residents (average age 85.5 years) of a skilled nursing facility whose mental status, memory, and functional status had been evaluated during life. Seventy-eight percent were demented using conservative criteria; 55% had characteristic Alzheimer's disease. Choline acetyltransferase and somatostatin were significantly reduced in the brains of patients with Alzheimer's disease as compared with age-matched nursing home control subjects, although the degree of the reduction was less severe than found in subjects less than 80 years of age. Ten subjects whose functional and cognitive performance was in the upper quintile of the nursing home residents, as good as or better than the performance of the upper quintile of residents without brain pathology (control subjects), showed the pathological features of mild Alzheimer's disease, with many neocortical plaques. Plaque counts were 80% of those of demented patients with Alzheimer's disease. Choline acetyltransferase and somatostatin levels were intermediate between controls and demented patients with Alzheimer's disease. The unexpected findings in these subjects were higher brain weights and greater number of neurons (greater than 90 micron 2 in a cross-sectional area in cerebral cortex) as compared to age-matched nursing home control subjects. These people may have had incipient Alzheimer's disease but escaped loss of large neurons, or alternatively, started with larger brains and more large neurons and thus might be said to have had a greater reserve.

A 6-item Orientation-Memory-Concentration Test has been validated as a measure of cognitive impairment. This test predicted the scores on a validated 26-item mental status questionnaire of two patient groups in a skilled nursing home, patients in a health-related facility, and in a senior citizens' center. There was a positive correlation between scores on the 6-item test and plaque counts obtained from the cerebral cortex of 38 subjects at autopsy. This test, which is easily administered by a nonphysician, has been shown to discriminate among mild, moderate, and severe cognitive deficits.

We have prospectively followed over a 5-year period 434 volunteers who were at intake ambulatory, functional, presumably nondemented, and between 75 and 85 years of age. Fifty-six (an incidence of 3.53 per 100 person-years at risk) developed a progressive dementia: 32 met diagnostic criteria for Alzheimer's disease (AD) (an incidence of 2.0 per 100 person-years at risk), 15 had vascular or mixed dementia, and 9 had other disorders or remain undiagnosed. New cases of dementia were as common as myocardial infarction and twice as common as stroke. Risk factors for both dementia and AD were age (over 80) and gender (female); other reported risk factors such as family history, prior head injury, thyroid disease, maternal age, and smoking were not risk factors for AD in this elderly cohort. Prior stroke was the major risk factor for vascular or mixed dementia; diabetes and left ventricular hypertrophy but not a history of hypertension per se were also risk factors for vascular dementia. The major predictor of the development of AD was the mental status score on entry. The 58.5% of the cohort who made zero to two errors on a 33-item mental status test had a less than 0.6% per year chance of developing AD, whereas the 16% of the cohort with five to eight errors on this test developed AD at a rate of over 12% per year. Thus, it is possible to identify a large cohort of 80-year-olds who are at low risk for AD and a smaller cohort at very high risk.

We showed previously that brief footshock stress and priming injections of heroin reinstate heroin-seeking after prolonged drug-free periods. Here, we examined whether the adrenal hormone, corticosterone, and brain corticotropin-releasing factor (CRF) were involved in such reinstatement. We tested the effects of adrenalectomy, chronic exposure to the corticosterone synthesis inhibitor metyrapone (100 mg/kg, s.c., twice daily), acute exposure to metyrapone, acute intracerebroventricular injections of CRF (0.3 and 1.0 microgram), and intracerebroventricular injections of the CRF antagonist alpha-helical CRF (3 and 10 micrograms). Rats were trained to self-administer heroin (100 micrograms/kg/infusion, i.v.) for 12-14 d. Extinction sessions were given for 4-8 d (saline substituted for heroin). Tests for reinstatement were given after priming injections of saline and of heroin (0.25 mg/kg, s.c.), and after intermittent footshock (15 or 30 min, 0.5 mA). Adrenalectomy (performed after training) did not affect reinstatement by heroin but appeared to potentiate the reinstatement by footshock. Chronic exposure to metyrapone (from the beginning of extinction) or an acute injection of metyrapone (3 hr before testing) did not alter the reinstatement of heroin-seeking induced by footshock or heroin. Acute exposure to metyrapone alone potently reinstated heroin-seeking. In addition, acute exposure to CRF reinstated heroin-seeking, and the CRF antagonist alpha-helical CRF attenuated stress-induced relapse. The effect of the CRF antagonist on reinstatement by heroin was less consistent. These results suggest that CRF, a major brain peptide involved in stress, contributes to relapse to heroin-seeking induced by stressors.

Epithelial ovarian cancer is the most lethal gynecological malignancy, and disease-specific biomarkers are urgently needed to improve diagnosis, prognosis, and to predict and monitor treatment efficiency. We present an in-depth proteomic analysis of selected biochemical fractions of human ovarian cancer ascites, resulting in the stringent and confident identification of over 2500 proteins. Rigorous filter schemes were applied to objectively minimize the number of false-positive identifications, and we only report proteins with substantial peptide evidence. Integrated computational analysis of the ascites proteome combined with several recently published proteomic data sets of human plasma, urine, 59 ovarian cancer related microarray data sets, and protein-protein interactions from the Interologous Interaction Database I 2 D (http://ophid.utoronto.ca/i2d) resulted in a short-list of 80 putative biomarkers. The presented proteomics analysis provides a significant resource for ovarian cancer research, and a framework for biomarker discovery.