A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice.

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic ß-amyloid protein 42 (Aß42) to Aß40. Because of its neurotoxicity, Aß42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aß40 has neuroprotective effects against Aß42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aß42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aß42-to-Aß40-converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/- mice and found that a decrease in ACE levels promoted Aß42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Is obesity associated with a decline in intelligence quotient during the first half of the life course?

Cross-sectional studies have found that obesity is associated with low intellectual ability and neuroimaging abnormalities in adolescence and adulthood. Some have interpreted these associations to suggest that obesity causes intellectual decline in the first half of the life course. We analyzed data from a prospective longitudinal study to test whether becoming obese was associated with intellectual decline from childhood to midlife. We used data from the ongoing Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort study of 1,037 children in New Zealand who were followed prospectively from birth (1972-1973) through their fourth decade of life with a 95% retention rate. Intelligence quotient (IQ) was measured in childhood and adulthood. Anthropometric measurements were taken at birth and at 12 subsequent in-person assessments. As expected, cohort members who became obese had lower adulthood IQ scores. However, obese cohort members exhibited no excess decline in IQ. Instead, these cohort members had lower IQ scores since childhood. This pattern remained consistent when we accounted for children's birth weights and growth during the first years of life, as well as for childhood-onset obesity. Lower IQ scores among children who later developed obesity were present as early as 3 years of age. We observed no evidence that obesity contributed to a decline in IQ, even among obese individuals who displayed evidence of the metabolic syndrome and/or elevated systemic inflammation.

Predicting work outcome in patients with schizophrenia: Influence of IQ decline.

BACKGROUND: Patients with schizophrenia show various trajectories in intelligence. However, whether the degree of IQ decline is associated with functional outcomes remains unclear. The purposes of the study were 1) to determine whether IQ decline was related with work outcome, and 2) to perform predictions for attaining a certain amount of work measured by work hours. METHODS: One hundred and forty patients with schizophrenia and 156 healthy volunteers enrolled in the study. The patients were classified into the deteriorated group or preserved group based on the degree of IQ decline. In addition to current and premorbid intelligence, functional outcomes and clinical conditions were also evaluated. Those variables were compared among the patient groups and healthy adults to select independent variables for logistic regression analyses. Four separate logistic regression analyses were conducted with work hours dichotomized by four criteria (0, 10, 20, or 30 h per week) as dependent variables. RESULTS: IQ decline remained significant in all regression models except the model with the 30 h per week criterion. Social function and psychiatric symptoms were also prominent factors in most models. Predictions were more accurate in the models with higher criteria. Individual probabilities to exceed each criterion were presented based on the equations derived from the regression models. CONCLUSION: Intellectual deterioration, in addition to impaired social function and psychiatric symptoms, may play a key role in work disturbances in patients with schizophrenia. Probability models presented here have strengths in evaluating the ability to work from statistical, clinical, and theoretical viewpoints.

Premorbid adjustment predictors of cognitive dysfunction in schizophrenia.

Premorbid adjustment (PA) in academic and social domain is a key-predictor of cognitive performance in schizophrenia. Prior studies provided inconsistent findings regarding the differential relationships of PA domains with post-illness cognition. Multivariate associations of academic and social PA in each developmental stage (childhood, early and late adolescence) with post-onset cognitive variables were explored. Furthermore, possible differential relationships of PA domain deterioration courses with post-onset cognitive dysfunction were investigated. Seventy-five schizophrenia patients were evaluated with Premorbid Adjustment Scale (PAS). General cognitive ability, verbal IQ, verbal memory and learning, processing speed, working memory, executive function and premorbid IQ were assessed. Canonical Correlation Analyses revealed that poorer academic PA across childhood and early adolescence was related to worse post-onset verbal IQ, working memory, verbal learning and executive function, while academic PA deterioration between early and late adolescence was associated with poorer verbal learning and executive function and, as further analysis indicated, predicts IQ decline. Academic PA was exclusively associated with post-onset cognitive impairment. New evidence emerged for the specificity of each developmental period in constructing academic PA in its relation to post-illness cognition. Early premorbid academic maladjustment possibly constitutes the onset of a cognitive dysmaturational process which results to post-diagnosis impaired cognition.