Plasma F2-isoprostane level and cognitive function over eight years in non-demented older adults: Findings from the Health ABC Study.

F2-isoprostanes (F2-IsoP) are reportedly increased in dementia patients, and are considered a reliable biomarker of oxidation. However, few studies have examined the predictive value of peripheral F2-IsoP levels in non-demented older adults. This study assesses the association between plasma F2-IsoP and change in cognitive function in non-demented elderly over eight years. Plasma F2-IsoP was measured by gas chromatography-mass spectrometry in a biracial cohort of 726 elderly men and women. Digit Symbol Substitution test and the Modified Mini-Mental State Exam were administered over time. No association was found between F2-IsoP tertile and baseline or change (slope) in cognitive function over eight years. Plasma F2-IsoP is not a valuable biomarker in predicting cognitive change over years in non-demented older adults.

COMT genotype and cognitive function: an 8-year longitudinal study in white and black elders.

OBJECTIVE: Catechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for cognitive function. Few studies have examined the prospective association between COMT (val(158)met) genotype and cognition in older adults. METHODS: We assessed a biracial cohort of 2,858 elderly subjects without dementia who were followed for 8 years. The Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) were administered at baseline and years 3, 5, and 8. COMT by race, gender, and APOE status interactions were examined. RESULTS: Stratified by race and adjusted for covariates, repeated-measures mixed-effects models showed no association between COMT genotype and baseline cognitive function in black or white subjects. In white subjects, COMT was associated with change in 3MS (Met/Met: -2.3 [0.60], Met/Val: -1.7 [0.40], and Val/Val: -1.2 [0.50]) and DSST (Met/Met: -5.60 [1.00], Met/Val: -4.80 [0.70], Val/Val: -4.00 [0.90]). In black subjects, COMT was associated with change in the DSST (Met/Met: -4.10 [2.1], Met/Val: -4.80 [0.90], Val/Val -2.60 [1.00]). CONCLUSION: These findings suggest that the Val allele has a protective impact on cognitive decline in late life.

Predictors of maintaining cognitive function in older adults: the Health ABC study.

BACKGROUND: Although several risk factors for cognitive decline have been identified, much less is known about factors that predict maintenance of cognitive function in advanced age. METHODS: We studied 2,509 well-functioning black and white elders enrolled in a prospective study. Cognitive function was measured using the Modified Mini-Mental State Examination at baseline and years 3, 5, and 8. Random effects models were used to classify participants as cognitive maintainers (cognitive change slope > or = 0), minor decliners (slope < 0 and > 1 SD below mean), or major decliners (slope < or = 1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner. RESULTS: Over 8 years, 30% of the participants maintained cognitive function, 53% showed minor decline, and 16% had major cognitive decline. In the multivariate model, baseline variables significantly associated with being a maintainer vs a minor decliner were age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55-0.77 per 5 years), white race (OR = 1.72, 95% CI 1.30-2.28), high school education level or greater (OR = 2.75, 95% CI 1.78-4.26), ninth grade literacy level or greater (OR = 4.85, 95% CI 3.00-7.87), weekly moderate/vigorous exercise (OR = 1.31, 95% CI 1.06-1.62), and not smoking (OR = 1.84, 95% CI 1.14-2.97). Variables associated with major cognitive decline compared to minor cognitive decline are reported. CONCLUSION: Elders who maintain cognitive function have a unique profile that differentiates them from those with minor decline. Importantly, some of these factors are modifiable and thus may be implemented in prevention programs to promote successful cognitive aging. Further, factors associated with maintenance may differ from factors associated with major cognitive decline, which may impact prevention vs treatment strategies.

Influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on stress markers in older adults: a 3-year study.

The present study examined the influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on GC secretion, cognition and personality in 66 healthy older adults. These particular variables were chosen given that they have been shown to be associated with human stress (i.e.stress markers). Measures included basal serum GC levels and cognitive scores on declarative memory obtained annually over 3 years. Also, self-esteem, neuroticism and depression were evaluated. Results showed that participants with the APOE E4-BCHE K variant (E4-K group) present increased basal levels of GCs and poorer cognitive performance when compared to non-carriers of these variants. In addition, the E4-K group reported lower self-esteem and higher levels of depression. These findings may indicate a genotype effect on markers of stress and cognitive integrity years before symptoms of dementia are apparent.

How valuable are animal models in defining antidepressant activity?

Animal models of depression have been utilised to screen novel compounds with antidepressant potential although uncertainty lingers concerning their clinical relevance. In order for a model to be considered of any value, it must possess predictive validity (does drug action in the model correspond to that in the clinic?), face validity (are there phenomenological similarities between the model and the clinic?) and construct validity (does the model possess a strong theoretical rationale?). On the one hand, there are models based on stress such as the learned helplessness model, the forced swimming test and the chronic mild stress model and, on the other hand, models based on neuronal deficits such as the olfactory bulbectomy model. To date, among models more frequently used in depression, none of them meet all these criteria. Moreover, improvements to tests are often poorly validated and estimating time of onset of action of antidepressants remains a major challenge in animal model research. Finally, reproducing the tests outside the laboratory of origin continues to be problematic and leads to variability in results. Although animal models of depression fail to be unequivocally valid, they represent the best tool to define potential antidepressant activity of drugs, to investigate their mechanism of action and, to a greater extent, explore this complex heterogeneous illness. Copyright 2001 John Wiley & Sons, Ltd.

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.

Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice.

The four-plate test (FPT) is an animal model of anxiety based on stress caused by unconditioned fear. An increase of spontaneous punished behavior was used as a measure to determine the anxiolytic effects of various antidepressants (ADs). In the present study. ADs with different mechanisms of action, including tricyclics, selective serotonin reuptake inhibitors (SSRIs), a monoamine oxidase inhibitor (MAOI), and atypicals, were studied in the FPT to evaluate their anxiolytic-like effects following acute administration. The number of punished crossings was dramatically increased by the SSRIs citalopram, fluvoxamine, and paroxetine, but not fluoxetine. The mixed 5-HT/NE reuptake inhibitors, milnacipran and venlafaxine, also demonstrated strong antipunishment effects. The specific NE reuptake inhibitors, desipramine and maprotiline, and the atypical AD trazodone, enhanced freezing behavior, suggesting anxiogenic-like behavior. It was concluded that, in the FPT, a model based on spontaneous response, where animals are exposed to an aversive environment from which they can only escape by being motionless, this kind of behavior might be related to anticipatory anxiety. In this situation, ADs acting preferentially on 5-HT transmission possessed clear anxiolytic like effects. The balance between the two transmitters, 5-HT and NE, seemed to be a crucial factor.