Longitudinal assessment of aggression and circadian rhythms in the APPswe mouse model of Alzheimer`s disease.

Agitation, which comprises verbal or physical aggression and hyperactivity, is one of the most frequent neuropsychiatric symptoms observed in patients with Alzheimer's disease (AD). It often co-occurs with dysregulated circadian rhythms. Current medications are associated with serious adverse effects, and novel therapeutics are therefore needed. Rodent models can be instrumental to provide a first signal for potential efficacy of novel drug candidates. Longitudinal data assessing the face validity of such models for AD-related agitation are largely missing. We employed telemeterized APPswe mice, a frequently used AD transgenic mouse line overexpressing the human beta-amyloid precursor protein (APP) with the Swedish KM670/671NL mutation, to study the occurrence and progression of changes in reactive aggressive behavior as well as the circadian profile of locomotor activity and body temperature. Analysis was conducted between 5 and 11 months of age, at regular 2-months intervals. The aggressivity of all mice was highest at 5 months and waned with increasing age. APPswe mice were more aggressive than WT at 5 and 7 months of age. The locomotor activity and body temperature of WT mice declined with increasing age, while that of APPswe mice remained rather constant. This genotype difference was solely evident during the active, dark phase. APPswe mice did not display a phase shift of their circadian rhythms. We conclude that the APPswe mouse line can recapitulate some of the behavioral disturbances observed in AD, including an agitation-relevant phenotype characterized by active phase hyperactivity and aggressivity. It does not recapitulate the nighttime disturbances (also characterized by hyperactivity) and the shift of circadian rhythms observed in AD patients. Therefore, the APPswe strain could be used at specific ages to model a subset of agitation-relevant behavioral problems and to test the modulatory effects of drugs.

Impact of hyperkalaemia definition on incidence assessment: implications for epidemiological research based on a large cohort study in newly diagnosed heart failure patients in primary care.

BACKGROUND: Various definitions of hyperkalaemia have been used in clinical research, and data from routine clinical practice on its incidence are sparse. We aimed to establish the incidence of hyperkalaemia in patients with newly diagnosed heart failure in the UK general population using different definitions for the condition. METHODS: We conducted a large retrospective cohort study using data from The Health Improvement Network primary care database. Patients with newly diagnosed heart failure (N = 19,194) were identified and followed until the first occurrence of hyperkalaemia. Different serum potassium (K(+)) thresholds were evaluated as possible definitions for hyperkalaemia, and incidence rates (IRs) calculated using a final operational definition both overall and among patient sub-groups. RESULTS: IRs of hyperkalaemia ranged from 0.92-7.93 per 100 person-years according to the definition. Based on considerable differences in the serum K(+) normal range used between practices, 2176 (11.3 %) individuals were identified with a record of hyperkalaemia using our operational definition of a proportional increase of ≥10 % above the upper bound of the normal range: IR 2.90 per 100 person-years (95 % CI 2.78-3.02) over a mean follow-up of 3.91 years. Incidence rates were higher in older patients, and in those with diabetes or renal impairment. CONCLUSIONS: Hyperkalaemia is a common finding in heart failure patients in primary care, but its incidence can vary nearly ten-fold depending on its definition. Since assessment of hyperkalaemia risk is essential for therapeutic decision making in heart failure patients, this finding warrants consideration in future epidemiological studies.

Incidence and risk factors for atrial fibrillation in patients with newly diagnosed heart failure.

AIMS: We aimed to identify the incidence and risk factors for first ever atrial fibrillation among patients with newly diagnosed heart failure following initial heart failure diagnosis. METHODS: A heart failure inception cohort of patients aged 20-89 years without atrial fibrillation or cancer (N = 14 457) from 2000 to 2005 was identified from The Health Improvement Network primary care database in the United Kingdom and followed for a mean of 2.67 years. First ever cases of atrial fibrillation were identified and controls (N = 3000) were frequency matched to cases by age and sex. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: One thousand four hundred and eighty-nine patients (10.3%) developed a first episode of atrial fibrillation: incidence rate 27.3/1000 person-years. A three-fold increased risk of atrial fibrillation was seen in the first 6 months after heart failure diagnosis, OR 3.62 (95% CI: 2.97-4.42) with the risk decreasing thereafter. Other risk factors were excessive alcohol consumption (OR 2.91, 1.60-5.30) and valvular heart disease (OR 1.98, 1.63-2.40) and use of oral steroids (OR 1.76, 95% CI: 1.40-2.22). Reduced risks of atrial fibrillation were found with use of statins (OR 0.65, 95% CI: 0.56-0.76) and ß-blockers (OR 0.78, 95% CI: 0.67-0.91). CONCLUSIONS: The incidence of first ever atrial fibrillation among newly diagnosed heart failure patients is high, especially in the first 6 months after diagnosis. This time relationship, together with the identified risk factors for atrial fibrillation, warrants consideration in the medical care of patients with heart failure.