Noradrenergic changes, aggressive behavior, and cognition in patients with dementia.

BACKGROUND: We wished to examine the integrity of the noradrenergic system in patients with Alzheimer's disease, mixed/other dementias and controls, and possible relationships between changes in the noradrenergic system and the presence of behavioral and psychiatric signs and symptoms in dementia. METHODS: Alpha(2) adrenoceptor sites were measured by radioligand binding in three cortical regions of 46 individuals with dementia and 33 elderly normal controls together with cortical noradrenaline concentration and locus coeruleus cell and neurofibrillary tangle counts. RESULTS: The alpha(2) adrenergic receptor density was unaltered in patients with Alzheimer's disease, mixed/other dementias compared with controls; however, there was a loss of locus coeruleus cells in subjects with dementia, reaching 50% within the rostral nucleus. In addition, a significant reduction was seen in the midtemporal cortical noradrenaline concentration (31% decrease) in patients with Alzheimer's disease. In subjects with dementia, there was a positive correlation between aggressive behavior and magnitude of rostral locus coeruleus cell loss, while the reduction in noradrenaline concentration correlated with cognitive impairment. CONCLUSIONS: Subgroups of patients with Alzheimer's disease may have different neurochemical changes from patients lacking these changes. Therefore, this study may have implications for the treatment of behavioral and psychiatric signs and symptoms in dementia, particularly aggressive behavior in patients with dementia.

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease.

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.

Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients.

Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.

Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease.

Previous studies have implicated brain serotonin 5-HT(1A) receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT(1A) receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT(1A) receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [(3)H]8-OH-DPAT binding assays. 5-HT(1A) receptor binding affinity (K(D)) and density (B(max)) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT(1A) receptor B(max) in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT(1A) receptor B(max) remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT(1A) receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT(1A) receptors as a pharmacological target for the treatment of behavioral symptoms in AD.

A serotoninergic basis for hyperphagic eating changes in Alzheimer's disease.

Hyperphagia and associated eating changes occur frequently in Alzheimer's disease (AD) and lead to considerable morbidity. However, the neurochemical basis for these neuropsychiatric behaviours is at present unclear. In this study, we measured serotonin transporters, 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors using radioligand binding assays in the postmortem temporal cortex of a cohort of controls and AD patients longitudinally assessed for hyperphagia. We found significant decreases in 5-HT(4) receptor densities in the hyperphagic, but not normophagic, AD group. Our data suggest that 5-HT(4) receptor deficits may be a specific neurochemical correlate of hyperphagia, and point to the potential pharmacotherapeutic utility of 5-HT(4) agonists for these behaviours in AD.

Risk factors for hospital admission related to excessive and/or prolonged postpartum vaginal blood loss after the first 24 h following childbirth.

A population case-control study was used to determine risk factors for excessive and/or prolonged vaginal bleeding (described collectively as vaginal loss problems) and uterine infection from 24 h to 3 months postpartum. Data were obtained from women whose maternity care took place in one of two health districts in the south of England. The cases were women remaining in or admitted to hospital with excessive or prolonged vaginal blood loss from 24 h to 3 months postpartum. Two controls for each case were identified; these were women whose delivery was the nearest in time and in the same location as the case delivery. Medical and midwifery records were searched retrospectively to cover hospital admissions for vaginal blood loss problems or uterine infection in postpartum women from 1 January 1994 to 31 December 1995. Data were analysed for 243 cases and 486 controls. Univariable analysis identified 28 variables associated with being a case. Using multivariable analysis, nine factors remained in the final model, with a history of secondary postpartum haemorrhage (PPH) being the most strongly predictive (OR [95% confidence interval] 6.0 [2.1, 16.8]). Vaginal bleeding prior to 24 weeks' gestation (OR 3.0 [1.6, 5.9]), third trimester hospital admission (OR 2.0 [1.4, 2.8]), maternal smoking (OR 2.7 [1.8, 3.9]), a prolonged (OR 3.1 [1.2, 7.5]) or incomplete third stage (OR 2.1 [1.0, 4.4]), and primary PPH (OR 4.7 [1.9, 11.6]) for blood loss >500 mL, were predictive of becoming a case. No significant association was identified for parity (OR 1.1 [0.8, 1.5]) or method of delivery, spontaneous (OR 1.0 [0.7, 1.3]), instrumental (OR 1.4 [0.9, 2.2]) or operative (OR 1.2 [0.8, 1.9]). This is a neglected area of women's health after childbirth, and the value of this study is in the identification of potential risk factors for postpartum morbidity related to vaginal blood loss. Where morbidity occurs, early diagnosis, management and treatment are likely to reduce its extent or duration. It is considered that raising awareness about these factors, both among healthcare professionals and women themselves, may play an important part in the recognition and treatment of postpartum morbidity.