Janet Keene

Predictors of institutionalization for people with dementia living at home with a carer.

Objective. This article examines the relationships between behaviour, psychological functioning, the caring environment and subsequent institutionalization in patients with dementia living at home with a carer.

Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up.

Abstract Objective: To investigate the contribution of neuroleptic drugs to cognitive decline in dementia. Design: Two year prospective, longitudinal study consisting of interviews every four months, with necropsy follow up. Setting: Community settings in Oxfordshire. Subjects: 71 subjects with dementia, initially living at home with informant. Main outcome measures: Cognitive function (score from expanded minimental state examination); behavioural problems (physical aggression, hallucinations, persecutory ideas, and disturbance of diurnal rhythm); and postmortem neuropathological assessment (cortical Lewy body pathology). Results: The mean (SE) decline in cognitive score in the 16 patients who took neuroleptics was twice that in the patients who did not (20.7 (2.9) v 9.3 (1.3), P=0.002). An increased rate of decline was also associated with aggression, disturbed diurnal rhythm, and persecutory ideas. However, only use of neuroleptics and severity of persecutory ideas were independently associated with more rapid cognitive decline when all other variables were adjusted for. The start of neuroleptic treatment coincided with more rapid cognitive decline: median rate of decline was 5 (interquartile range 8.5) points per year before treatment and 11 (12) points per year after treatment (P=0.02). Cortical Lewy body pathology did not account for association between neuroleptic use and more rapid decline. Conclusions: Neuroleptic drugs that are sometimes used to treat behavioural complications of dementia may worsen already poor cognitive function. Randomised controlled trials are needed to confirm a causal relation. Key messages Neuroleptic drugs are used to treat behavioural problems in patients with dementia, but they may cause more rapid decline in cognitive function In our longitudinal study of patients with dementia we found that the rate of cognitive decline in patients taking neuroleptics was twice that in those not taking neuroleptics Furthermore, the start of neuroleptic treatment was associated with an increase in the rate of cognitive decline Cortical Lewy body pathology at necropsy did not account for the association between neuroleptic use and more rapid decline Although our study does not prove a causal relation, we suggest that there should be regular review of the need for patients to continue taking neuroleptic drugs

Cholinergic deficits contribute to behavioral disturbance in patients with dementia

Background: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness. Method:— Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs. Results: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior. Conclusions: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.–1467

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

BACKGROUND We wished to examine the integrity of the noradrenergic system in patients with Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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.

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.

Psychosis of Alzheimer’s disease is associated with elevated muscarinic M2 binding in the cortex

Objectives: Results from recent drug trials suggest a role for the cholinergic system in the manifestation of neuropsychiatric symptoms in AD. To date, the status of muscarinic acetylcholine receptor subtypes in AD in relation to accompanying behavioral disturbances is unknown. This study aimed to measure alterations of muscarinic M1 and M2 receptor binding in the frontal and temporal cortex of AD and to correlate the neurochemical findings with clinical features. Methods: The cognitive and behavioral features of 26 patients with AD were assessed prospectively using standardized tests. Together with 14 matched controls, the status of muscarinic M1 and M2 receptors in the postmortem frontal and temporal cortex of these patients were measured by radioligand binding assays and were correlated with clinical data. Results: Compared with controls, M2 receptor density was reduced only in the frontal cortex of AD, whereas M1 was unaffected. Within the AD group, the neurochemical variables were not affected by demographic factors, disease severity, or cognition. Instead, M2 receptor density was increased in the frontal and temporal cortex of patients with AD with psychotic symptoms compared with those without these symptoms. Conclusions: This study suggests a role for M2 receptors in the psychosis of AD and may provide the rationale for treatment of behaviorally perturbed patients with AD with cholinomimetics and M2 antagonists.

Behaviour changes in dementia 2: Are there behavioural syndromes?

Objective. To establish whether robust behavioural ‘syndromes’ can be identified from among the widely heterogeneous behavioural changes which occur in dementia.

Behaviour changes in dementia. 1: Point of entry data of a prospective study

Objective. This article analyses behaviour changes in dementia at the point of entry to a longitudinal study.

Natural history of aggressive behaviour in dementia.

This article analyses changes in aggressive behaviour throughout the course of dementia.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RationalePrevious studies have demonstrated reductions of serotonin 5-HT2A receptors in the neocortex of Alzheimer’s disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD.ObjectivesTo correlate neocortical 5-HT2A receptor alterations with cognitive decline in AD.MethodsPostmortem frontal and temporal cortical 5-HT2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms.Results5-HT2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms.ConclusionsOur data suggest that loss of neocortical 5-HT2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.