Jonathan H. Williams

Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer’s disease

Background: Although epidemiological, clinical, and experimental evidence indicates that the inducible isoform of cyclo-oxygenase (COX-2) may be involved in the pathogenesis of several neurodegenerative disorders, the mechanisms whereby COX-2 contributes to Alzheimer’s disease are largely unknown. Objective: To undertake a longitudinal study of CSF levels of a major product of COX activity, prostaglandin E2 (PGE2), in relation to cognitive decline and survival in patients with Alzheimer’s disease. Methods: CSF PGE2 was measured on at least three annual visits in 35 controls and 33 Alzheimer patients (26 necropsy confirmed) who completed the Cambridge cognitive assessment (CAMCOG). Results: Compared with controls, CSF PGE2 was higher in patients with mild memory impairment, but lower in those with more advanced Alzheimer’s disease. The median survival time of patients with higher initial PGE2 levels was five years longer than those with lower levels. Conclusions: COX activity in Alzheimer’s disease varies with stage of the disease. PGE2 levels correlate positively with patient survival. These findings suggest that inhibition of COX activity does not represent a major target for the pharmacological treatment of Alzheimer’s disease.

Haloperidol enhances latent inhibition in visual tasks in healthy people

Abstract We have previously shown that 0.5mg haloperidol (IV) increased latent inhibition in one of two visual tasks. The present study analysed the effects of a higher dose of haloperidol (1.0 mg, IV) on latent inhibition in these two visual tasks in healthy volunteers in a randomised controlled trial. In the task where 0.5 mg haloperidol had enhanced latent inhibition, 1.0 mg had the same effect, thus replicating the previous result. In the task where 0.5 mg haloperidol had been ineffective, 1.0 mg haloperidol enhanced latent inhibition in high schizotypal subjects only. This indicates that subjects with higher schizotypy scores are more sensitive to dopamine blockade. A comparison of the results from the studies at the two different doses suggests a dose dependence of haloperidol’s effects on latent inhibition that parallels results from animal work.

Effects of tobacco smoking, schizotypy and number of pre-exposures on latent inhibition in healthy subjects

Abstract Latent inhibition is a slowing of learning about a stimulus that when previously experienced had no consequences. This study investigated the effects of tobacco smoking and personality traits on a latent inhibition task. Two-hundred and five healthy adults performed an auditory masking task during which half of them were pre-exposed to bursts of white noise. All subjects were then asked to detect an association of the white noise with a change on a computer screen. Subjects who had heard the white noises before were slower to learn the association than subjects who had not, i.e. they showed latent inhibition. Latent inhibition was stronger when subjects were pre-exposed to 10 rather than 6 bursts of white noise. Latent inhibition was reduced in subjects who smoked tobacco and in non-smoking subjects who scored highly on a schizotypy questionnaire. These two effects were independent. We conclude that tobacco smoking should be taken into account in interpreting the results of human latent inhibition studies.

5,7-Dihydroxytryptamine lesions in the fornix—fimbria attenuate latent inhibition

When animals are preexposed to a stimulus without consequence they are subsequently slower to associate this stimulus with an important event, such as footshock. This retarding effect of stimulus preexposure is called latent inhibition and can be demonstrated in a variety of classical and instrumental paradigms and in a wide range of species, including man. Latent inhibition is disrupted in acute schizophrenics and by amphetamine treatment in both rat and man. The present study investigated the role of hippocampal 5HT terminals in latent inhibition using a conditioned suppression procedure with male Sprague-Dawley rats. Microinjections of 5,7-dihydroxytryptamine in the fornix-fimbria significantly reduced hippocampal indoleamine levels and attenuated latent inhibition of conditioned suppression. This finding supports the hypothesis that the destruction of mesolimbic 5-hydroxytryptamine terminals reduces latent inhibition. This result is discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder. In addition to the predicted lesion effect, biochemical analyses indicated that experimental treatments in the latent inhibition procedure altered neurotransmitter turnover: utilization ratios for 5-hydroxytryptamine and/or dopamine were increased in preexposed relative to nonpreexposed animals in four of the six brain regions sampled.

Antipsychotic drug effects in a model of schizophrenic attentional disorder: A randomized controlled trial of the effects of haloperidol on latent inhibition in healthy people

We studied the effects of haloperidol (0.5 mg, intravenously) on latent inhibition in an auditory paradigm and two visual paradigms in healthy subjects. Haloperidol increased latent inhibition in one visual paradigm and tended to increase latent inhibition in an auditory task, compared to saline-injected controls. These results indicate that haloperidol can enhance the selectivity of attention. In contrast, previous studies have reported that acute schizophrenics show reduced latent inhibition.

TOBACCO SMOKING CORRELATES WITH SCHIZOTYPAL AND BORDERLINE PERSONALITY TRAITS

Abstract We analysed relationships between tobacco smoking and schizotypal or borderline personality traits. Three-hundred and sixty healthy adults gave information about their smoking habits and completed a computerised personality questionnaire. Schizotypal and borderline traits correlated with tobacco smoking. These correlations remained significant in analyses which covaried age, gender, educational level, neuroticism and psychoticism. The associations of tobacco smoking with schizotypal and borderline traits may illuminate the relationships of smoking and schizotypy with clinical disorders, such as schizophrenia.

Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex

The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimers disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.

Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia

BackgroundAdvanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimers type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.MethodsBrain Sections from 25 cases of the OPTIMA (Oxford Project to Investigate Memory and Ageing) cohort, with varying degrees of cerebrovascular pathology and cognitive dysfunction (but only minimal Alzheimer type pathology) were immunostained for Nε-(carboxymethyl)-lysine (CML), the most abundant AGE. The level of staining in vessels and neurons in the cortex, white matter and basal ganglia was compared to neuropsychological and other clinical measures.ResultsThe probability of cortical neurons staining positive for CML was higher in cases with worse cognition (p = 0.01) or a history of hypertension (p = 0.028). Additionally, vascular CML staining related to cognitive impairment (p = 0.02) and a history of diabetes (p = 0.007). Neuronal CML staining in the basal ganglia related to a history of hypertension (p = 0.002).ConclusionCML staining in cortical neurons and cerebral vessels is related to the severity of cognitive impairment in people with cerebrovascular disease and only minimal Alzheimer pathology. These findings support the possibility that cerebral accumulation of AGEs may contribute to dementia in people with cerebrovascular disease.

Effects of GABAergic drugs, fornicotomy, hippocampectomy and septal lesions on the extinction of a discrete-trial fixed ratio 5 lever-press response

The effects of certain GABA-modulating drugs, fornicotomy, hippocampectomy and various septal lesions were analysed in a discrete-trial fixed ratio 5 (FR5) bar-press paradigm. Chlordiazepoxide, fornicotomy, hippocampectomy, electrolytic lateral septal lesions and ibotenic acid medial septal lesions facilitate extinction of the FR5 response. Some of these treatments (chlordiazepoxide, hippocampectomy, electrolytic lateral septal lesions) have previously been found to increase resistance to extinction of alley-running after continuously reinforced (CRF) acquisition training. The treatments which facilitated extinction in the discrete-trial FR5 paradigm have been found to reduce or abolish the partial reinforcement extinction effect in the alley. These results indicate that the discrete-trial FR5 paradigm is not analogous to a runway CRF schedule, but may be analogous to a runway partial reinforcement schedule.

Can exposure to a terrestrial trunked radio (TETRA)-like signal cause symptoms? A randomised double-blind provocation study

Objectives Concerns have been raised about possible health effects from radiofrequency fields pulsing at around 16 Hz. A radio system used by UK police (TETRA) employs signals which pulse at 17.6 Hz. We tested whether exposure to a continuous wave signal at 385.25 MHz or a TETRA-like signal resulted in symptoms among users reporting sensitivity to TETRA compared to users not reporting sensitivity to TETRA. Methods 60 sensitive and 60 non-sensitive users were exposed to three 50 min conditions: a signal with a 16 Hz component, a continuous wave condition and a sham condition. The mean radiated power for the 16 Hz and continuous wave conditions was 250 mW. The order of conditions was randomised and testing was conducted double-blind. Participants reported the severity of eight symptoms during and after each exposure, their mood state at the end of each exposure, and whether they could tell which sessions involved active signals. The study was registered in advance with the ISRCTN register. Results Exposure to the continuous wave signal increased ratings of headache in all participants, fatigue in non-sensitive participants and difficulty concentrating in sensitive participants. Paradoxically, it reduced sensations of itching in sensitive participants. These effects were not observed in the condition with 16 Hz pulsing, except for those relating to concentration. Adjusting for multiple comparisons removed most significant effects, but not those relating to itch. Conclusions The results suggested that exposure to TETRA signals is not responsible for symptoms reported by some users, although exposure to a continuous wave signal may affect symptoms. Clinical trial number ISRCTN 73321766.