Biomedical subjects
R M Ridley
Publications and source records attributed to R M Ridley.
Oral transmission of BSE to primates.
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Spontaneous spongiform encephalopathy in a monkey.
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Failure to transmit bovine spongiform encephalopathy to marmosets with ruminant-derived meal.
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Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Study so far provides no evidence for maternal and horizontal transmission.
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Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Aetiology of scrapie in certain circumstances is not evidence against another aetiology in different circumstances.
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To what extent is strain variation evidence for an independent genome in the agent of the transmissible spongiform encephalopathies?
The apparent existence of multiple strains of the 'transmissible agent' associated with spongiform encephalopathy (prion disease) has been used to support the argument that these diseases are caused by an independent, replicating agent with its own genome. However, the length of the incubation period (time from injection of infected material to onset of clinical signs) and the lesion profile (regional distribution of neuropathology), which are the key features used to define the strain of agent, have been shown to be influenced by the prion protein of the host and the donor, such that it is only the variance in these measures which remains after variation due to all other factors has been taken into account, which can be used as evidence for the existence of different strains of agent. The donor is the animal from which infectious material is prepared for injection into the host. Almost all aspects of pathogenesis, including most of the variance in incubation time, can be explained in terms of interactions between donor and host prion protein. We argue that the number of separate strains of agent may be more limited than is usually represented. It is important to distinguish between the hypothesis that the prion protein of the host 'permits' the selection of mutated strains and the hypothesis that it 'induces' changes in the agent. The former is consistent with the concept of an agent with an independent genome while the latter is consistent with the concept that 'strain of agent' is another expression of the involvement of prion protein in the pathogenesis of transmissible spongiform encephalopathy.
Assessment of functional impairment following permanent middle cerebral artery occlusion in a non-human primate species.
The purpose of the present study was to examine and quantify the functional consequence of a focal cerebral ischaemic lesion in a primate species, the marmoset. Following craniotomy and retraction of the frontal and temporal lobes, the middle cerebral artery was permanently occluded by means of electrocoagulation. Three and eight weeks after surgery, various behavioural tests were used to give a quantifiable measure to the neurological deficits produced. These tests required the monkeys to reach into tubes for foodbits, retrieve rewards from the steps of two designs of 'staircases', respond to one of two simultaneously presented rewarded tubes, remove adhesive labels attached to their feet, and respond to sensory stimuli. Unilateral motor impairment of the contralateral forelimb and neglect of contralateral tactile stimuli were seen in all subjects, and spatial neglect was also present in some monkeys. Subsequent histological analysis revealed unilateral cortical damage in all subjects with varying amounts of injury to the caudate and the putamen in some animals. These results demonstrate the potential for the use of this species in future investigations to examine the effect of neuroprotective treatment on functional outcome after a focal ischaemic insult.
Neurochemical modulation of the hippocampus in learning, remembering and forgetting in primates.
Information about the outside world is carried into the hippocampus by glutamatergic pyramidal cell pathways from the posterior association cortex via the subiculum. Processed information is carried away from the hippocampus by a reciprocal glutamatergic pathway back into posterior association cortex. These pathways are thought to be crucial for the acquisition of long term memories although it seems likely that memories are stored in cortex rather than within the hippocampus. The hippocampus is supported by functionally excitatory cholinergic modulation via fornical afferents and by functionally inhibitory serotonergic modulation specifically via 5HT1A receptors. Cholinergic modulation of the hippocampus is necessary for efficient acquisition of visuospatial tasks but not for retention of similar tasks first acquired prior to surgery. Cholinergic modulation of areas outside the hippocampus may contribute to the maintenance of memories and non-cholinergic efferents in the fornix may be required for retrieval of tasks first learnt when the hippocampus was intact. Impairments on acquisition of visuospatial tasks brought about by fornix transection can be ameliorated by direct stimulation of cholinergic receptors using pilocarpine or by blockade of the serotonergic inhibitory modulation of the hippocampus using the 5HT1A receptor antagonist, WAY100635, indicating an equal-but-opposite modulatory effect of these two neurotransmitters on hippocampal function.
Effects of lesions of different parts of the septo-hippocampal system in primates on learning and retention of information acquired before or after surgery.
Data from a large series of experiments on marmosets with lesions of the septal/diagonal band area (DB), fornix or CA1 area of the hippocampus are analysed in terms of retention of information learned before surgery, acquisition of new information and retention of information acquired after surgery. It is shown that although all three lesions impair acquisition of a specific type of new information, lesions of CA1 result in a severe retrograde amnesia but no forgetting of that type of information adequately acquired after surgery, whereas lesions of the DB do not cause retrograde amnesia but do result in significant forgetting. Monkeys with fornix transection occupied an intermediate position in their pattern of learning impairments; some animals showed evidence of forgetting, whereas the great majority showed retrograde amnesia. These data may be relevant to an understanding of the different extent of amnesia in patients with different pathology within the medial temporal lobe and associated subcortical structures.
What went wrong in BSE? From prion disease to public disaster.
The recent report of 10 cases of a new variant of Creutzfeldt-Jakob disease (CJD) which could be related to bovine spongiform encephalopathy (BSE) has precipitated alarm throughout Europe. The beef trade in the UK has collapsed and the European beef market has been seriously damaged. What went wrong? Much of the difficulty of handling the BSE epidemic arose from the 4-5 year incubation period which made it difficult to ascertain whether measures taken to contain the epidemic had been effective. Public consternation and scientific equivocation arose because these prion diseases are unlike any other group of infectious diseases. Rather than being caused by a conventional micro-organism, the primary pathogenic event consists of the transformation of a normal protein (the prion protein) into an abnormal form, which can transmit disease. Prion disease is endemic in humans and sheep where it is associated with polymorphisms or mutations within the prion protein gene. Although the disease in these cases arises spontaneously, it produces an infectious prion protein. Under certain circumstances, abnormal prion protein contaminates other animals or humans resulting in epidemics of acquired prion disease. This review describes the events of the BSE epidemic and considers the difficulties in assessing the current risk to human health.
Variation on a theme of Creutzfeldt-Jakob disease: implications of new cases with a young age at onset.
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The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset.
Fornix transection in the marmoset produces a specific pattern of cognitive deficits, notably a lack of ability to recall visuospatial tasks learnt preoperatively, and a deficit in acquiring new visuospatial tasks following transection. Previous work has shown that this learning impairment can be ameliorated by cholinergic agonists, suggesting that it occurs as a consequence of destroying the cholinergic projection from the vertical limb of the diagonal band to the hippocampus which runs through the fornix. We have now shown that this deficit in new learning can be significantly alleviated by the 5-HT1A antagonist, WAY 100635. This result supports the suggestion that 5-HT1A projections are inhibitory on the same target cells for which cholinergic projections are excitatory, and that loss of function in the target cells caused by loss of excitatory tone can be compensated by blockade of inhibitory tone. Since cholinergic loss in the hippocampus (and neocortex) occurs in association with cognitive decline in Alzheimer's disease, these results suggest that 5-HT1A antagonists may have a role in the treatment of some of the cognitive symptoms of dementia.
Creutzfeldt-Jakob disease and bovine spongiform encephalopathy: any connection?
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The myth of maternal transmission of spongiform encephalopathy.
It has long been accepted that the pattern of occurrence of scrapie--the form of spongiform encephalopathy associated with sheep--is determined mainly by maternal transmission, and this view has had a profound influence on policy decisions in the control of bovine spongiform encephalopathy and on public concern over the risk to human health form this disease. The occurrence of maternal transmission is, however, not predicted by modern knowledge of the aetiology of spongiform encephalopathy, and even though claims of maternal transmission have been reiterated frequently in the literature, re-examination of the source data reveals that these data are extremely scanty, unreplicated, and probably subject to ascertainment bias. The probability of maternal transmission of spongiform encephalopathy in any species should be viewed with the greatest scepticism.
A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions.
The behaviour of marmosets with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle and grafts of embryonic mesencephalon in either the caudate nucleus or the putamen was compared with that of lesion-alone and unoperated controls. The grafts comprised injections of cell suspensions prepared from marmoset ventral mesencephalon (i.e. allografts) targeted at four sites either entirely within the caudate nucleus or entirely within the putamen. Behavioural tests, including measures of amphetamine-induced rotation, neglect and use of each arm to retrieve food from inside tubes, were given before and after the 6-hydroxydopamine lesion and at regular intervals for 6 months after transplantation surgery. Grafts in the caudate nucleus reduced the ipsilateral rotation induced by amphetamine, whereas grafts in the putamen did not. Despite the absence of an effect on rotation, the putamen grafts were effective in reducing lesion-induced deficits on the task in which the marmosets were required to reach into tubes. In this latter task, the caudate grafts were also effective when the monkeys were given a free choice of which hand to use. However, when constrained to use the hand contralateral to the lesion and graft, the performance of the marmosets with caudate grafts was not significantly improved compared with that of lesion-alone controls. Neither the grafts in the caudate nucleus nor the grafts in the putamen abolished the contralateral somatosensory neglect induced by the lesion, although there was a trend for the marmosets with putamen grafts to contact the label on the contralateral side more quickly than those with caudate grafts or the lesion-alone controls. These results demonstrate that the location of embryonic nigral grafts within the primate striatum influences the profile of functional recovery.
Conditional learning and memory impairments following neurotoxic lesion of the CA1 field of the hippocampus.
Monkeys with bilateral lesions of the CA1 field of the hippocampus produced by the injection of neurotoxin diagonally along the length of the hippocampus were found to have a severe impairment on the retention of a conditional task learnt prior to surgery and on the new acquisition of several types of this task. They were equally impaired on conditional tasks that required a spatial response or an object choice in response to either visual or spatial cues. They were not impaired on simple visual discrimination tasks, simple spatial discrimination tasks or reversal learning of these tasks. This patterns of impairment resembles that seen in the same species with neurotoxic lesions within the vertical limb of the diagonal band of Broca or transection of the fornix. Monkeys with subtotal lesions of the adjacent medial temporal area were not consistently impaired on any of these tasks. The results suggest that hippocampal lesions produce anterograde and retrograde amnesia for information other than reward association.
Behavioral assessment of the effects of embryonic nigral grafts in marmosets with unilateral 6-OHDA lesions of the nigrostriatal pathway.
Grafts of embryonic nigral tissue were made into the striatum of marmosets (Callithrix jacchus) which had previously received a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal bundle. The grafts comprised injections of cell suspensions prepared from embryonic (74 day) marmoset ventral mesencephalic tissue targeted at multiple striatal sites in the caudate nucleus, the putamen, and the nucleus accumbens on the same side as the initial lesion. A series of behavioral tests was used to assess the monkeys prior to surgery, following the 6-OHDA lesion, and at regular intervals for 6 months after transplantation surgery. Lesioned and grafted (n = 6) or lesion alone (n = 4) monkeys were matched as far as possible with respect to their scores prior to transplantation so that explicit graft-derived recovery could be distinguished from any spontaneous recovery that might occur. Sham-lesioned or unoperated monkeys served as further controls (n = 5). The grafts were functionally effective as measured by a reduction, and in some cases a reversal, of spontaneous, amphetamine- and apomorphine-induced rotation. The reversal of amphetamine-induced rotation correlated with the number of dopaminergic neurons in the grafts visualized by tyrosine hydroxylase immunohistochemistry. Successful use of the hands was restored by the grafts on tasks in which the monkeys reached into tubes to retrieve food. However, functional recovery was not seen on some other behavioral tests. In particular, grafts did not influence ipsilateral biases induced by the lesion, including the position of the head with respect to the rest of the body, hand preference while reaching for food at a conveyor belt, and neglect of contralateral stimuli either at the conveyor belt or of adhesive labels placed around the feet. Indeed, the graft group was impaired compared with the lesion group in the accuracy of reaches at the conveyor belt. Overall, these results indicate that embryonic nigral grafts can yield a partial recovery from the symptoms induced by unilateral nigrostriatal lesions in a primate model of hemiparkinsonism.