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Biomedical subjects

R M Ridley

Publications and source records attributed to R M Ridley.

At least 91 records · Page 5Linked to original sources
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies.

Genealogical and molecular studies were carried out in four families in which early onset dementia is inherited as an autosomal dominant. These studies indicated that the four families derive from four siblings whose parents were born in the late 18th century in South-East England. The disease was found to be closely linked to a 144 bp insertion within the open reading frame of the prion protein (PrP) gene with a maximum LOD score of 11.02 at zero recombination. Within the general population the PrP gene is polymorphic at codon 129 (allele frequency approximately 30% valine, 70% methionine). The insertion in this family is always within a methionine-129 allele. The age at death of affected individuals whose normal allele encoded methionine at codon 129 was significantly lower than those whose normal allele encoded valine. The clinical features which were very variable and the neuropathological findings, which sometimes included spongiform encephalopathy, but which often did not, are described fully in the accompanying article (Collinge et al., 1992).

Base Sequence↗
PubMed1992

A test of the hypothesis that age at onset in Huntington disease is controlled by an X-linked recessive modifier.

Data from the Research Roster for Huntington Disease Patients and Families were used to assess the hypothesis that juvenile onset in Huntington disease is determined by an X-linked recessive modifying gene in the affected parent. The observed proportion of affected fathers to affected mothers who had such offspring was not compatible with this hypothesis. Furthermore, neither the excess of affected grandfathers nor the existence of juvenile-onset and adult-onset cases within a sibship would be predicted by this model. We also rejected a more general hypothesis that a major change in gene expression across generations, measured by the presence of juvenile onset and/or major anticipation, is determined by an X-linked modifier. However, the inheritance of a propensity toward juvenile onset via the affected male line could be due to an abnormal pattern of paternal genomic imprinting.

Adolescent↗
PubMed1991

Cholinergic neural transplants into hippocampus restore learning ability in monkeys with fornix transections.

Monkeys with bilateral transections of the fornix were severely but selectively impaired at learning visuospatial conditional tasks presented in a Wisconsin General Test Apparatus. Bilateral transplantation of cholinergic-rich embryonic basal forebrain tissue into the hippocampus led to complete recovery from this specific learning impairment across a range of task difficulties. Administration of the direct cholinergic agonist pilocarpine to ungrafted animals immediately before testing also reduced this impairment, suggesting that the graft-associated recovery was mediated by acetylcholine release. Transection of the fornix produced a marked loss of acetylcholinesterase (AChE) staining confined to hippocampus and entorhinal cortex relative to controls. In all transplanted animals densely AChE-staining cellular masses were seen bilaterally in temporal lobe structures, with fibre outgrowth into surrounding host tissue.

Acetylcholinesterase↗
PubMed1991

Can fetal neural transplants restore function in monkeys with lesion-induced behavioural deficits?

Experiments are now being conducted in monkeys to see whether the transplantation of fetal neural tissue, rich in certain neurotransmitter-producing cells, can restore behaviour in animals with movement or learning impairments induced by lesions that have destroyed important neurotransmitter pathways. Transplantation of dopamine neurons in humans may prove to be a useful therapy in Parkinson's disease, in which a severe movement disorder is associated with degeneration of the dopamine system. Transplantation of cholinergic neurones in monkeys can overcome a severe learning impairment induced by lesion of the cholinergic system. Cholinergic transplantation may eventually be of use in a variety of neurodegenerative dementing illnesses.

Animals↗
PubMed1991

Patterns of inheritance of the symptoms of Huntington's disease suggestive of an effect of genomic imprinting.

The interaction of symptomatology (rigidity/chorea) in Huntington's disease (HD) with age of onset (AO) was examined using data from the Research Roster for Huntington's Disease Patients and Families. It was shown that AO varies between families and between paternal and maternal transmission and that rigidity is associated specifically with very early onset, major anticipation, paternal transmission, and young parental AO. It is proposed that AO depends on the state of methylation of the HD locus, which varies as a familial trait, and as a consequence of 'genomic imprinting' determined by parental transmission. Young familial AO and paternal imprinting interact to produce, occasionally, a major change in gene expression, that is, the early onset/rigid variant.

Adolescent↗
PubMed1990

Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Sträussler-Scheinker diseases.

A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Sträussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.

Animals↗
PubMed1989

Learning about rules but not about reward is impaired following lesions of the cholinergic projection to the hippocampus.

Common marmosets with bilateral ibotenic acid-induced destruction of the neurones of the vertical limb of the diagonal band of Broca, which provide the major cholinergic input to the hippocampal formation, were impaired on the acquisition but not on the retention of a repeated-trial visuospatial discrimination learning task. They were also impaired on serial spatial reversal learning (but not on serial object reversal learning), on acquisition of a trial-independent successive concurrent discrimination using novel objects (but not on acquisition of a comparable discrimination in which two familiar objects had predictable reward value) and were unable to acquire a difficult conditional object discrimination. It is argued that the role of the hippocampus is in the acquisition but not the retention of ruled-based behaviour (which includes spatial responding) in contrast to the acquisition of discriminations based on stimulus-reward association formation.

Animals↗
PubMed1989

Social withdrawal following amphetamine administration to marmosets.

Approaches and leaves from social encounters by marmosets which had received amphetamine injected either intramuscularly or into the nucleus accumbens or caudate nucleus were recorded and used to determine whether social behaviour was disrupted as a result of behavioural competition or more active social withdrawal. The social isolation observed after the marmosets had received an IM injection of amphetamine (2 mg/kg) was not due to drug-induced increases in alternative behaviours. Drugged animals immediately withdrew from social encounters, interrupting their stereotypies in order to do so, whenever they were approached by an undrugged animal. In contrast, the reduced time spent in social encounters following amphetamine injections into the nucleus accumbens (10, 20 or 40 micrograms) appeared to be a direct consequence of the concurrent increase in locomotion. Animals continued to initiate social encounters despite being hyperactive. Amphetamine injections into the caudate nucleus were without effect on any of the social or individual behavioural measures.

Animals↗
PubMed1989

A re-investigation of the behavioural effects of intracerebral injection in marmosets of cytopathic cerebrospinal fluid from patients with schizophrenia or neurological disease.

In experiments designed to investigate transmission, cerebrospinal fluid (CSF) from patients with schizophrenia or neurological disease (Huntington's disease) which had been found to induce a cytopathic effect (CPE) in human embryonic fibroblast cell culture was injected intracerebrally into common marmosets. Behavioural observations were made on the animals during a period of 2 1/2 years prior to injection and for 2 1/2 years after injection. In an earlier study (Baker et al. 1983 b) we found that animals injected with CPE + ve CSF became progressively more inactive when compared with those injected with non-cytopathic (CPE -ve) CSF from control patients. In the present study we were unable to replicate this finding. No difference in behaviour emerged between animals injected with control CSF and animals injected with CSF from schizophrenics or patients with neurological disease, nor between animals injected with CPE + ve CSF and animals injected with CPE -ve CSF. The numbers of offspring produced and surviving did not differ between the groups. We conclude that the original findings were due to factors unconnected with the nature of the injected material.

Animals↗
PubMed1988

Visuospatial learning impairment following lesion of the cholinergic projection to the hippocampus.

Ibotenic acid lesions of the vertical limb of the diagonal band of Broca (VDB) in marmosets produced significant depletions in choline acetyltransferase (ChAT) activity and a decrease in acetylcholinesterase (AChE) staining in the hippocampal formation and entorhinal cortex (to which the cholinergic neurones of the VDB project) but not in the neocortex or amygdala. Marmosets with VDB lesions were impaired on acquisition (but not retention) of repeated trial visuospatial tasks. This impairment was ameliorated by pretreatment with the cholinergic agonist pilocarpine indicating (a) that the learning impairment was a consequence of damage to the cholinergic system and (b) that the cholinergic projections exert a modulatory or enabling function on the target areas which can be substituted by a non-impulse-dependent drug action. Unlike marmosets with lesions of the basal nucleus of Meynert (NBM), VDB-lesioned animals were not impaired on learning repeated trial object discrimination and showed no change in general behaviour although they did become hypothermic and mesomorphic. These results are consistent with the suggestion that the hippocampus (perhaps in conjunction with the entorhinal cortex) is concerned primarily with memory for responses but not memory for reward and that lesions of the cholinergic system produce impairments equivalent to the effects of ablation of the terminal areas.

Animals↗
PubMed1988

Stereotyped responding on a two-choice guessing task by marmosets and humans treated with amphetamine.

The performance of normal human volunteers and marmosets on a 2-choice guessing task was assessed after saline (control) or amphetamine administration. In human subjects the drug increased the number of alternation responses, which can be interpreted as an increase in stereotyped switching and which is similar to the response pattern produced by some groups of psychotic patients on the same task (Frith and Done 1983; Lyon et al. 1986). Marmosets treated with amphetamine showed an increase in perseverative responding compatible with that seen on other types of task. Our conclusion is that dopaminergic systems are involved in behavioural choice mechanisms and that a dysfunction of these systems may contribute to the symptomatology of psychosis.

Animals↗
PubMed1988

Anticipation in Huntington's disease is inherited through the male line but may originate in the female.

Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers. Analysis of the grandparental origin of the Huntington allele suggests that while propensity to anticipation is heritable for a number of generations through the male line, it originates at the time of differentiation of the germ line of a male who acquires the Huntington allele from his mother. It is suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of the 'genomic imprinting', that is, in the mechanism by which the parental origin of alleles is indicated.

Adolescent↗