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Biomedical subjects

R Dolan

Publications and source records attributed to R Dolan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington's disease.

We showed recently that chronic administration of the mitochondrial inhibitor 3-nitropropionic acid (3NP) in primates produces various dyskinetic movements and dystonic postures associated with selective striatal lesions displaying many similarities with the pathological features of Huntington's disease (HD). In the present study, we examined whether such a toxic treatment could also induce frontal-type deficits similar to those observed in HD patients. Cognitive performances of 3NP-treated and control baboons were compared using the object retrieval detour task (ORDT), a test designed to assess the functional integrity of the frontostriatal pathway in human and nonhuman primates. During the same time, the motor function of each animal was assessed under spontaneous "no drug" conditions, and time-sampled neurological observations were used after apomorphine administration. A significant impairment in the ORDT was observed in the 3NP animals after 3-6 weeks of treatment, occurring in the absence of spontaneous abnormal movements by in the presence of apomorphine-inducible dyskinesias. Prolonged 3NP treatment resulted in the progressive appearance of spontaneous abnormal movements. Histological evaluation of these animals showed selective bilateral caudate-putamen lesions with sparing of the cerebral cortex, notably the prefrontal cortex. The present study demonstrates that chronic 3NP treatment replicates in primates the basic pathophysiological triad of HD, including spontaneous abnormal movements, progressive striatal degeneration, and a frontostriatal syndrome of cognitive impairment.

Animals↗
PubMed1996

The role of the prefrontal cortex in higher cognitive functions.

The higher cognitive functions, working memory, mental imagery and willed action, are all intimately associated with consciousness. The common process underlying all these functions is that information is "held in mind" for a period of time. This information, which may be about stimuli or responses, can be derived from the past or generated for the future. Brain imaging studies show that "holding something in mind" is associated with activity in an extended system which involves both prefrontal cortex and more posterior areas whose location is determined by the nature of the information being held in mind. Automatic actions and perceptions which do not involve consciousness are associated with activity in the relevant posterior areas, but not in the prefrontal cortex. These studies demonstrate that activity occurs in the same posterior area whether the associated information comes from the outside world or is internally generated. This raises the problem of how we know whether our experience derives from mental imagery or from something happening in the outside world. There is evidence that patients with schizophrenia have precisely this problem since they perceive their own thoughts and even sub-vocal speech as coming from outside (hallucinations). Recent brain imaging studies suggest that there is a disconnection between prefrontal and posterior areas in these patients which could explain their characteristic misperceptions.

Choice Behavior↗
PubMed1996

Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates.

Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of 3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis.

Animals↗
PubMed1995

Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study.

We have used PET to study striatal D1 and D2 receptor binding in 10 patients with either the choreic or akinetic-rigid variants of Huntington's disease and in three patients with other causes of chorea. Background rigidity and bradykinesia in choreic patients were scored with a four-point scale. PET studies showed a severe and parallel reduction of both striatal D1 and D2 receptor binding in Huntington's disease patients irrespective of their predominant phenotype (mean reduction 60%). Huntington's disease patients with rigidity showed more pronounced reduction of striatal D1 and D2 binding compared with those without rigidity. A case of chorea associated with systemic lupus erythematosus had normal D2 binding. These results suggest that the presence of chorea per se may not be determined by alterations in striatal dopamine receptor binding, but that rigidity in Huntington's disease is associated with severe striatal D1 and D2 receptor loss.

Adult↗
PubMed1992

Measuring the neuromodulatory effects of drugs in man with positron emission tomography.

Cognitive activation in conjunction with pharmacological challenge was used to demonstrate neuromodulation in man. Using positron emission tomography (PET), measurements of regional cerebral blood flow were made during the performance of memory tasks, before and after the administration of apomorphine (dopamine agonist), buspirone (5-HT1A partial agonist) or placebo. Drug effects on memory-induced increases in regional cerebral blood flow were assessed, on a voxel-by-voxel basis, using statistical parametric mapping. Increases of regional cerebral blood flow in response to the memory challenge were attenuated by apomorphine in the dorsolateral prefrontal cortex and augmented in the retrosplenial region of the posterior cingulate. Conversely, buspirone attenuated blood flow increases in the retrosplenial region. These interactions between drugs and a cognitive challenge can best be interpreted as neuromodulatory effects.

Adult↗
PubMed1992

The effect of apomorphine and buspirone on regional cerebral blood flow during the performance of a cognitive task-measuring neuromodulatory effects of psychotropic drugs in man.

Psychopharmacological activation, in conjunction with positron emission tomographic measurements of regional cerebral blood flow (rCBF), was used to investigate the neurotransmitter basis of a specific cognitive function in man. Monoaminergic neurotransmission was pharmacologically manipulated during performance of auditory - verbal memory tasks. Statistical parametric mapping was used to identify the brain sites of interaction between memory-induced increases in rCBF and active drugs. Memory task-induced increases in rCBF in the left prefrontal cortex were attenuated by apomorphine, a non-selective dopamine agonist, whilst buspirone, a serotonin1A partial agonist, augmented rCBF increases in this area. In addition, apomorphine and buspirone augmented memory-induced increases in rCBF centred in the posterior cingulate cortex, whilst buspirone alone attenuated rCBF increases in the retrosplenial cortex and posterior parahippocampal gyrus. These regionally selective interactions may represent neuromodulatory effects of monoaminergic neurotransmission on a specific cognitive function in man.

Journal Article↗
PubMed1991

Accessibility of crystallins to HCI gas.

Different crystallins (alpha, beta H, beta L and LMW) were isolated from bovine lenses. Lyophilized samples of single components (homoaggregates) and those of mixtures (heteroaggregates) were exposed to HCI vapor in a high vacuum vapor sorption apparatus. Lyophilized 5-microns sections of bovine lens were similarly exposed to HCI vapors. Sorption and desorption isotherms were obtained at two temperatures on all samples. Fourier transform infrared (FT IR) spectroscopy was conducted on solid samples of crystallin with and without irreversibly sorbed HCI gas. From the IR spectra the nature of interaction between HCI and protein were ascertained. From the sorption parameters, mainly from the irreversibly sorbed HCI, the accessibilities of homo and hetero aggregates were calculated. The accessibilities provided information on the preferential interactions among crystallins. One of the main conclusions derived from this and also from previous ammonia sorption studies is that the supramolecular organization in the lens fibers is not governed solely by the thermodynamically preferential interactions of crystallins, but also by other possibly cytoskeletal organizations of crystallins.

Animals↗
PubMed1991

Citalopram: labelling with carbon-11 and evaluation in rat as a potential radioligand for in vivo PET studies of 5-HT re-uptake sites.

In vivo autoradiography of [N-methyl-3H]citalopram in rat brain shows a differential regional localization which correlates with the localization of 5-HT re-uptake binding sites defined in vitro. A comparison of the biodistribution of [N-methyl-3H]citalopram over 2 h after i.v. injection in (1) control rats (2) rats pre-dosed with either citalopram or paroxetine and (3) rats chemically-lesioned with p-chloroamphetamine provides an estimate of specific binding relative to total binding in vivo. The ratio of binding in certain regions (e.g. cingulate) to binding in a reference tissue (e.g. cerebellum) at 30-120 min post injection is c. 1.4. In view of these results a method was developed for labelling citalopram with carbon-11 (t1/2 = 20.3 min, beta + = 99.8%) to provide a potential radioligand for studies using positron emission tomography. Thus, reaction of nca [11C]iodomethane, prepared from cyclotron-produced [11C]carbon dioxide, with norcitalopram in ethanol containing 2,2,6,6-tetramethyl-piperidine for 5 min at 95 degrees C gives crude [N-methyl-11C]citalopram in 60% radiochemical yield, decay-corrected. HPLC on silica gel provides radiochemically and chemically pure [N-methyl-11C]citalopram, as assessed by TLC, HPLC and MS. This product (isolated radiochemical yield, 49%) is easily formulated for i.v. injection. Up to 2 GBq of formulated product with a specific activity of c. 15 GBq/mumol have been prepared within 40 min from the end of radionuclide production. The described radiosynthesis has also been applied to give the single biologically active (+)-enantiomer of [N-methyl-11C]citalopram rather than the racemate. This product gives enhanced specific signal in the rat following i.v. injection, the ratio of uptake in regions of interest relative to cerebellum approaching 2 at 90 min.

Animals↗
PubMed1991

Positron emission tomography as a research tool in the investigation of psychiatric and psychological disorders.

The principles of positron emission tomography (PET) are described, and illustrations of how these can be applied to clinical psychiatric questions relating to schizophrenia and depression are delineated. The metabolic changes in the frontal lobes which have been described in both depression and schizophrenia and depression are reviewed and discussed. More recent PET techniques allow several serial measurements of changes in regional blood flow in response to either a pharmacological challenge or a specific psychological task. This method provides a promising new approach to the study of the dopaminergic system in schizophrenia. New tracer methods of quantitating changes in in vivo concentrations of opioid receptors allow direct pharmacological access to the endogenous opioid system in the brain. Observations of regional cortical differences in opioid receptor concentration in relation to the medial and lateral pain systems are described. In addition, changes in receptor occupancy during sleep using [11C]diprenorphine and changes in the mu-specific tracer [11C]carfentanil in temporal lobe epilepsy are discussed.

Brain↗
PubMed1991

Predictors of post-traumatic stress disorder following physical trauma: an examination of the stressor criterion.

A prospective study documenting psychopathology was undertaken in 48 subjects exposed to a range of physical trauma, but whose injuries were of similar severity. No support was found for the DSM-III-R view correlating the severity of the stressor with the development of post-traumatic stress disorder (PTSD). Distress post injury (high scores on the impact of event scale), indicative of difficulty with cognitive assimilation of the traumatic event, was found to be highly predictive of psychiatric morbidity and PTSD at 6 months.

Accidents, Traffic↗
PubMed1990

Attributions and self-esteem in depression and chronic fatigue syndromes.

There is considerable overlap in symptomatology between chronic fatigue syndrome (CFS) and affective disorder. We report a comparison of depressive phenomenology and attributional style between a group of CFS subjects seen in a specialized medical setting, which included a high proportion with depression diagnosed by Research Diagnostic Criteria (RDC), and depressed controls seen in a specialized psychiatric setting. Significant symptomatic differences between the depressed CFS group and depressed controls were observed for features such as self-esteem and guilt as well as attribution of illness. All the CFS groups tended to attribute their symptoms to external causes whereas the depressed controls experienced inward attribution. This may have resulted from differences in the severity of mood disorder between the samples, but it is also suggested that an outward style of attribution protects the depressed CFS patients from cognitive changes associated with low mood but at the expense of greater vulnerability towards somatic symptoms such as fatigue.

Adult↗
PubMed1988

Urinary Charcot-Leyden crystals in the hypereosinophilic syndrome with acute renal failure.

A 48-year-old man with idiopathic hypereosinophilic syndrome (IHS) developed blast crisis along with a fulminant autoimmune hemolytic anemia. Hemoglobinuria and anuric acute renal failure (ARF) ensued. Urinalysis revealed countless Charcot-Leyden crysals (CLC). This is the only known report of Charcot-Leyden crystalluria. The CLC protein (lysophospholipase) should normally undergo glomerular filtration and catabolism by the tubules during reabsorption. Its abundant presence in the urine of our patient may reflect impairment of tubular reabsorption, saturation of the tubular reabsorptive process by excessive CLC load through residual functioning glomeruli, or a combination thereof. The extreme degree of hypereosinophilia suggests a massive load of CLC protein and acute tubular necrosis implies impaired tubular function, so both mechanisms should have been operative. At the autopsy, no eosinophilic infiltrates were present in the kidneys, which points against a local spillage of CLC protein into the tubules.

Acute Kidney Injury↗