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Biomedical subjects

D J Brooks

Publications and source records attributed to D J Brooks.

At least 73 records · Page 4Linked to original sources
PubMed2000

Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil.

We used the benzodiazepine GABA(A) marker [(11)C] flumazenil to study cerebral dysfunction in amyotrophic lateral sclerosis (ALS) with PET. Seventeen non-demented patients with clinically definite or probable ALS were scanned and statistical parametric maps were derived to localize changes in regional flumazenil volumes of distribution (FMZVD), which correlate closely with receptor density (B(max)), and the results were compared with those of 17 controls. The ALS group showed statistically significant decreases in relative FMZVD in the prefrontal cortex (areas 9 and 10 bilaterally), parietal cortex (area 7 bilaterally), visual association cortex (area 18 bilaterally) and left motor/premotor cortex (including area 4) (P < 0.001). Relative reductions in FMZVD were also seen in the left ventrolateral and dorsolateral prefrontal cortex (areas 45, 46 and 47), Broca's area and the right temporal (area 21) and right visual association cortex (area 19). These observations suggest that cerebral dysfunction in ALS involves motor/premotor and extramotor areas, particularly the prefrontal regions.

Adult↗
PubMed2000

Cortical dysfunction in non-demented Parkinson's disease patients: a combined (31)P-MRS and (18)FDG-PET study.

Regional cerebral phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) was performed in 10 non- demented Parkinson's disease patients and nine age-matched control subjects. Five of the patients undergoing (31)P-MRS and four additional Parkinson's disease patients had cerebral 2-[(18)F]fluoro-2-deoxy-D-glucose PET ((18)FDG-PET), the results of which were compared with those of eight age-matched control subjects. All Parkinson's disease patients underwent neuropsychological testing including performance and verbal subtests of the Wechsler Adult Intelligence Scale-Revised, Boston Naming Test, Controlled Oral Word Association test (FAS Test) and California Learning Test to exclude clinical dementia. (31)P MR spectra from right and left temporo-parietal cortex, occipital cortex and a central voxel incorporating basal ganglia and brainstem were obtained. (31)P MR peak area ratios of signals from phosphomonoesters (PMEs), inorganic phosphate (P(i)), phosphodiesters (PDEs), alpha-ATP, gamma-ATP and phosphocreatine (PCr) relative to beta-ATP were measured. Relative percentage peak areas of PMEs, P(i), PDEs, PCr, and alpha-, beta- and gamma-ATP signals were also measured with respect to the total (31)P-MRS signal. Significant bilateral increases in the P(i)/beta-ATP ratio were found in temporoparietal cortex (P = 0.002 right and P = 0.014 left cortex) for the non-demented Parkinson's disease patients compared with controls. In the right temporoparietal cortex, there was also a significant increase in the mean relative percentage P(i) (P = 0.001). (18)FDG-PET revealed absolute bilateral reductions in glucose metabolism after partial volume effect correction in posterior parietal and temporal cortical grey matter (P < 0.01 and P < 0.05, respectively) for the Parkinson's disease group, using both volume of interest analysis and statistical parametric mapping. There were significant correlations between right temporoparietal P(i)/beta-ATP ratios and estimated reductions in performance IQ (r = 0.96, P < 0.001). Left temporoparietal P(i)/beta-ATP ratios correlated with full scale IQ and verbal IQ (r = -0.82, P = 0.006, r = -0.86, P = 0.003, respectively). In summary, temporoparietal cortical hypometabolism was seen in non-demented Parkinson's disease patients with both (31)P-MRS and (18)FDG-PET, suggesting that both glycolytic and oxidative pathways are impaired. This dysfunction may reflect either the presence of primary cortical pathology or deafferentation of striato-cortical projections. (31)P-MRS and (18)FDG-PET may both provide useful predictors of future cognitive impairment in a subset of Parkinson's disease patients who go on to develop dementia.

Aged↗
PubMed2000

Self-initiated versus externally triggered movements. II. The effect of movement predictability on regional cerebral blood flow.

Event-related potential studies in man suggest a role for the supplementary motor area (SMA) in movement preparation, particularly when movements are internally generated. In a previous study combining PET with recording of movement-related cortical potentials, we found similar SMA activation and early pre-movement negativity during self-initiated and predictably paced index finger extensions. Early pre-movement negativity was absent when finger movements were paced by unpredictable cues. We postulated that preparation preceding self-initiated and predictably cued movements was responsible for equivalent levels of SMA activation in these two conditions. To test this, we have performed further studies on six normal volunteers with H2(15)O-PET. Twelve measurements of regional cerebral blood flow were made in each subject under three conditions: rest; self-initiated right index finger extension at a variable rate of once every 2-7 s; and finger extension triggered by pacing tones at unpredictable intervals (at a rate yoked to the self-initiated movements). Activation associated with these conditions was compared using analysis of covariance and t statistics. Compared with rest, unpredictably cued movements activated the contralateral primary sensorimotor cortex, caudal SMA and contralateral putamen. Self-initiated movements additionally activated rostral SMA, adjacent anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC). Direct comparison of the two motor tasks confirmed significantly greater activation of these areas and of caudal SMA in the self-initiated condition. These results, combined with our previous data, suggest that rostral SMA plays a primary role in movement preparation while caudal SMA is a motor executive area. In this experiment and in our earlier study, DLPFC was activated only during the self-initiated task, in which decisions were required about the timing of movements.

Adult↗
PubMed2000

Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease.

Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

Adult↗
PubMed2000

Increased availability of central benzodiazepine receptors in patients with chronic hepatic encephalopathy and alcohol related cirrhosis.

BACKGROUND/AIMS: To measure cerebral benzodiazepine receptor binding using (11)C-flumazenil positron emission tomography in patients with stable chronic hepatic encephalopathy, who were also characterised by proton magnetic resonance spectroscopy. METHODS: Six abstinent patients of mean age 61 years with alcohol related cirrhosis and grade I-II hepatic encephalopathy and 11 matched healthy volunteers were studied. Each patient's encephalopathy was defined according to clinical, psychometric, electroencephalographic, and magnetic resonance spectroscopy criteria. Using positron emission tomography, the brain volume of distribution of (11)C-flumazenil was obtained; this reflects benzodiazepine receptor availability. Proton magnetic resonance spectra were acquired at 1.5 T using a multivoxel technique; peak area ratios were calculated for choline, glutamine/glutamate, N-acetylaspartate, and creatine resonances. RESULTS: The mean volume of distribution of (11)C-flumazenil was significantly higher in the cortex, cerebellum, and the basal ganglia in the patients compared with controls (p<0.001). In the patient group, the mean glutamine/glutamate to creatine ratio was significantly increased and the mean choline to creatine ratio was significantly decreased in all brain areas, compared with healthy volunteers. However, the N-acetylaspartate to creatine ratio was unchanged compared with controls. CONCLUSIONS: The spectroscopy results reflect the cerebral metabolic derangement associated with hepatic encephalopathy. Stable grade I-II chronic hepatic encephalopathy in alcohol related cirrhosis may be associated with increased cerebral benzodiazepine receptor availability. However, a direct effect of previous chronic exposure to alcohol cannot be excluded.

Adult↗
PubMed2000

Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome.

Huntington's disease is characterised by hyperkinetic movements, mainly chorea, cognitive dysfunction, and psychiatric abnormalities. Non-dopa responsive parkinsonism occurs in the later stages of choreic disease or as the predominant feature of juvenile patients (Westphal variant). Late onset Huntington's disease presenting as levodopa responsive parkinsonism is rare. A series of four patients with late onset Huntington's disease presenting as levodopa responsive parkinsonism and cardiovascular dysautonomia, initially misdiagnosed as multiple system atrophy (MSA) in three patients, is reported. Levodopa treatment did not unmask significant chorea. These cases suggest the presence of a distinct phenotypic variant of Huntington's disease to be added to the differential diagnosis of other akinetic rigid syndromes.

Aged↗
PubMed2000

The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson's disease.

OBJECTIVES: Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an adjunct to standard levodopa preparations, but there is little experience of the effect of entacapone on controlled release levodopa preparations. METHODS: A double blind, placebo controlled, single dose, randomised, cross over trial was performed in 14 patients with Parkinson's disease with motor fluctuations to investigate the clinical effect of a single dose of entacapone (200 mg) when administered with either standard levodopa-carbidopa (Sinemet) or controlled release levodopa-carbidopa preparations (Sinemet CR). RESULTS: When entacapone was administered with standard Sinemet the duration of the clinical response to standard Sinemet was longer in comparison with the response after placebo (p=0.02). Moreover, in the same patients, entacapone significantly increased the duration of the clinical response to Sinemet CR (p=0.05) without prolonging the latency of response or enhancing dyskinesias. CONCLUSIONS: These data confirm the clinical efficacy of entacapone-standard Sinemet combination. They also indicate that adding entacapone to controlled release levodopa preparations might provide a useful treatment option in patients with Parkinson's disease with motor fluctuations. A double blind clinical trial with a chronically administered entacapone-Sinemet CR combination is, however, required to verify this viewpoint.

Adult↗
PubMed2000

Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans.

Much evidence suggests that lesions of the prefrontal cortex (PFC) produce marked impairments in the ability of subjects to shift cognitive set, as exemplified by performance of the Wisconsin Card Sorting Test (WCST). However, studies with humans and experimental primates have suggested that damage to different regions of PFC induce dissociable impairments in two forms of shift learning implicit in the WCST (that is, extradimensional (ED) shift learning and reversal shift learning), with similar deficits also being apparent after damage to basal ganglia structures, especially the caudate nucleus. In this study, we used the same visual discrimination learning paradigm over multidimensional stimuli, and the H215O positron emission tomography (PET) technique, to examine regional cerebral blood flow (rCBF) changes associated with these subcomponent processes of the WCST. In three conditions, subjects were scanned while acquiring visual discriminations involving either (i) the same stimulus dimension as preceding discriminations (intradimensional (ID) shifts); (ii) different stimulus dimensions from previous discriminations (ED shifts) or (iii) reversed stimulus-reward contingencies (reversal shifts). Additionally, subjects were scanned while responding to already learnt discriminations ('performance baseline'). ED shift learning, relative to ID shift learning, produced activations in prefrontal regions, including left anterior PFC and right dorsolateral PFC (BA 10 and 9&frasl;46). By contrast, reversal learning, relative to ID shift learning, produced activations of the left caudate nucleus. Additionally, compared to reversal and ID shift learning, ED shift learning was associated with relative deactivations in occipito-temporal pathways (for example, BA 17 and 37). These results confirm that, in the context of visual discrimination learning over multidimensional stimuli, the control of an acquired attentional bias or'set', and the control of previously acquired stimulus-reinforcement associations, activate distinct cortical and subcortical neural stations. Moreover, we propose that the PFC may contribute to the control of attentional-set by modulating attentional processes mediated by occipito-temporal pathways.

Adult↗
PubMed2000

The role of entacapone in the management of Parkinson's disease.

Catechol-O-methyltransferase (COMT) inhibition is an important advance in the treatment of Parkinson's disease. This consensus statement provides guidelines for the optimal use of the only currently available COMT inhibitor, entacapone (Comtess, Orion Pharma (UK) Ltd, Newbury, Berkshire).

Antiparkinson Agents↗
PubMed2000

Neuroimaging of dyskinesia.

Dyskinesias are observed in the majority of Parkinson's disease (PD) patients who have been chronically exposed to levodopa, and these may result from supersensitivity of postsynaptic striatal dopamine D1 and D2 receptors following loss of nigral dopaminergic projections. Dyskinetic and nondyskinetic PD patients were studied using 11C-SCH23390 and 11C-raclopride positron emission tomography (PET). No difference in mean putamen or caudate D1 or D2 receptor binding between the two patient subgroups was found, suggesting that dyskinesias are unlikely to arise from a primary disturbance of dopamine receptor availability. When dyskinetic and nondyskinetic patients were studied with 11C-diprenorphine PET, the former showed a significant reduction (p < 0.05) in striatal and thalamic opioid site availability, compatible with the presence of raised levels of endogenous opioid peptides. H2(15)O PET activation studies of patients with focal limb dyskinesias showed that resting levels of regional cerebral blood flow after oral levodopa were increased during dyskinesias in lentiform nuclei, motor, premotor and dorsal prefrontal cortex. These results suggest that dyskinesias are associated with derangement of basal ganglia opioid transmission, resulting in overactivity of basal ganglia-frontal projections.

Dopamine Agents↗
PubMed2000

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts.

Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinson's disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement-related activation of frontal cortical areas in 4 PD patients using H2 15O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F-dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinson's Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F-dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD.

Adult↗
PubMed2000

The effects of surgical treatment of Parkinson's disease on brain function: PET findings.

Positron emission tomography allows a quantitative assessment of the impact of functional neurosurgery in Parkinson's disease (PD) by measuring regional cerebral flow and glucose and oxygen consumption as indicators of metabolic activity of specific brain regions. PET can also be used to study the dopaminergic nigrostriatal system, and therefore serves as a surrogate marker of the evolution of striatal grafts for PD. Pallidotomy has been associated with increased activation of premotor areas (supplementary motor area and dorsolateral prefrontal cortex) and reduced hyperactivity of the lentiform nucleus (augmented preoperatively). Pallidal (GPi) and subthalamic (STN) stimulation also increase activation of premotor areas but decrease activation of primary motor area. Suppression of unilateral tremor with thalamic stimulation is associated with a reduction in cerebellar blood flow. These main findings are in keeping with the general notion that increased activity in the STN GPi projection is directly implicated in the pathophysiology of PD. Surgical blockage of these output nuclei leads to partial restoration of cortical physiology.

Adult↗
PubMed1999

[11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis.

This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.

Adolescent↗
PubMed1999

Association of abnormal cerebellar activation with motor learning difficulties in dyslexic adults.

BACKGROUND: In addition to their impairments in literacy-related skills, dyslexic children show characteristic difficulties in phonological skill, motor skill, and balance. There is behavioural and biochemical evidence that these difficulties may be attributable to mild cerebellar dysfunction. We wanted to find out whether there was abnormal brain activation when dyslexic adults undertook tasks known normally to involve cerebellar activation. METHODS: Brain activation was monitored by positron emission tomography in matched groups of six dyslexic adults and six control adults as they carried out either a prelearned sequence or learned a novel sequence of finger movements. FINDINGS: Brain activation was significantly lower (p<0.01) for the dyslexic adults than for the controls in the right cerebellar cortex and the left cingulate gyrus when executing the prelearned sequence, and in the right cerebellar cortex when learning the new sequence. INTERPRETATION: The results provided direct evidence that, for this group of dyslexic adults, the behavioural signs of cerebellar abnormality reflect underlying abnormalities in cerebellar activation.

Adult↗
PubMed1999

Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies.

OBJECTIVE: To use PET to study striatal dopaminergic function in restless legs syndrome (RLS). BACKGROUND: RLS is a common disorder experienced by as much as 5% of the population. It has been suggested that this condition is associated with a disturbance of dopaminergic transmission. METHODS: The authors measured nigrostriatal terminal dopamine storage with 18F-dopa and striatal D2 receptor binding with 11C-raclopride PET in 13 RLS patients, five of whom were receiving treatment with L-dopa at the time of scanning. RLS results were compared with those of age-matched control subjects. RESULTS: Mean caudate and putamen 18F-dopa uptake were mildly reduced in the RLS patients compared with control subjects, and this reached significance (p = 0.04) in the putamen. Mean D2 binding was reduced in the caudate (p = 0.01) and the putamen (p = 0.008) in RLS patients compared with control subjects. Six of the 13 RLS patients had caudate and putamen D2 binding reduced below the control range. Three other RLS patients showed only reduced putamen D2 binding. There were no significant differences in striatal 18F-dopa uptake or D2 binding between L-dopa-naive and L-dopa-treated RLS patients. CONCLUSIONS: These PET findings support the hypothesis of central dopaminergic dysfunction in RLS.

Aged↗