Biomedical subjects

D J Brooks

Publications and source records attributed to D J Brooks.

At least 19 recordsLinked to original sources

PubMed1998

Evidence for striatal dopamine release during a video game.

Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.

Adult↗

PubMed1998

In vivo [11C]flumazenil-PET correlates with ex vivo [3H]flumazenil autoradiography in hippocampal sclerosis.

By using [11C]flumazenil-positron emission tomography ([11C]FMZ-PET), we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [11C]FMZ-PET and ex vivo binding using [3H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [11C]FMZ volume of distribution ([11C]FMZ Vd) obtained in 10 patients with refractory mTLE due to unilateral, histologically verified HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([3H]FMZ Bmax). After correction for partial volume effect, [11C]FMZ Vd in the body of the epileptogenic hippocampus was reduced by a mean of 42.1% compared with normal controls. [3H]FMZ Bmax, determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neurons in HS can be reliably detected in vivo by using [11C]FMZ-PET after correction for partial volume effect.

Adult↗

PubMed1998

Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group.

The efficacies of ropinirole and levodopa were compared after 6 months of treatment in a planned interim analysis of a 5-year, double-blind, randomized, multicenter study of patients with early Parkinson's disease requiring dopaminergic therapy. The percentage of improvement in the Unified Parkinson's Disease Rating Scale total motor examination score was significantly higher for levodopa (44%) than for ropinirole (32%). The proportion of "responders" (Unified Parkinson's Disease Rating Scale improvement of at least 30%) did not differ between groups (levodopa, 58%; ropinirole, 48%). There was no difference between the groups for improvement on the Clinical Global Impression scale in patients with Hoehn and Yahr stages I, I.5, or II, but a significantly higher proportion of patients with Hoehn and Yahr stages II.5 or III showed Clinical Global Impression score improvement with levodopa. Emergent adverse events occurred in 84% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (8% for ropinirole, 9% for levodopa). The results suggest that ropinirole and levodopa are equally effective in less severe Parkinson's disease; in more advanced Parkinson's disease, levodopa is superior.

Adult↗

PubMed1998

Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group.

We compared the efficacy and safety of ropinirole with that of bromocriptine after 6 months of treatment in a planned interim analysis of a 3-year, double-blind, randomized, multicenter study of 335 patients with early Parkinson's disease requiring dopaminergic therapy. Patients, treated with or without selegiline, received either ropinirole or bromocriptine. The mean Unified Parkinson's Disease Rating Scale (UPDRS) total motor examination scores (Part III) at baseline were similar in the four strata. Overall, and in the non-selegiline subgroup, the percentage improvement in the UPDRS total motor examination score was significantly higher for ropinirole than for bromocriptine, as was the proportion of "responders." In the selegiline subgroup, however, there was no significant difference between treatments. Similarly, in the non-selegiline subgroup, there was a significantly higher proportion of "improvers" on the Clinical Global Impression scale with ropinirole than with bromocriptine, whereas in the selegiline subgroup, there was no significant difference. Emergent adverse events occurred in 80% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (3% for ropinirole, 6.6% for bromocriptine). The data indicate that (a) in the absence of selegiline, ropinirole is effective and superior to bromocriptine; and (b) selegiline does not affect the response in patients treated with ropinirole, but enhances the effects of bromocriptine.

Adult↗

PubMed1998

Increased activation of frontal areas during arm movement in idiopathic torsion dystonia.

Most positron emission tomography (PET) studies of regional cerebral function in idiopathic torsion dystonia (ITD) have failed to show abnormalities, but there have been few studies of the changes in regional cerebral blood flow (rCBF) that occur during movement in dystonia. Using PET, we have studied six patients with familial generalized ITD both at rest and while moving a joystick with the right hand. The patterns of CBF change obtained were compared with those in six age-matched control subjects. In the dystonia group, free selection of movement was associated with relative increases in rCBF above that observed in control subjects in the left premotor area, the supplementary motor area (SMA), the anterior cingulate cortex, and the left dorsolateral prefrontal area. Subcortical increases were observed within the cerebellum and the putamen. There was a relative decrease in flow through the contralateral primary sensorimotor cortex. These findings contrast with those reported in patients with Parkinson's disease undertaking the same task in which the activity in the SMA and putamen was decreased. We suggest that arm dystonia in ITD is associated with overactivity of the premotor areas, including the SMA, and that this results from release of the thalamus from the normal inhibitory influence of the globus pallidus internal segment. Other abnormalities of basal ganglia control of brain stem centers may be involved in axial dystonia.

Adult↗

PubMed1998

Comparison of EEG, MRI and PET in reading epilepsy: a case report.

The pathophysiological and neuroanatomical bases of reading epilepsy (RE) are unclear. We performed video-EEG, high quality MRI and [11C]diprenorphine PET in a patient with RE to detect structural and functional abnormalities. EEG showed multifocal seizure onset bilaterally in temporal and fronto-central regions. MRI was normal, whereas [11C]diprenorphine PET revealed peri-ictal opioid binding decreases in both temporal lobes and the left frontal lobe. These findings confirm that RE is due to abnormal activity in the network subserving reading.

Adult↗

PubMed1998

A study of medial pallidotomy for Parkinson's disease: clinical outcome, MRI location and complications.

We have studied the effects of unilateral ventral medial pallidotomy in 26 patients with medically intractable Parkinson's disease with marked drug-induced dyskinesias. Preoperatively, all patients were assessed during one 5-day admission according to the Core Assessment Programme for Intracerebral Transplantation (CAPIT) protocol, including rating in the 'practically defined off' and 'best on' states before and during a single-dose levodopa challenge. Motor performance was assessed with subset categories of the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a standard dyskinesia rating scale. Pallidotomy was performed under stereotaxic CT guidance with intra-operative extracellular microelectrode recording made from the basal ganglia. All patients were re-assessed 3 months postoperatively and a subgroup (n = 9) have so far also been re-assessed after 1 year. Pre- and postoperative performance scores were compared in order to determine which categories of performance improved postoperatively. Significance was accepted at P < 0.005 in order to take into account the multiple number of comparisons performed. Patient medication was compared pre- and postoperatively and the morbidity associated with surgery was also recorded. The most significant improvement postoperatively was the diminution of 'on' dyskinesias contralaterally (67%, P = 0.0001); however, ipsilateral (45%, P = 0.0006) and axial (50%, P = 0.0008) dyskinesias also improved. Contralateral to pallidotomy, the median 'off' motor UPDRS score improved by 27% (P = 0.001) and a significant improvement was also observed in contralateral rigidity by 25% (P = 0.001). There were trends towards improvement in contralateral tremor (33%, P = 0.016) and bradykinesia (24%, P = 0.013) scores. Ipsilateral rigidity improved by 22% (P = 0.005), but other ipsilateral motor scores did not alter significantly. The 'off' gait/postural instability score and 'off' walking time showed marginally significant improvements by 7% (P = 0.007) and 29% (P = 0.014), respectively. On medication, no significant postoperative improvements in parkinsonism were detected. Anti-parkinsonian medication increased by 11% postoperatively. In the subgroup who were available for assessment 1 year postoperatively, responses were generally maintained. Two (7.7%) of the 26 patients had fatal complications (one cerebral haemorrhage and one haemorrhagic infarct) directly related to surgery. Among the remaining 24 patients, four (15.4% of the total 26) had major complications (two persisting and two transient). Ten patients (38.5%) had minor complications. The majority of the complications (major and minor) occurred in the earlier operated patients and the complication rate subsequently declined with increasing operative experience. The remaining 10 patients (38.5%) had no significant side-effects. One of these 10 patients died from an incidental malignant glioma 6 months postoperatively. These findings confirm that levodopa-induced dyskinesias are dramatically reduced following ventral medial pallidotomy and constitute the principal indication for pallidotomy. Improvements in underlying parkinsonism were of smaller magnitude. Pallidotomy may also offer some patients an opportunity to increase antiparkinsonian medication. Patient selection for medial pallidotomy should, therefore, be based largely on anticipated improvements in levodopa-induced dyskinesias, but this must be balanced against the associated morbidity and mortality.

Aged↗

PubMed1998

Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET.

OBJECTIVES: To measure the rate of progression in striatal [18F]dopa metabolism in a large group (n=32) of patients with Parkinson's disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period. METHODS: Thirty two patients with Parkinson's disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [18F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis. RESULTS: The mean annual rate of deterioration in [18F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed t test) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [18F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson's disease was estimated at a mean putamen [18F]dopa uptake (Ki) of 75% of normal and a mean caudate [18F]dopa uptake (Ki) of 91% of normal. CONCLUSIONS: Estimation of mean rate of progression varies according to the sensitivity of a functional imaging method to clinical severity. Sensitivity and reproducibility of method must be considered when designing studies of disease progression and neuroprotection. The mean preclinical period in Parkinson's disease is unlikely to be longer than seven years.

Aged↗

PubMed1998

Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H2 15O PET.

The aim of this study was to investigate the functional anatomy of distributed cortical and subcortical motor areas in the human brain that participate in the central control of overlearned complex sequential unimanual finger movements. On the basis of previous research in nonhuman primates, a principal involvement of basal ganglia medial premotor loops [corrected] was predicted for central control of finger sequences performed automatically. In pertinent areas, a correlation of activation levels with the complexity of a motor sequence was hypothesized. H2 15O positron emission tomography (PET) was used in a group of seven healthy male volunteers [mean age 32.0 +/- 10.4 yr] to determine brain regions where levels of regional cerebral blood flow (rCBF) correlated with graded complexity levels of five different key-press sequences. All sequences were overlearned before PET and involved key-presses of fingers II-V of the right hand. Movements of individual fingers were kept constant throughout all five conditions by external pacing at 1-Hz intervals. Positive correlations of rCBF with increasing sequence complexity were identified in the contralateral rostral supplementary motor area (pre-SMA) and the associated pallido-thalamic loop, as well as in right parietal area 7 and ipsilateral primary motor cortex (M1). In contrast, while rCBF in contralateral M1 and [corrected] extensive parts of caudal SMA was increased compared with rest during task performance, significant correlated increases of rCBF with sequence complexity were not observed. Inverse correlations of rCBF with increasing sequence complexity were identified in mesial prefrontal-, medial temporal-, and anterior cingulate areas. The findings provide further evidence in humans supporting the notion of a segregation of SMA into functionally distinct subcomponents: although pre-SMA was differentially activated depending on the complexity of a sequence of learned finger movements, such modulation was not detectable in caudal SMA (except the most antero-superior part), implicating a motor executive role. Our observations of complexity-correlated rCBF increases in anterior globus pallidus suggest a specific role for the basal ganglia in the process of sequence facilitation and control. They may act to filter and focus input from motor cortical areas as patterns of action become increasingly complex.

Adult↗

PubMed1998

Positron emission tomography studies in movement disorders.

Positron emission tomography (PET) scanning provides a sensitive means of detecting and characterizing regional changes in brain metabolism and receptor binding in movement disorders. PET allows the quantitative examination of regional cerebral blood flow, regional glucose and oxygen metabolism, and brain pharmacology. In this article, the particular use of PET to determine the effects of therapeutic stereotactic surgery, including transplantation, on brain function in Parkinson's disease and in tremor patients is highlighted.

Humans↗

PubMed1997

The effect of movement frequency on cerebral activation: a positron emission tomography study.

Knowledge of the effect of performance frequency on activation of motor areas in positron emission tomography (PET) studies is crucial to the interpretation of experiments in which performance is a variable. We studied this effect in six normal right-handed volunteers using H2(15)O PET to measure regional cerebral blood flow (rCBF). Subjects were scanned at rest and while executing joystick movements with the right hand in freely chosen directions at different frequencies. Significant frequency dependent increases in rCBF were demonstrated in contralateral sensorimotor cortex, lateral premotor cortex bilaterally, posterior supplementary motor area (SMA), and ipsilateral cerebellar hemisphere and vermis. The striatum and the right dorsal prefrontal cortex were also activated by joystick movement compared with rest, but the magnitude of activation found in these areas was independent of the frequency of movement. The results suggest that primary motor cortex, posterior SMA, lateral premotor cortex and cerebellum are involved in determining the basic parameters of movement. Frequency dependent activation in these areas suggests phasic activity related to movement. In contrast, activation of the dorsal prefrontal cortex and the striatum is not frequency dependent. This may reflect continuous rather than phasic activity in these areas during the task and suggests their role is not simply related to movement execution but higher level during this free selection joystick task.

Adult↗

PubMed1997

Stereotactic thalamotomy in tremor-dominant Parkinson's disease: an H2(15)O PET motor activation study.

Stereotactic thalamotomy is an effective treatment for severe drug-resistant tremor. The thalamus, however, facilitates motor activity, and thalamotomy would be predicted to inhibit movement-associated cortical activation. Two tremulous parkinsonian patients were studied with H2(15)O positron emission tomography before and after left ventralis intermedius thalamotomy. Subjects were scanned at rest and during performance of externally paced joystick movements in freely selected directions with the right hand. Thalamotomy relieved tremor but, as predicted, led to decreased activation of the left sensorimotor cortex, lateral premotor cortex, and parietal area 7 on hand movement.

Aged↗

PubMed1997

Dopaminergic function in familial Parkinson's disease: a clinical and 18F-dopa positron emission tomography study.

There is increasing evidence for familial aggregation in Parkinson's disease (PD). It is possible that some asymptomatic relatives of PD patients have subclinical nigral Lewy body pathology and their identification could help determine the true prevalence of the disease. We used 18F-dopa positron emission tomography to investigate nigrostriatal dopaminergic terminal function in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism. Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen 18F-dopa uptake (2.5 standard deviations below the normal mean). When discriminant function analysis was applied, all of these 8 subjects plus another 3 were classified with high probability as having PD. On neurological examination, 5 of the 32 relatives scanned had an isolated mild postural tremor and 2 of these 5 had reduced putamen uptake. Our findings provide further support for a role of inheritance in the etiology of PD and suggest that the penetrance for nigrostriatal dopaminergic dysfunction in familial clusters of PD is higher than the prevalence of clinical parkinsonism reported in epidemiological surveys.

Adult↗

PubMed1997

Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease.

Six patients with Parkinson's disease were followed for 10 to 72 months after human embryonic mesencephalic tissue from four to seven donors was grafted unilaterally into the putamen (4 patients) or putamen plus caudate (2 patients). After 8 to 12 months, positron emission tomography showed a 68% increase of 6-L-[18F]-fluorodopa uptake in the grafted putamen, no change in the grafted caudate, and minor decreases in nongrafted striatal regions. There was therapeutically valuable improvement in 4 patients, but only modest changes in the other 2, both of whom developed atypical features. Patient 4 was without L-dopa from 32 months and had normal fluorodopa uptake in the grafted putamen at 72 months. Overall, the L-dopa dose was reduced by a mean of 10 and 20%, "off" time was reduced by 34 and 44%, and the "off" phase Unified Parkinson's Disease Rating Scale motor score by 18 and 26%, and the duration of the response to a single L-dopa dose increased by 45 and 58% during the first and second years after surgery, respectively. Rigidity and hypokinesia improved bilaterally, but mainly contralateral to the implant. No consistent changes in dyskinesias were observed. We conclude that transplantation of embryonic mesencephalic tissue leads to highly reproducible survival of dopaminergic neurons, inducing clinically valuable improvements in most recipients.

Adult↗

PubMed1997

Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias.

Levodopa-induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa-induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [11C]diprenorphine to assess changes in cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.

Adult↗

PubMed1997

Cerebral glucose metabolism in corticobasal degeneration: comparison with progressive supranuclear palsy and normal controls.

The regional metabolic rate of glucose was estimated using 18F-labeled 2-deoxyglucose and positron-emission tomography (PET) in eight patients with corticobasal degeneration (CBD). Measures of cerebral glucose metabolism in these patients were compared with those for nine age-matched normal controls and eight patients with progressive supranuclear palsy (PSP). Compared with that in the normal controls, the CBD patients showed significantly reduced cerebral glucose metabolism in the contralateral hemisphere to the clinically most affected side in the dorsolateral frontal, medial frontal, inferior parietal, sensorimotor, and lateral temporal cortex, as well as in the corpus striatum and the thalamus. In comparison with that in PSP, in CBD the glucose metabolism in the contralateral hemisphere was significantly decreased in the inferior parietal, sensorimotor, lateral temporal cortex, and the corpus striatum. These results confirm the marked asymmetric cerebral involvement in CBD and suggest that there are significant differences between CBD and PSP in the cerebral metabolism in some cerebral regions such as the inferior parietal cortex and sensorimotor cortex, which might reflect the differences in their clinical characteristics.

Aged↗

PubMed1997

Parkinsonism associated with acute intracranial hematomas: an [18F]dopa positron-emission tomography study.

We present the case of a 36-year-old woman with a right temporal hematoma and an overlying subdural hematoma following rupture of a right middle cerebral artery aneurysm. Three weeks after recovering consciousness, she developed a levodopa-responsive parkinsonian syndrome involving the right limbs. A year after the vascular event, she reported subjective improvement in her parkinsonism, which has remained stable since. 18F-dopa positron-emission tomography showed a marked reduction of uptake in the left putamen, raising the possibility that the intracranial hemorrhage unmasked latent Parkinson's disease. To the best of our knowledge, this is the first case of parkinsonism associated with spontaneous acute intracerebral and subdural hematomas.

Acute Disease↗

PubMed1997

PET and the investigation of dementia in the parkinsonian patient.

Parkinsonism and dementia are present in a number of neurodegenerative conditions. They may be a manifestation of isolated brain stem (Parkinson's disease) or diffuse Lewy body disease (DLBD), or be secondary to combined Lewy body and Alzheimer's disease (AD) pathologies. Positron emission tomography (PET) studies show a resting pattern of fronto-temporo-parietal hypometabolism in both, AD and in parkinsonism-dementia (PD-dementia) patients, even when only isolated brain stem Lewy body disease is found at pathology. We have studied three patients fulfilling clinical criteria for diagnosis of DLBD. Their 18F-fluorodeoxyglucose (FDG) PET results showed an AD pattern of fronto-temporo-parietal hypometabolism, though these patients had only mild cognitive dysfunction. Parkinsonism associated with apraxia is observed in corticobasal degeneration (CBD) while impairment of frontal functions, such as planning and sorting, is seen in patients with progressive supranuclear palsy (PSP). PET studies in CBD patients have shown an asymmetric hypometabolism of cortex and thalamus contralateral to the affected limbs, while in PSP patients there is a global metabolic reduction most pronounced in frontal areas and the basal ganglia. These results suggest that metabolic PET studies can help to distinguish PD-dementia, PSP and CBD, but are unable to distinguish PD-dementia from AD. Further studies with post-mortem confirmation are required to establish if DLBD is associated with a distinctive pattern of resting hypometabolism.

Aged↗