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David J Brooks

Publications and source records attributed to David J Brooks.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Aged↗
PubMed2005

Plasma-promoted dielectric heating in the microwave synthesis of spinels.

Comparison between the rates of synthesis of the spinel phases (MAl2O4, M = Mg, Zn, Ni; and MFe2O4, M = Mg, Zn, Mn) using an O2 microwave-induced plasma (MIP) and conventional (tube furnace) methods indicate that a MIP promotes microwave dielectric heating at elevated temperatures.

Journal Article↗
PubMed2005

The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study.

Opioids have been shown to provide symptomatic relief from dysaesthesias and motor symptoms in restless legs syndrome (RLS). However, the mechanisms by which endogenous opioids contribute to the pathophysiology of RLS remain unknown. We have studied opioid receptor availability in 15 patients with primary RLS and 12 age-matched healthy volunteers using PET and [11C]diprenorphine, a non-selective opioid receptor radioligand. Ligand binding was quantified by generating parametric images of volume of distribution (V(d)) using a plasma-derived input function. Statistical parametric mapping (SPM) was used to localize mean group differences between patients and controls and to correlate ligand binding with clinical scores of disease severity. There were no mean group differences in opioid receptor binding between patients and controls. However, we found regional negative correlations between ligand binding and RLS severity (international restless legs scale, IRLS) in areas serving the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex and orbitofrontal cortex). Pain scores (affective component of the McGill Pain Questionnaire) correlated inversely with opioid receptor binding in orbitofrontal cortex and anterior cingulate gyrus. Our findings suggest that, the more severe the RLS, the greater the release of endogenous opioids within the medial pain system. We therefore discuss a possible role for opioids in the pathophysiology of RLS with respect to sensory and motor symptoms.

Adult↗
PubMed2005

Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1.

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.

Aged↗
PubMed2005

Chorea associated with thyroxine replacement therapy.

Chorea is an uncommonly reported manifestation of hyperthyroidism. We report the first description of generalized chorea due to iatrogenic thyrotoxicosis and propose that the movement disorder is due to a direct effect of thyroxine on the basal ganglia rather than being an autoimmune phenomenon.

Aged↗
PubMed2005

Periventricular white matter flumazenil binding and postoperative outcome in hippocampal sclerosis.

PURPOSE: In patients with hippocampal sclerosis (HS), anterior temporal lobe resection offers the possibility of a long-lasting suppression of seizures in two thirds of patients. White matter (WM) [11C]flumazenil volume of distribution (FMZ-Vd) reflects the number of neuronal cell bodies in WM. Our objective was to correlate WM FMZ-Vd in patients with unilateral HS and postsurgical outcome. METHODS: We performed [11C]FMZ-PET in 15 patients with refractory mesial temporal lobe epilepsy (mTLE) and a quantitative MRI diagnosis of unilateral HS subsequently histologically verified in all cases. Median follow-up was 7 years (range, 6-9 years). Metabolite-corrected arterial plasma input functions and spectral analysis were used to generate parametric images of [11C]FMZ-Vd. Statistical parametric mapping (SPM99) with explicit masking was used to investigate the entire brain volume including WM. RESULTS: Eight patients had Engel class IA outcome (completely seizure free since surgery), and seven were not seizure free. Comparison of seizure-free patients with those who continued to have seizures after surgery revealed areas of increased FMZ binding around the posterior horns of the ipsilateral (z=3.7) and contralateral (z=2.7) ventricles in those with suboptimal outcomes. CONCLUSIONS: Preoperative [11C]FMZ-PET can detect periventricular increases of WM FMZ binding, implying heterotopic neurons in WM, in patients with mTLE. The presence of such increases correlates with a poorer outcome.

Adult↗
PubMed2005

Positron emission tomography and single-photon emission computed tomography in central nervous system drug development.

In this review, the value of functional imaging [positron emission tomography (PET)/single-photon emission computed tomography (SPECT)] in drug development is considered. Radionuclide imaging can help establish the diagnosis of neurodegenerative disorders where this is in doubt and provides a potential biomarker for following drug effects on disease progression. PET and SPECT can help understand mechanisms of disease and determine the functional effects of therapeutic approaches on neurotransmission and metabolism. Synthesizing radiotracer analogs of novel drugs can provide proof of principle that these agents reach their enzyme or receptor targets and delineate their regional brain distribution. If such radiotracers do not prove to have ideal properties for imaging, the concept of microdosing potentially allows multiple other drug analogs to be tested with less stringent regulatory requirements than for novel medicinals. Finally, PET tracers can provide receptor and enzyme active site dose occupancy profiles, thereby guiding dosage selection for phase 1 and phase 2 trials. The eventual hope is that radiotracer imaging will provide a surrogate marker for drug efficacy, although this has yet to be realized, and progress the concept of personalized medicine where receptor/enzyme binding profiles help predict therapeutic outcome.

Animals↗
PubMed2004

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

Adult↗
PubMed2004

[123I]AM281 single-photon emission computed tomography imaging of central cannabinoid CB1 receptors before and after Delta9-tetrahydrocannabinol therapy and whole-body scanning for assessment of radiation dose in tourette patients.

BACKGROUND: The cannabinoid CB1 receptor agonist Delta9-THC has been suggested for treatment of Tourette syndrome (TS). Based on animal studies, the CB1 antagonist [123I]AM281 (N-(Morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-[123I]iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide) has been proposed for single photon emission computed tomography (SPECT) in humans. Our aims were to 1) evaluate specific binding of [123I]AM281 to CB1 receptors in TS patients and 2) assess radiation exposure associated with the use of AM281 labeled with 123I for SPECT and 124I for positron emission tomography. METHODS: We employed [123I]AM281 in six TS patients before and after Delta9-THC treatment. Dynamic SPECT, plasma measurements (including metabolite analysis with thin layer chromatography), and whole-body imaging were performed. Regions of interest derived from magnetic resonance images were used to extract from SPECT uptake in an area with high CB1 density (lentiform nuclei) and reference regions. Specific over nonspecific partition coefficients V3" were calculated. Whole-body images were carried out for dosimetric analysis. Data obtained with [123I]AM281 were used to predict doses from [124I]AM281. RESULTS: Mean V3" ranged from .19 to .31 and did not change significantly after Delta9-THC treatment. Nevertheless, in the only patient with a marked clinical response, V3" clearly declined. Thin layer chromatography revealed biexponential kinetics of tracer metabolism; about 60% remained nonmetabolized after 3 hours. Effective doses of .011 mSv/MBq for [123I]AM281 and .34 for [124I]AM281 were computed. CONCLUSIONS: This study suggests that specific binding of [123I]AM281 to CB1 receptors can be detected in patients using SPECT. Radiation exposure with [123I]AM281 is low; that with [124I]AM281 is higher but acceptable for single investigations.

Adult↗
PubMed2004

Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism.

To investigate striatal and cortical pre- and postsynaptic dopaminergic function in parkin-linked parkinsonism, 13 unrelated patients homozygous or compound heterozygous for parkin mutations were studied with [(18)F]dopa and [(11)C]raclopride (RAC) PET. Data were compared with a young-onset Parkinson's disease (YOPD) cohort, matched for age, disease severity and duration, but negative for parkin mutations. Significant changes in [(18)F]dopa uptake and RAC binding potential (BP) were localized in striatum using regions of interest (ROIs) and throughout the entire brain volume with statistical parametric mapping (SPM). As expected, both YOPD and parkin patients showed significant decreases in striatal [(18)F]dopa uptake; however, in parkin patients, additional reductions in caudate and midbrain were localized with SPM. The RAC-BP was significantly decreased in striatal, thalamic and cortical areas (temporal, orbito-frontal and parietal cortex) in parkin compared with YOPD patients. Our [(18)F]dopa PET findings suggest that, compared with YOPD, parkin disease is associated with more severe and widespread presynaptic dopaminergic deficits. The global decreases in D2 binding found in parkin compared with YOPD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term dopaminergic agent exposure. Cortical reductions in D2 binding may contribute to the behavioural problems reported in parkin patients.

Adult↗
PubMed2004

The human premotor cortex is 'mirror' only for biological actions.

Previous work has shown that both human adults and children attend to grasping actions performed by another person but not necessarily to those made by a mechanical device. According to recent neurophysiological data, the monkey premotor cortex contains "mirror" neurons that discharge both when the monkey performs specific manual grasping actions and when it observes another individual performing the same or similar actions. However, when a human model uses tools to perform grasping actions, the mirror neurons are not activated. A similar "mirror" system has been described in humans, but whether or not it is also tuned specifically to biological actions has never been tested. Here we show that when subjects observed manual grasping actions performed by a human model a significant neural response was elicited in the left premotor cortex. This activation was not evident for the observation of grasping actions performed by a robot model commanded by an experimenter. This result indicates for the first time that in humans the mirror system is biologically tuned. This system appears to be the neural substrate for biological preference during action coding.

Adult↗
PubMed2004

Safety and tolerability of COMT inhibitors.

Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Aged↗
PubMed2004

Cardiovascular effects of methamphetamine in Parkinson's disease patients.

Cardiovascular responses after intravenous methamphetamine were assessed in 11 Parkinson's disease (PD) patients. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and electrocardiogram (ECG) were monitored for 103 minutes. After methamphetamine administration, SBP and DBP increased significantly in both PD and normal controls whereas placebo had no effect. In PD patients, however, the duration of SBP and DBP responses to methamphetamine and the maximum increase from baseline was attenuated compared with the controls. A significant correlation was found between individual BP responsiveness and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These findings suggest that in PD there is impairment of catecholamine release from peripheral sympathetic presynaptic terminals, which correlates with motor impairment.

Adrenergic Fibers↗
PubMed2004

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative parkinsonian disorder of unknown cause that shows considerable clinical heterogeneity. In CBD, activated microglia have been shown to be associated closely with the extensive tau pathology found in the affected basal ganglia, brainstem nuclei, and cortical regions. We report on the use of [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) (PK11195) positron emission tomography (PET), a marker of peripheral benzodiazepine binding sites (PBBS) that are expressed by activated microglia, to demonstrate in vivo the degree and distribution of glial response to the degenerative process in 4 patients with CBD. Compared with normal age-matched controls, the CBD patient group showed significantly increased mean [(11)C](R)-PK11195 binding in the caudate nucleus, putamen, substantia nigra, pons, pre- and postcentral gyrus, and the frontal lobe. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in CBD patients involving cortical regions and the basal ganglia that corresponds well with the known distribution of neuropathological changes, which may therefore help to characterize in vivo the underlying disease activity in CBD.

Aged↗
PubMed2004

Opioid binding in DYT1 primary torsion dystonia: an 11C-diprenorphine PET study.

The opioid transmitters enkephalin and dynorphin are known to regulate pallidal output and consequently cortical excitability. Indeed, abnormal basal ganglia opioid transmission has been reported in several involuntary movement disorders, including levodopa-induced dyskinesias in Parkinson's disease (PD), tardive dyskinesias/dystonia, Huntington's disease, and Tourette's syndrome. Moreover, a previous 11C-diprenorphine PET study investigating levodopa-induced dyskinesias found reduced opioid receptor availability in PD with but not without dyskinesias. We wished to investigate if a similar alteration in basal ganglia opioid binding was present in DYT1 primary torsion dystonia (PTD). Regional cerebral 11C-diprenorphine binding was investigated in 7 manifesting carriers of the DYT1 gene and 15 age-matched normal controls using a region-of-interest (ROI) approach and statistical parametric mapping (SPM). No difference in regional mean 11C-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of dystonia and opioid binding was seen. We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement.

Adult↗
PubMed2004

Cognitive and motor effects of dopaminergic medication withdrawal in Parkinson's disease.

AIMS: Recent evidence points towards dissociable effects of dopaminergic medication on motor function and cognitive function mediated by different fronto-striatal neural circuits. This study aimed to clarify the role of dopaminergic medication in spatial working memory, and reinforcement-based associative learning in relation to clinical changes in motor function in early Parkinson's disease (PD). METHOD: We tested 14 patients with mild to moderate PD on and off dopaminergic medication, on a spatial delayed-response working memory task, and on spatial and non-spatial (visual) trial-and-error learning tasks based on reinforcement, carefully matched for motor requirements. In addition, we explored relationships between the effects of withdrawal on motor symptom expression and performance on the cognitive tasks. RESULTS: Withdrawal from dopaminergic medication significantly exacerbated motor symptoms. This was related to spatial learning, but not visual learning, or delayed response accuracy. Moreover, medication withdrawal led to dissociable effects of response latency on the spatial learning and spatial delayed response tasks, with patients becoming faster after spatial learning, but relatively slower on the delayed response task. These changes in response latency were unrelated to motor symptom impairment. CONCLUSION: Our findings suggest dissociable effects of dopamine medication withdrawal on cognitive processes putatively mediated by dorsal and ventral striatal regions.

Aged↗
PubMed2004

Reward processing in health and Parkinson's disease: neural organization and reorganization.

It has been suggested that motivational processes mediated by dopaminergic neural systems may be relatively spared in Parkinson's disease (PD) and activation of these pathways may be of therapeutic relevance. To investigate the behavioural and neural correlates of motivation in unmedicated PD patients, we used H(2)(15)O positron emission tomography to measure brain activation patterns related to the processing of monetary rewards of different magnitudes during a spatial search task in PD patients withdrawn from medication, and age-matched healthy controls. Both groups showed increased search efficiency with increasing reward, but demonstrated different patterns of neuronal activation. In healthy controls activity in prefrontal and rhinal cortices, and thalamic activity correlated with reward magnitude. In contrast, activity in the cerebellar vermis in PD patients increased with increasing reward magnitude, suggesting it was sensitive to motivational state. We interpret these relative increases in cerebellar activation as evidence for the presence of compensatory neural mechanisms in unmedicated PD patients.

Aged↗