Biomedical subjects

David J Brooks

Publications and source records attributed to David J Brooks.

At least 55 records · Page 3Linked to original sources

PubMed2004

Neuroimaging in Parkinson's disease.

In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson's disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.

Brain↗

PubMed2004

Positron emission tomography imaging of transplant function.

In this article, the role of functional imaging for providing objective evidence that grafts of fetal tissue can survive and form connections in Parkinson's and Huntington's disease patients is reviewed. The dissociation between dopamine storage capacity, clinical improvement, and normalization of brain metabolism in PD is discussed, and possible mechanisms underlying the phenomenon of dyskinesias off medication are presented. It is concluded the positron emission tomography and single photon emission computed tomography can provide valuable ancillary information alongside clinical observations but are not currently appropriate modalities for use as surrogate endpoints.

Animals↗

PubMed2004

A technique for standardized central analysis of 6-(18)F-fluoro-L-DOPA PET data from a multicenter study.

UNLABELLED: We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6 different PET centers around the world and then analyzed at a single site. To our knowledge, this is the first time such a centralized approach has been employed with (18)F-DOPA PET and this descriptive basic science article outlines the methods used. METHODS: One hundred eighty-six PD patients were randomized (1:1) to ropinirole or L-DOPA therapy, and (18)F-DOPA PET was performed at baseline and again at 2 y. The primary outcome measure was the percentage change in putamen (18)F-DOPA influx rate constant (K(i)) from Patlak graphical analysis. Dynamic images were acquired and reconstructed using each center's individual protocols before being transferred to the site performing the central analysis. Once there, individual parametric K(i) images were created using a single analysis program without file formats being transformed from the original. Parametric images were then normalized to standard space and K(i) values extracted with a region of interest analysis. Significant K(i) changes were also localized at a voxel level with statistical parametric mapping. These processes required numerous checks to ensure the integrity of each dataset. RESULTS: Three hundred twenty-five (170 baseline, 155 follow-up) dynamic PET datasets were acquired, of which 12 were considered uninterpretable due to missing time frames, radiopharmaceutical problems, lack of measured attenuation correction, or excessive head movement. In those datasets suitable for central analysis, after quality control and spatial normalization of the images had been applied, putamen (18)F-DOPA signal decline was found to be significantly (one third) slower in the ropinirole group compared with that of the L-DOPA group. CONCLUSION: Paired (18)F-DOPA-PET images acquired from multiple sites can be successfully analyzed centrally to assess the efficacy of potential disease-modifying therapies in PD. However, numerous options must be considered and data checks put in place before adopting such an approach. Centralized analysis offers the potential for improved detection of outcomes due to the standardization of the analytic approach and allows the analysis of large numbers of PET studies.

Algorithms↗

PubMed2003

Monoamine neuron innervation of the normal human brain: an 18F-DOPA PET study.

18F-DOPA positron emission tomography (PET) has been used for two decades to study the organization and pathology of the striatal dopamine system in the human brain, particularly in Parkinson's disease. High resolution 3D PET allows a more detailed analysis than previously available and was employed in this study to determine the regional uptake of 18F-DOPA in control brain. Eleven healthy volunteers underwent 18F-DOPA PET with a region of interest (ROI) study performed using individual volumetric MRI's coregistered to the PET ADD image. A Patlak linear graphical analysis was undertaken to obtain influx constant (Ki) values. The highest Ki values were from neostriatal areas, with a rostrocaudal gradient of increasing Ki values from head of caudate nucleus to rostral putamen to caudal putamen. However, Ki values for transaxial slices from dorsal to ventral through the caudate and putamen were uniform. Ventral striatum Ki was 81% with red nucleus and globus pallidus Ki values of approximately 40% of neostriatum. In limbic areas, highest values were obtained from amygdala (35% neostriatal Ki). Neocortical Ki values varied from 22% in temporal pole to 6% in occipital cortex of neostriatal values. Hypothalamic Ki was high (45%) in comparison to thalamus (17%) and retina (17%). 18F-DOPA is taken up by serotonin (raphe, 51%), and noradrenaline (locus coeruleus, 37%) as well as dopamine neurons. These data indicate that 18F-DOPA PET can be used with detailed, anatomically based ROIs as a tool for in vivo analysis of regional changes in monoamine neuron systems throughout the brain in Parkinson's disease and other disorders.

Adult↗

PubMed2003

Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.

Dihydroxyphenylalanine↗

PubMed2003

Plasticity of the nigropallidal pathway in Parkinson's disease.

The degeneration of nigrostriatal dopamine neurons in early Parkinson's disease (PD) is compensated in part by increased transmitter turnover in surviving neurons of the pathway. In this (18)F-dopa positron emission tomography study, we demonstrate compensatory changes in PD in another midbrain dopamine projection to the basal ganglia, the nigropallidal projection to the internal segment of the globus pallidus (GPi). Increased (18)F-dopa uptake in the GPi is seen in early PD which then is lost in advanced PD. Our early PD cases show an absence of significant clinical progression in the face of a continuing loss of nigrostriatal projections. This indicates a compensatory neuronal plasticity that we now show to involve the nigropallidal dopamine pathway to the GPi but not to the external segment of the globus pallidus (GPe). Enhanced function of the dopamine projection to the GPi serves, we propose, to maintain a more normal pattern of pallidal output to ventral thalamus and motor cortex in early PD, whereas loss of this adaptive pathway in advanced disease may be a pivotal step in the progression of the disease.

Adult↗

PubMed2003

Imaging end points for monitoring neuroprotection in Parkinson's disease.

In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD.

Brain↗

PubMed2003

Endogenous dopamine release after pharmacological challenges in Parkinson's disease.

Using (11)C-raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in (11)C-raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by (18)F-dopa uptake. Localization of significant changes in (11)C-raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease.

Aged↗

PubMed2003

Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study.

Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.

Adult↗

PubMed2003

Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe.

Probabilistic atlases of neuroanatomy are more representative of population anatomy than single brain atlases. They allow anatomical labeling of the results of group studies in stereotaxic space, automated anatomical labeling of individual brain imaging datasets, and the statistical assessment of normal ranges for structure volumes and extents. No such manually constructed atlas is currently available for the frequently studied group of young adults. We studied 20 normal subjects (10 women, median age 31 years) with high-resolution magnetic resonance imaging (MRI) scanning. Images were nonuniformity corrected and reoriented along both the anterior-posterior commissure (AC-PC) line horizontally and the midsagittal plane sagittally. Building on our previous work, we have expanded and refined existing algorithms for the subdivision of MRI datasets into anatomical structures. The resulting algorithm is presented in the Appendix. Forty-nine structures were interactively defined as three-dimensional volumes-of-interest (VOIs). The resulting 20 individual atlases were spatially transformed (normalized) into standard stereotaxic space, using SPM99 software and the MNI/ICBM 152 template. We evaluated volume data for all structures both in native space and after spatial normalization, and used the normalized superimposed atlases to create a maximum probability map in stereotaxic space, which retains quantitative information regarding inter-subject variability. Its potential applications range from the automatic labeling of new scans to the detection of anatomical abnormalities in patients. Further data can be extracted from the atlas for the detailed analysis of individual structures.

Adult↗

PubMed2003

Dopamine release during sequential finger movements in health and Parkinson's disease: a PET study.

Parkinson's disease is associated with slowness, especially of sequential movements, and is characterized pathologically by degeneration of dopaminergic neurons, particularly targeting nigrostriatal projections. In turn, nigrostriatal dopamine has been suggested to be critical for the execution of sequential movements. The objective of this study was to investigate in vivo, with [(11)C]raclopride, PET changes in regional brain levels of dopamine in healthy volunteers and Parkinson's disease patients during the execution of paced, stereotyped sequential finger movements. Striatal [(11)C]raclopride binding reflects dopamine D(2) receptor availability and is influenced by synaptic levels of endogenous dopamine. During execution of a pre-learned sequence of finger movements, a significant reduction in binding potential (BP) of [(11)C]raclopride was seen in both caudate and putamen in healthy volunteers compared with a resting baseline, consistent with release of endogenous dopamine. Parkinson's disease patients also showed attenuated [(11)C]raclopride BP reductions during the same motor paradigm in striatal areas less affected by the disease process. These findings confirm that striatal dopamine release is a component of movement sequencing and show that dopamine release can be detected in early Parkinson's disease during a behavioural manipulation.

Adult↗

PubMed2003

Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Adult↗

PubMed2003

Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients.

In 20-30% of potential surgical candidates with refractory focal epilepsy, standard MRI does not identify the cause. gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. [(11)C]Flumazenil (FMZ) PET images most subtypes of GABA(A) receptors, present on most neurons. We investigated [(11)C]FMZ binding in grey and white matter in 16 normal controls and in 44 patients with refractory neocortical focal epilepsy and normal optimal MRI. Fourteen patients had unilateral frontal lobe epilepsy, five occipital lobe epilepsy (OLE), six parietal lobe epilepsy (PLE) and 19 neocortical epilepsy that was not clearly lobar. Parametric images of FMZ volume of distribution (FMZ-V(d)) were computed. Statistical parametric mapping (SPM99) with explicit masking, including the white matter, was used to analyse individual patients and groups. Thirty-three of the 44 patients showed focal abnormal FMZ-V(d); increases in 16, decreases in eight, and both increases and decreases in nine. In seven patients, the increases in FMZ binding were periventricular, in locations normally seen in periventricular nodular heterotopia on MRI. There were frontal and parietal increases in FMZ binding in grey and white matter in the PLE group and decreases in the cingulate gyrus in the OLE group. FMZ binding increases, particularly periventricular increases, were a prominent feature of MRI-negative focal epilepsies and may represent neuronal migration disturbances.

Adolescent↗

PubMed2003

PET studies on the function of dopamine in health and Parkinson's disease.

Positron emission tomography (PET) can detect the presence of striatal, pallidal, midbrain, and cortical dopamine terminal dysfunction in vivo in Parkinson's disease (PD). In addition, dopamine release during motor tasks can be assessed as reflected by changes in receptor availability to PET ligands. Furthermore, the functional effects of focal dopamine replacement via implantation of fetal cells or glia-derived neurotrophic factor (GDNF) infusion into putamen can be monitored. In this review, the insight that PET has given us concerning the role of dopamine in motor control is presented, and the functional substrates underlying PD symptomatologies are discussed.

Animals↗

PubMed2002

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Aged↗

PubMed2002

Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study.

PARK6, a locus for early-onset recessive parkinsonism, has been causally implicated in nine unrelated families from four different countries. The gene is still unidentified and hence the importance of PARK6 as a cause of Parkinson's disease is unknown. To date, no pathology or functional imaging studies are available on PARK6-linked parkinsonism. We have used (18)F-dopa positron emission tomography to study four patients who are homozygous and three asymptomatic relatives who are heterozygous for PARK6. The clinically affected PARK6 subjects had a similar 85% reduction in posterior dorsal putamen (18)F-dopa uptake to a group of idiopathic Parkinson's disease patients matched for clinical disease severity and duration but showed significantly greater involvement of head of caudate and anterior putamen. The group of asymptomatic PARK6 carriers showed a significant mean 20 to 30% reduction in caudate and putamen (18)F-dopa uptake in comparison with controls, individual values falling toward the bottom of the normal range. Our results indicate that PARK6 pathology results in a more uniform loss of striatal dopamine terminal function than Parkinson's disease. The subclinical loss of striatal dopamine storage capacity found in the PARK6 carriers implies that the unidentified gene on the short arm of chromosome 1 exhibits either haploinsufficency or a dominant negative effect.

Adult↗

PubMed2002

Implementation and application of a brain template for multiple volumes of interest.

We present a region template and a protocol for transforming that template to define anatomical volumes of interest (VOIs) in the human brain without operator intervention, based on software contained in the SPM99 package (Statistical Parametric Mapping, Wellcome Department of Cognitive Neurology, London, UK). We used an MRI of a reference brain to create an anatomical template of 41 VOIs, covering the entire brain, that can be spatially transformed to fit individual brain scans. Modified software allows for the reslicing and adaptation of the transformed template to any type of coregistered functional data. Individually defined VOIs can be added. We present an assessment of the necessary spatial transformations and compare results obtained for scans acquired in two different orientations. To evaluate the spatial transformations, 11 landmarks distributed throughout the brain were chosen. Euclidean distances between repeat samples at each landmark were averaged across all landmarks to give a mean difference of 1.3 plus minus 1.0 mm. Average Euclidean distances between landmarks (MRI:transformed template) were 8.1 plus minus 3.7 mm in anterior-posterior commissure (ACPC) and 7.6 plus minus 3.7 mm in temporal lobe (TL) orientation. In this study, we use [(11)C]-flumazenil-(FMZ-)PET as an example for the application of the region template. Thirty-four healthy volunteers were scanned, 21 in standard ACPC orientation, 13 in TL orientation. All had high resolution MRI and FMZ-PET. The average coefficient of variation (CV) of FMZ binding for cortical regions was 0.15, comparable with CVs from manually defined VOIs. FMZ binding was significantly different in 6/19 anatomical areas in the control groups obtained in the different orientations, probably due to anisotropic voxel dimensions. This new template allows for the reliable and fast definition of multiple VOIs. It can be used for different imaging modalities and in different orientations. It is necessary that imaging data for groups compared are acquired in the same orientation.

Adult↗

PubMed2002

An imaging study of parkinsonism among African-Caribbean and Indian London communities.

We previously reported on 131 parkinsonian patients of African-Caribbean and Indian origin attending movement disorders clinics in six London Hospitals, of whom approximately 20% manifested atypical parkinsonism with a late-onset, akinetic-rigid predominant syndrome, postural instability and minimal resting tremor refractory to levodopa therapy and dopamine agonists (see Hu et al., Neurology 2000;54[Suppl.3]: A188 and Hu et al., Mov Disord 2000;15[Suppl.3]:S212). To better elucidate the phenotype of these atypical patients (18)FDG/(18)F-dopa positron emission tomography (PET) were performed in a subgroup to look for cortical and striatal metabolic changes suggestive of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or dementia with Lewy bodies. Magnetic resonance imaging (MRI) rating of cerebral vascular lesion load, putaminal atrophy, and neuropsychological testing were also performed. Discriminant function analysis of (18)F-dopa/(18)FDG striatal metabolism in 43 patients failed to separate atypical ethnic minority from typical Caucasian Parkinson's disease (PD) patients. Additionally, atypical Indian and African-Caribbean patients did not show cortical reductions in glucose metabolism suggestive of PSP, CBD, or DLB. Cerebral vascular lesion load rated in these patients did not differ between atypical and typical PD groups, and none of the atypical patients had MRI changes suggestive of MSA or PSP. Our results suggest the atypical parkinsonian phenotype seen in African-Caribbean and Indian patients represents a levodopa-refractory form of PD separate from MSA or PSP in most patients.

Adult↗