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Biomedical subjects

David J Brooks

Publications and source records attributed to David J Brooks.

At least 19 recordsLinked to original sources
PubMed2007

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study.

BACKGROUND: Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD). OBJECTIVE: We conducted a phase I-II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD. METHODS: Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1-3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT-PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson's Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson's Disease Rating Scale III score in the off-medication state. Seven patients had 18F-dopa positron emission tomography scans before and 1 year after transplantation. RESULTS: Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6-12 months after transplantation (5-74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15-48%). None of the patients developed off-period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non-significant 5% increase in mean putaminal 18F-dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal 18F-dopa uptake (r = -0.829; p = 0.042). CONCLUSIONS: CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.

Adult↗
PubMed2007

Statistical neuroanatomy of the human inferior frontal gyrus and probabilistic atlas in a standard stereotaxic space.

We manually defined the inferior frontal gyrus (IFG) on high-resolution MRIs in native space in 30 healthy subjects (15 female, median age 31 years; 15 male, median age 30 years), resulting in 30 individual atlases. Using standard software (SPM99), these were spatially transformed to a widely used stereotaxic space (MNI/ICBM 152) to create probabilistic maps. In native space, the total IFG volume was on average 5%, and the gray matter (GM) portion 12% larger in women (not significant). Expressed as a percentage of ipsilateral frontal lobe volume (i.e., correcting for brain size), the IFG was an average of 20%, and the GM portion of the IFG 27%, larger in women (P < 0.005). Correcting for total lobar volume yielded the same result. No asymmetry was found in IFG volumes. There were significant positional differences between the right and left IFGs, with the right IFG being further lateral in both native and stereotaxic space. Variability was similar on the left and right, but more pronounced anteriorly and superiorly. We show differences in IFG volume, composition, and position between sexes and between hemispheres. Applications include probabilistic determination of location in group studies, automatic labeling of new scans, and detection of anatomical abnormalities in patients.

Adult↗
PubMed2007

Reference and target region modeling of [11C]-(R)-PK11195 brain studies.

UNLABELLED: PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level. METHODS: The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease. RESULTS: The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596). CONCLUSION: Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain.

Algorithms↗
PubMed2006

STN stimulation alters pallidal-frontal coupling during response selection under competition.

To investigate the effects of bilateral subthalamic nucleus (STN) stimulation on patterns of brain activation during random number generation (RNG), a task that requires suppression of habitual counting and response selection under competition. We used H(2)(15)O positron emission tomography to investigate the changes of regional cerebral blood flow (rCBF) induced by bilateral STN stimulation during a RNG task, in six patients with Parkinson's disease. Paced RNG at 1 Hz was compared with a control counting task. Both tasks were performed off medication with deep brain stimulation on and off. Subthalamic nucleus stimulation had a negative effect on performance of fast-paced RNG, leading to reduced randomness and increased habitual counting. Subthalamic nucleus stimulation also induced a reduction of rCBF in the left dorsal frontal gyrus, inferior frontal gyrus, dorsolateral prefrontal cortex, posterior and right anterior cingulate, and an increase of rCBF in the right internal globus pallidum (GPi) during RNG. Stimulation of the STN significantly altered pallidal coupling with frontal and temporal areas compared with when the stimulators were off. In conclusion, during RNG: (i) STN stimulation activates its output neurons to the GPi; (ii) STN stimulation induces increased inhibition of a prefrontal-cingulate network. This is the first direct evidence that STN stimulation significantly alters pallidal coupling with prefrontal, cingulate, and temporal cortices during performance of a task that requires response selection under competition.

Cerebrovascular Circulation↗
PubMed2006

Impaired recognition of facial expressions of anger in Parkinson's disease patients acutely withdrawn from dopamine replacement therapy.

We have previously reported that acute dopaminergic blockade in healthy volunteers results in a transient disruption of the recognition of facial expressions of anger, whilst leaving intact the recognition of other facial expressions (including fear and disgust) and facial identity processing. Parkinson's disease (PD) is characterised by cell loss in dopaminergic neuronal populations, and hence we predicted that PD would be associated with impaired anger recognition. We reasoned that treatment with dopamine replacement therapy (DRT) could mask any deficit present in PD, and therefore studied facial expression recognition in a group of PD patients transiently withdrawn from DRT. Seventeen PD patients were compared to 21 age- and IQ-matched controls on the Ekman 60 task, which required the forced-choice labelling of 10 exemplars of each of six facial expressions (anger, disgust, fear, sadness, happiness, surprise). In line with our predictions, PD patients showed a selective impairment in the recognition of facial expressions of anger. This deficit was not related to the PD patients' performance on the Benton unfamiliar-face matching task, which was normal, nor was the deficit related to overall disease severity, or to depression symptoms. However, as predicted by simulation theories, impaired anger recognition in PD was related to reduced levels of the anger-linked temperament trait, exploratory excitability. The results extend our previous findings of a role for dopamine in the processing of facial expressions of anger, and demonstrate the power of adopting a phylogenetic, comparative perspective on emotions.

Aged↗
PubMed2006

Imaging in Parkinson's disease: the role of monoamines in behavior.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can measure striatal dopamine (DA) terminal function in vivo as reflected by DA storage capacity and transporter binding. In Parkinson's disease (PD) posterior dorsal putamen DA terminals are initially targeted, the anterior putamen and head of caudate subsequently becoming affected. In contrast, dopaminergic function in pallidal, amygdala, and cingulate regions is upregulated in early PD and only later becomes reduced. Rigidity and bradykinesia in PD have been shown to correlate with loss of putamen dopaminergic function, whereas performance on executive and working memory tasks correlates with integrity of caudate dopaminergic terminals. 11C-RTI32 PET, a marker of noradrenergic and dopaminergic transporter binding, can be used to assess noradrenergic along with dopaminergic terminal function. Serotonergic transporter binding can be assessed with 11C-DASB PET and 123I-beta CIT SPECT, whereas HT1A binding can be measured with 11C-WAY100635 PET. With these modalities, the relationship between mood, noradrenergic and serotonergic function can be examined in PD. The functional effects of focal DA replacement on DA storage capacity and patterns of brain activation via implantation of fetal midbrain cells or glial derived neurotrophic factor (GDNF) infusion into putamen of PD patients has been examined with PET. Both approaches lead to consistently increased levels of putamen 18F-dopa uptake, and cell implantation can restore levels of frontal activation. Clinical outcome, however, has proved to be variable and off-medication dyskinesias are an unwanted side effect in transplanted cases. Dopamine release after pharmacological challenges or during behavioral tasks can be assessed indirectly by studying changes in receptor availability to PET radioligands. Stereotyped sequential movements are associated with striatal DA release, and this increases with more complex behaviors and the presence of financial incentives, which also increase frontal DA levels. Parkinson patients release less putamen DA than healthy control subjects during stereotyped finger movements. Interestingly, those PD patients who develop a dopa dependency syndrome, craving their medication, generate significantly greater levels of ventral striatal DA compared with similarly disabled patients without such a psychological dependency. In the future, functional imaging is likely to throw light on the roles of peptide transmission in regulating mood and behavior as non-peptide analogue ligands become available. Novel markers of amyloid plaque load will also help clarify the etiology of dementia in PD.

Brain↗
PubMed2006

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Adult↗
PubMed2006

Compulsive drug use linked to sensitized ventral striatal dopamine transmission.

OBJECTIVE: A small group of Parkinson's disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa-induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients. METHODS: We used a two-scan positron emission tomography protocol to calculate the percentage change in (11)C-raclopride binding potential from a baseline withdrawal (off drug) state to the binding potential after an oral dose of levodopa. We related the subjective effects of levodopa to the effects on endogenous dopamine release of a pharmacological challenge with levodopa in eight control PD patients and eight patients with DDS. RESULTS: PD patients with DDS exhibited enhanced levodopa-induced ventral striatal dopamine release compared with levodopa-treated patients with PD not compulsively taking dopaminergic drugs. The sensitized ventral striatal dopamine neurotransmission produced by levodopa in these individuals correlated with self-reported compulsive drug "wanting" but not "liking" and was related to heightened psychomotor activation (punding). INTERPRETATION: This provides evidence that links sensitization of ventral striatal circuitry in humans to compulsive drug use.

Aged↗
PubMed2006

Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study.

To determine the relationship between cerebral amyloid plaque load and rates of cerebral atrophy in Alzheimer's disease. (11)C-PIB((11)C-6-OH benzothiazole)PET (positron emission tomography) findings were correlated with volumetric magnetic resonance imaging (MRI) measurements in nine subjects with mild to moderate AD. Analysis revealed a positive correlation between rates of whole brain atrophy and whole brain (p = 0.019) and regional (11)C-PIB uptake. This provides support for the central role of amyloid deposition in the pathogenesis of AD.

Aged↗
PubMed2006

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease presenting with voluntary gaze difficulties, early falls, and Parkinsonism. Neuronal loss, associated with intracellular neurofibrillary tangles and activated microglia, is found targeting the basal ganglia, brainstem nuclei, and frontal cortex. [11C](R)-PK11195 PET is a marker of peripheral benzodiazepine binding sites (PBBS) expressed by activated microglia. We have used [11C](R)-PK11195 PET to demonstrate in vivo the degree and distribution of the glial response to the degenerative process in four patients with PSP. Compared to normal age-matched controls, the PSP patient group showed significantly increased mean [11C](R)-PK11195 binding in the basal ganglia, midbrain, the frontal lobe, and the cerebellum. Two of the patients were rescanned after 6 to 10 months and during that time the level of microglial activation remained stable. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in PSP patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes. [11C](R)-PK11195 PET, therefore, may help in characterizing in vivo the underlying disease activity in PSP.

Aged↗
PubMed2006

Nigral degeneration and striatal dopaminergic dysfunction in idiopathic and Parkin-linked Parkinson's disease.

We have used MR segmented inversion recovery ratio imaging (SIRRIM) of the substantia nigra pars compacta to detect and correlate nigral signal change in idiopathic Parkinson's disease (PD) and parkin patients with striatal (18)F-dopa uptake. Nine PD patients, nine parkin patients, and eight control subjects were studied with a combination of MR inversion recovery sequences sensitive to nigral cell loss. Blinded independent observer rating and quantified nigral signal analysis were performed on all subjects. Striatal regions of interest were defined on T(1)-weighted MRI co-registered to (18)F-dopa positron emission tomography. On blinded observer rating of the SIRRIM dorsal and ventral nigral images, 25% (2/8) of control subjects, 44% (4/9) of PD patients, and 67% (6/9) of parkin patients were classified as abnormal. Quantified total nigral signal intensities were reduced to a greater extent in the parkin compared to PD patients. There was a greater predilection for signal reduction in the ventral nigral slice of the PD compared to the parkin patient group, who showed a more uniform involvement. All PD and parkin patients were discriminated from controls on the basis of caudate and putamen (18)F-dopa Ki reductions. Our results suggest that MR segmented inversion recovery ratio imaging shows poor sensitivity for discriminating parkin and idiopathic PD patients from normal controls. Where nigral signal abnormalities were seen, parkin patients manifested generalized nigral cell loss with widespread striatal dopamine terminal dysfunction compared with the lateral nigral targeting seen in PD and selective loss of putamen (18)F-dopa uptake.

Adult↗
PubMed2006

Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.

Adult↗
PubMed2006

New developments of brain imaging for Parkinson's disease and related disorders.

Parkinson's disease (PD) and related disorders are subcortical degenerations targeting the nigrostriatal dopaminergic system and basal ganglia. Traditionally, MRI has been used to detect structural and positron emission tomography and single emission computed tomography functional neurochemical and metabolic changes associated with these disorders. Recently, advances in diffusion-weighted MRI, ultrasonography, and radiotracer-based imaging have yielded greater sensitivity for revealing structural change and allowed detection of changes in brain dopamine levels after levodopa and during behavioral tasks. This review focuses on these recent advances in neuroimaging technology and their use for the diagnosis and assessment of PD and other parkinsonian disorders.

Blood-Brain Barrier↗
PubMed2006

Development of dyskinesias in a 5-year trial of ropinirole and L-dopa.

A 5-year trial of ropinirole and levodopa in early Parkinson's disease showed that ropinirole is associated with reduced incidence of dyskinesias. This post hoc analysis investigated whether the dyskinesia-sparing benefit of ropinirole is lost when levodopa is added to the regimen and evaluated other risk factors for developing dyskinesias. Patients receiving levodopa had a significantly higher risk of dyskinesias than those taking ropinirole monotherapy (hazard ratio [HR], 6.67; 95% confidence interval [CI], 3.23-14.29; P < 0.001). When patients randomized to ropinirole were treated with supplementary levodopa, the development of dyskinesias was not significantly different from that in those receiving levodopa from the start (HR, 0.80; 95% CI, 0.48-1.33; P = 0.39). However, the onset of dyskinesias was delayed by around 3 years compared with levodopa monotherapy. Adjusted analyses taking into account baseline and on-treatment factors that influenced use of supplementary levodopa or the development of dyskinesias produced similar results. In conclusion, the risk of developing dyskinesias during maintained initial ropinirole monotherapy is very low. Only once levodopa is added does the risk substantially change. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started, with no evidence of a subsequent rapid "catch-up" or a persisting preventive effect.

Antiparkinson Agents↗
PubMed2006

Dopaminergic action beyond its effects on motor function: imaging studies.

Along with motor programming, it is now thought that tonic release of dopamine in the striatum acts to focus and filter non-motor activities such as working memory, implicit learning, decision making, and planning. Additionally, thresholds to painful stimuli may well be dopamine dependant. Phasic (burst) release of dopamine in the basal ganglia and frontal areas is thought to play a role in alerting organisms to novel and potentially rewarding stimuli and in mediating contextual learning. Dopamine release also drives a craving for stimuli and facilitates their enjoyment. Functional imaging can help elucidate the role of dopamine in mediating non-motor activities. The integrity of dopamine terminal function can be measured with PET and SPECT in vivo in health and Parkinson's disease (PD) and this can be correlated with performance of executive tasks. In addition, these imaging modalities allow dopamine release in response to stimuli (both rewarding and unrewarding) to be detected, as reflected by changes in D2 receptor availability to radioligands. Finally, the functional effects of dopamine deficiency and its replacement can be monitored by studying patterns of brain activation, as evidenced by regional blood flow changes. In this review, some of the insights that imaging has given us concerning the role of dopamine in non-motor functions is presented.

Depression↗
PubMed2005

Factors affecting the clinical outcome after neural transplantation in Parkinson's disease.

Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18F-dopa and 11C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased 18F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of 18F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of 18F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between 18F-dopa uptake and methamphetamine-induced change of 11C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between 11C-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of 18F-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.

Carbon Radioisotopes↗