Biomedical subjects

D J Brooks

Publications and source records attributed to D J Brooks.

At least 19 recordsLinked to original sources

PubMed2006

Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study.

OBJECTIVE: To evaluate the relationship between clinical improvement and in vivo synaptic dopamine (DA) release after a single oral dose of levodopa (LD) in patients with advanced Parkinson disease (PD). METHODS: We studied 16 patients with advanced PD with [(11)C]raclopride (RAC) PET. Each patient had RAC PET twice: once when medication had been withdrawn and once after an LD challenge. On the day of the LD challenge scan, oral 250 mg LD/25 mg carbidopa was given before scanning. Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were rated in an "off" state before LD and again at the end of PET. RESULTS: All the patients were still in "on" state at the end of their LD challenge RAC PET scans. Following LD, mean caudate and putamen RAC binding potentials (BPs) were significantly lower vs baseline, consistent with increased synaptic DA. Individual LD-induced improvements in UPDRS score correlated significantly with reductions in putaminal BP. Additionally, large putaminal RAC BP changes were associated with higher dyskinesia scores. When motor UPDRS subitems were examined, improvements in rigidity and bradykinesia, but not in tremor or axial symptoms, correlated with putamen DA release. CONCLUSION: In advanced Parkinson disease, the improvement of rigidity and bradykinesia and the presence of dyskinesias after a single dose of oral levodopa are governed by the level of dopamine generated at striatal D2 receptors. In contrast, relief of parkinsonian tremor and axial symptoms is not related to striatal synaptic dopamine levels and presumably occurs via extrastriatal mechanisms.

Administration, Oral↗

PubMed2006

Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study.

OBJECTIVE: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, and cognition. METHODS: Nineteen subjects with AD and 14 controls had [11C]PIB-PET and underwent a battery of psychometric tests. Twelve of those subjects with AD and eight controls had [18F]FDG-PET. Parametric images of [11C]PIB binding and rCMRGlc were interrogated with a region-of-interest atlas and statistical parametric mapping. [11C]PIB binding and rCMRGlc were correlated with scores on psychometric tests. RESULTS: AD subjects showed twofold increases in mean [11C]PIB binding in cingulate, frontal, temporal, parietal, and occipital cortical areas. Higher cortical amyloid load correlated with lower scores on facial and word recognition tests. Two patients fulfilling the clinical criteria for AD had normal [11C]PIB at baseline. Over 20 months this remained normal in one but increased in the cingulate of the other. Mean levels of temporal and parietal rCMRGlc were reduced by 20% in AD and these correlated with mini mental scores, immediate recall, and recognition memory test for words. Higher [11C]PIB uptake correlated with lower rCMRGlc in temporal and parietal cortices. CONCLUSION: [11C]PIB-PET detected an increased amyloid plaque load in 89% of patients with clinically probable Alzheimer disease (AD). The high frontal amyloid load detected by [11C]PIB-PET in AD in the face of spared glucose metabolism is of interest and suggests that amyloid plaque formation may not be directly responsible for neuronal dysfunction in this disorder.

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PubMed2006

Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study.

We analyzed (18)F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced (18)F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal (18)F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal (18)F-dopa uptake in susceptible relatives may predict later clinical disease.

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PubMed2006

Microglial activation correlates with severity in Huntington disease: a clinical and PET study.

BACKGROUND: Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process. METHODS: To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [(11)C](R)-PK11195 PET, a marker of microglia activation, and [(11)C]raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function. RESULTS: In HD patients, a significant increase in striatal [(11)C](R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [(11)C]raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate. CONCLUSIONS: These [(11)C](R)-PK11195 PET findings show that the level of microglial activation correlates with Huntington disease (HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [(11)C](R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.

Adult↗

PubMed2005

Distributed neural actions of anti-parkinsonian therapies as revealed by PET.

There is a limited understanding of how different anti-parkinsonian treatments act at the neuronal systems level. Using positron emission tomography we examined the effects of levodopa and deep brain stimulation of the subthalamic nucleus on patterns of regional cerebral blood flow in patients with Parkinson's disease during a homogenous cognitive-behavioural state rather than during an unspecified resting state. We found that when medicated precuneus, frontal, parietal, cerebellar and midbrain areas were relatively more activated than when stimulated, whereas when stimulated the precentral gyrus, caudate and thalamus were relatively more activated than when medicated. Areas that were activated by both treatments included the temporal gyri, anterior thalamus, and midbrain. Regions of prefrontal cortex showed relatively greater activation in the "off treatment" conditions of both the medicated and stimulated groups. Our findings suggest that the two treatment methods may lead to symptomatic relief via both common and different sites of action.

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PubMed2005

Treatment of end-of-dose wearing-off in parkinson's disease: stalevo (levodopa/carbidopa/entacapone) and levodopa/DDCI given in combination with Comtess/Comtan (entacapone) provide equivalent improvements in symptom control superior to that of traditional levodopa/DDCI treatment.

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo (levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

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PubMed2005

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

RATIONALE: Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. OBJECTIVES: We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. METHODS: Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. RESULTS: A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. CONCLUSIONS: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

Adult↗

PubMed2005

Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET.

Five to ten percent of amyotrophic lateral sclerosis (ALS) cases are associated with mutations of the superoxide dismutase-1 (SOD1) gene, and the 'D90A' mutation is associated with a unique phenotype and markedly slower disease progression (mean survival time 14 years). Relative sparing of inhibitory cortical neuronal circuits might be one mechanism contributing to the slower progression in patients homozygous for the D90A mutation (homD90A). The GABA(A) receptor PET ligand [11C]flumazenil has demonstrated motor and extra-motor cortical changes in sporadic ALS. In this study, we used [11C]flumazenil PET to explore differences in the pattern of cortical involvement between sporadic and genetically homogeneous ALS groups. Twenty-four sporadic ALS (sALS) and 10 homD90A patients underwent [11C]flumazenil PET of the brain. In addition, two subjects homozygous for the D90A mutation, but without symptoms or signs ('pre-symptomatic', psD90A), also underwent imaging. Results for each group were compared with those for 24 healthy controls of similar age. Decreases in the binding of [11C]flumazenil in the sALS group were found within premotor regions, motor cortex and posterior motor association areas. In the homD90A group of ALS patients, however, decreases were concentrated in the left fronto-temporal junction and anterior cingulate gyrus. In the two psD90A subjects, a small focus of reduced [11C]flumazenil binding at the left fronto-temporal junction was seen, similar to the pattern seen in the clinically affected patients. Within the sALS group, there was no statistically significant association between decreases in cortical [11C]flumazenil binding and revised ALS functional rating scale (ALSFRS-R score), whereas the upper motor neuron (UMN) score correlated with widespread and marked cortical decreases over the dominant hemisphere. In the homD90A group, there was a stronger statistical association between reduced cortical [11C]flumazenil binding and the ALSFRS-R, rather than the UMN, score, and also with disease duration. This study provides evidence for differences in the distribution of reduced cortical [11C]flumazenil binding in homD90A compared with sALS patients. We hypothesize that this might reflect differences in cortical neuronal vulnerability.

Adult↗

PubMed2005

[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Adult↗

PubMed2005

The role of radiotracer imaging in Parkinson disease.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Biomarkers↗

PubMed2005

Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation.

Parkin disease is usually autosomal recessive; however, two studies have shown that asymptomatic heterozygotes have nigrostriatal dysfunction and even manifest subtle extrapyramidal signs. The authors used 18F-dopa PET to study 13 asymptomatic parkin heterozygotes and found a significant reduction of (18)F-dopa uptake in caudate, putamen, ventral, and dorsal midbrain compared with control subjects. Four had subtle extrapyramidal signs. Parkin heterozygosity is a risk factor for nigrostriatal dysfunction and in some may contribute to late-onset Parkinson disease.

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PubMed2005

Long duration asymmetrical postural tremor is likely to predict development of Parkinson's disease and not essential tremor: clinical follow up study of 13 cases.

BACKGROUND: Patients presenting with asymmetrical postural tremor with or without mild rest tremor may be diagnosed as having essential tremor (ET), although there is considerable diagnostic uncertainty as to the long term outcome of these patients. OBJECTIVE: In this study, retrospective observations were made on 13 patients presenting originally with asymmetrical postural tremor, initially thought to have ET based on tremor characteristics, alcohol responsiveness, and family history but who subsequently met the criteria of Parkinson's disease (PD). METHODS: The patients were observed and followed up clinically with ancillary imaging using dopamine transporter SPECT scan or levodopa challenge tests in some cases. The diagnosis at original presentation with postural tremor was made with retrospective case note review. RESULTS: After a variable and long latent period all patients developed additional signs suggesting a clinical diagnosis of PD although picking up an initial label of ET. CONCLUSIONS: We suggest exercising caution regarding a diagnosis of ET in patients presenting with late onset asymmetrical postural tremor even if there is no rest tremor. Alcohol sensitivity of tremor, family history of tremor, or responsiveness to beta blockers may not be helpful in diagnosing ET in these cases and some may develop PD in the long term.

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PubMed2005

Mills' and other isolated upper motor neurone syndromes: in vivo study with 11C-(R)-PK11195 PET.

(11)C-(R)-PK11195 positron emission tomography (PET) was used to explore and delineate in vivo the cortical lesion in three clinically isolated upper motor neurone syndromes of similar presentation, with reference to the syndrome of progressive spastic hemiparesis first described by Mills. Three patients with isolated UMN syndromes underwent (11)C-(R)-PK11195 PET of the brain. One patient fulfilled criteria for PLS. Two others had clinical features similar to the cases described by Mills; one of these had a high cervical cord inflammatory lesion previously noted on magnetic resonance imaging. The patient with PLS showed focal increase in the binding of (11)C-(R)-PK11195, indicating microglial activation, in the motor cortex contralateral to the predominantly affected limbs. Of the other two patients, one demonstrated marked increases in binding in the superior frontal region (supplementary motor region) contralateral to the affected limbs. In contrast, no focal areas of increased binding were seen in the cerebral cortex of the third patient, who had a high cervical cord lesion and was presumed to have extra-cerebral inflammatory disease. (11)C-(R)-PK11195 PET demonstrates in vivo that active pathology may be detectable many years after the onset of symptoms, and that it can occur in disparate sites with clinically similar presentations. We conclude that Mills' syndrome is a purely clinical description that should be reserved for patients with a progressive spastic hemiparesis for which no other explanation can be found.

Adult↗

PubMed2005

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS.

BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Adult↗

PubMed2005

Lateralisation of striatal function: evidence from 18F-dopa PET in Parkinson's disease.

OBJECTIVES: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using (18)F-6-fluorodopa positron emission tomography ((18)F-dopa PET) in PD subjects with early cognitive changes. METHODS: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and (18)F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which (18)F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET. RESULTS: SPM localised significant covariation between right caudate (18)F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and (18)F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases. CONCLUSIONS: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.

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PubMed2004

A novel method for estimating ancestral amino acid composition and its application to proteins of the Last Universal Ancestor.

MOTIVATION: Knowledge of how proteomic amino acid composition has changed over time is important for constructing realistic models of protein evolution and increasing our understanding of molecular evolutionary history. The proteomic amino acid composition of the Last Universal Ancestor (LUA) of life is of particular interest, since that might provide insight into the early evolution of proteins and the nature of the LUA itself. RESULTS: We introduce a method to estimate ancestral amino acid composition that is based on expectation-maximization. On simulated data, the approach was found to be very effective in estimating ancestral amino acid composition, with accuracy improving as the number of residues in the dataset was increased. The method was then used to infer the amino acid composition of a set of proteins in the LUA. In general, as compared with the modern protein set, LUA proteins were found to be richer in amino acids that are believed to have been most abundant in the prebiotic environment and poorer in those believed to have been unavailable or scarce. Additionally, we found the inferred amino acid composition of this protein set in the LUA to be more similar to the observed composition of the same set in extant thermophilic species than in extant mesophilic species, supporting the idea that the LUA lived in a thermophilic environment. AVAILABILITY: The program is available at http://compbio.cs.princeton.edu/ancestralaa

Algorithms↗

PubMed2004

Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.

Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.

Adult↗

PubMed2003

[11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy.

Microglia, the brain's intrinsic macrophages, bind (R)-PK11195 when activated by neuronal injury. The authors used [11C](R)-PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (MSA). Increased [11C](R)-PK11195 binding was primarily found in the dorsolateral prefrontal cortex, putamen, pallidum, pons, and substantia nigra, reflecting the known distribution of neuropathologic changes in MSA. Providing an indicator of disease activity, [11C](R)-PK11195 PET can thus be used to characterize the in vivo neuropathology of MSA.

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