Biomedical subjects

G J M Parker

Publications and source records attributed to G J M Parker.

12 recordsLinked to original sources

PubMed2007

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T(1)-weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.

Angiogenesis Inhibitors↗

PubMed2006

In vivo diffusion tensor imaging of the human optic nerve: pilot study in normal controls.

Diffusion tensor imaging (DTI) of the optic nerve (ON) was acquired in normal controls using zonally oblique multislice (ZOOM) DTI, which excites a small field of view (FOV) using a fast sequence with a shortened EPI echo train. This combines the benefit of low sensitivity to motion (due to the single-shot acquisition used), with the additional advantage of reduced sensitivity to magnetic field susceptibility artifacts. Reducing the bright signal from the fat and cerebrospinal fluid (CSF) surrounding the nerve are key requirements for the success of the presented method. Measurements of mean diffusivity (MD) and fractional anisotropy (FA) indices were made in a coronal section of the middle portion of the optic nerve (ON) in the right (rON) and left (lON) ONs. The average values across 10 healthy volunteers were FArON = 0.64 +/- 0.09 and FAlON = 0.57 +/- 0.10, and MDrON = (1173 +/- 227) x 10(-6) mm2 s(-1) and MDlON = (1266 +/- 170) x 10(-6) mm2 s(-1). Measurements of the principal eigenvalue of the DT and its orthogonal component were also in agreement with those expected from a highly directional structural organization.

Adult↗

PubMed2005

MR tractography predicts visual field defects following temporal lobe resection.

A superior homonymous quadrantanopia is a well recognized complication of anterior temporal lobe resection and occurs because of disruption of the Meyer loop, the anterior part of the optic radiation. The authors used diffusion tensor imaging tractography to visualize the optic radiation before and after surgery, demonstrating the disruption of Meyer loop in a patient who developed a quadrantanopia. Preoperative imaging of the optic radiation will be useful in predicting visual field defects following temporal lobe resection.

Adult↗

PubMed2004

Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

Adult↗

PubMed2004

Noninvasive in vivo demonstration of the connections of the human parahippocampal gyrus.

MR tractography techniques provide a method for noninvasively studying white matter pathways in vivo. In this study we have used diffusion tensor imaging (DTI) and the fast marching tractography (FMT) algorithm to plot the structural connectivity of the human parahippocampal gyrus (PHG) in 10 healthy subjects, using seed points selected in the anterior parahippocampal gyrus. Our results demonstrate connectivity between the parahippocampal gyrus and the anterior temporal lobe, orbitofrontal areas, posterior temporal lobe and extrastriate occipital lobe via the lingual and fusiform gyri. We also demonstrate for the first time noninvasively direct connectivity between the parahippocampal gyrus and the hippocampus itself. These results agree with previous histological tract-tracing studies in animals. The connections demonstrated between neocortical areas and the hippocampus via the parahippocampal gyrus may provide the structural basis for theoretical models of memory and higher visual processing.

Adult↗

PubMed2004

Analysis of MR diffusion weighted images.

Diffusion-weighted MR images provide information that is present in no other imaging modality. Whilst some of this information may be appreciated visually in diffusion weighted images, much of it may be extracted only with the aid of data post-processing. This review summarizes the methods available for interpreting diffusion weighted imaging (DWI) information using the diffusion tensor and other models of the DWI signal. This is followed by an overview of methods that allow the estimation of fibre tract orientation and that provide estimates of the routes and degree of anatomical cerebral white matter connectivity.

Anisotropy↗

PubMed2003

From diffusion tractography to quantitative white matter tract measures: a reproducibility study.

The aim of this study is to propose methods for assessing the reproducibility of diffusion tractography algorithms in future clinical studies and to show their application to the tractography algorithm developed in our unit, fast marching tractography (FMT). FMT estimates anatomical connectivity between brain regions using the information provided by diffusion tensor imaging. Three major white-matter pathways were investigated in 11 normal subjects--anterior callosal fibers, optic radiations, and pyramidal tracts. FMT was used to generate maps of connectivity metric, and regions of voxels with highest connectivity metric to an anatomically defined starting point were identified for each tract under investigation. The reproducibilities of tract-"normalized" volume (NV) and fractional anisotropy (FA) measurements were assessed over such regions. The values of tract volumes are consistent with the postmortem data. Coefficients of variation (CVs) for FA and NV ranged from 1.7 to 7.1% and from 2.2 to 18.6%, respectively. CVs were lowest in the anterior callosal fibers (range: 1.7- 7.8%), followed by the optic radiations (range: 1.2-18.6%) and pyramidal tracts (range: 2.6-15.5%), suggesting that fiber organization plays a role in determining the level of FMT reproducibility. In conclusion, these findings underline the importance of assessing the reliability of diffusion tractography before investigating white matter pathology.

Adult↗

PubMed2003

Diffusion tractography based group mapping of major white-matter pathways in the human brain.

Tractography uses diffusion tensor imaging data to trace white matter pathways in vivo within the brain. We have constructed group maps that represent three major white matter tracts-the anterior callosal fibers, optic radiations, and pyramidal tracts-in a group of 21 volunteers. For each individual tract the fast marching tractography (FMT) algorithm was used to generate a VSC (voxel scale connectivity) map in native space. Using SPM99 these maps were transformed into a standard reference frame and three group mapping techniques were investigated: the first averaged the individual VSC maps, the second produced maps that demonstrate intersubject tract variability and degree of overlap, and the third used an SPM analysis to construct a statistical image that represents the group effect. The group maps reconstructed for each tract under investigation conform well to known anatomy and are consistent with data derived from postmortem human brains. Greater intersubject variability is found around the terminal projections of the tracts adjacent to cerebral cortex, whereas the "core" of each tract is characterized by lower variability. No significant differences were found between the left and right side of the pyramidal tracts and optic radiations. The group mapping techniques utilize the VSC maps in different but complementary ways. In the future, group mapping could investigate in vivo white matter differences between normal subjects and patients affected by neurological and psychiatric diseases.

Adult↗

PubMed2003

The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study.

BACKGROUND: Studies have suggested that T2 lesion activity is prominent in early relapsing-remitting multiple sclerosis, whereas brain atrophy, while seen early, appears more evident in later progressive disease. The temporal relation between these processes remains unclear. OBJECTIVE: To explore the association between changing brain lesion loads and subsequent tissue atrophy in multiple sclerosis. METHODS: 28 subjects with clinically probable or definite multiple sclerosis (mean age 46.0 years; 17 female and 11 male) were followed for 14 years after first onset of symptoms. T2 lesion loads were estimated soon after symptom onset and at around five, 10, and 14 years later. Disease related atrophy was estimated at the 14 year follow up by comparing brain tissue volumes (proportional to total intracranial volumes) determined in the multiple sclerosis group with data from 29 normal control subjects (mean age 36.7 years; 16 female, 13 male) using multiple linear regression analyses to allow for differences in age and sex distributions. RESULTS: Change in lesion load in the first five years was more closely correlated to disease related brain atrophy at 14 years than later changes in lesion load, although the correlation was only moderate (Spearman correlation = -0.528, p = 0.004). CONCLUSIONS: From this, it appears that early rather than later focal lesion accumulation relates to subsequent brain atrophy, but factors unconnected directly with lesion formation probably also play a significant role in determining such atrophy.

Adult↗

PubMed2002

Brain atrophy in clinically early relapsing-remitting multiple sclerosis.

Brain atrophy measured by MRI is a potentially useful tool for monitoring disease progression in multiple sclerosis. The location, extent and mechanisms of brain atrophy in early disease are not well documented. Using quantitative MRI, this study investigated whole brain, grey and white matter atrophy in clinically early relapsing-remitting multiple sclerosis and its relationship to lesion measures. Data came from 27 normal control subjects (14 females and 13 males, mean age 36.1 years) and 26 subjects with clinically definite multiple sclerosis (18 females and eight males, mean age 35.1 years, mean delay from first symptom to scan 1.8 years, median Expanded Disability Status Scale score 1.0). All had three-dimensional fast spoiled gradient recall (3D FSPGR), T(1)-weighted pre- and post-gadolinium-enhanced and T(2)-weighted scans. The 3D FSPGR images were automatically segmented into grey and white matter and cerebrospinal fluid using SPM99. 3D FSPGR hypo-intense, T(2) hyper-intense, T(1) hypo-intense and T(1) post-gadolinium-enhancing lesion volumes were determined by semi-automatic lesion segmentation. The SPM99 output was combined with the 3D FSPGR lesion segmentations to quantify tissue volumes as fractions of total intracranial volumes, producing values for the brain parenchymal fraction (BPF), white matter fraction (WMF) and grey matter fraction (GMF). Comparing multiple sclerosis with control subjects, BPF, GMF and WMF were significantly reduced (P < 0.001 for all tissue fractions). Using Pearson correlations, T(2) hyper-intense and T(1) hypo-intense lesion volumes were inversely related to BPF (T(2) r = -0.78, P < 0.001; T(1) r = -0.59, P = 0.002) and GMF (T(2) r = -0.73, P < 0.001; T(1) r = -0.53, P = 0.006), but not WMF (T(2) r = -0.30, P = 0.134; T(1) r = -0.26, P = 0.199). T(1) post-gadolinium-enhancing lesion volumes were not correlated with any fractional volumes. These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.

Adult↗

PubMed2002

T1 histograms of normal-appearing brain tissue are abnormal in early relapsing-remitting multiple sclerosis.

OBJECTIVE: To use both whole-brain and normal-appearing brain tissue (NABT) T1 relaxation time histograms to investigate abnormalities in early relapsing-remitting (RR) multiple sclerosis (MS). BACKGROUND: In patients with established MS, both lesions and NABT exhibit an increase in T1 relaxation time. By using T1 histogram analysis, it is hoped that such changes in early disease can be detected. METHOD: Twenty-seven patients and 14 age- and sex-matched controls underwent magnetic resonance imaging (MRI) of the brain, which included the following sequences: 1) proton density (PD)- and T2-weighted fast spin echo (FSE) to measure T2 lesion load, 2) PD- and T1-weighted gradient echos from which T1 relaxation was calculated, and 3) T1-weighted SE imaging pre- and post-triple dose (0.3 mmol/kg) gadolinium (Gd-DTPA) to measure T1 hypointense and gadolinium-enhancing lesion loads, respectively. All patients had RR MS with disease duration <3 years (median 1.7 years). Statistical parametric mapping (SPM) 99 was used to segment brain from cerebrospinal fluid (CSF), and lesions were segmented using a local thresholding technique. RESULTS: Both whole-brain and NABT histograms were abnormal for all six T1 histogram parameters that were measured. For NABT, the mean T1 was 1,027 (+/- 74) ms in patients and 969 (+/- 41) ms in controls (p=0.003). There was little difference between the global and NABT histograms, which indicates that most of the whole-brain histogram abnormality derives from normal-appearing tissues. There was a correlation between the Nine-Hole Peg Test and NABT T1 measures. CONCLUSION: There are widespread abnormalities of NABT in early RR MS, which were sensitively detected by T1 relaxation time histogram analysis. As such, T1 histogram analysis appears promising for studying the natural history of early RR MS, and in the monitoring of response to treatment

Adult↗

PubMed2002

Quantitative 1H MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis.

clinically isolated syndromes (CIS) are events suggestive for emerging multiple sclerosis (MS). A majority of patients develop MS within months or years whilst others remain clinically isolated. The goal of this study was to investigate whether biochemical metabolites detectable by 'H magnetic resonance spectroscopy (MRS) may serve to distinguish between these two groups. We investigated 41 patients 14 years after presentation with a CIS and 21 controls with combined quantitative short echo 'H MRS and magnetic resonance imaging (MRI) and assessed disability according to the Expanded Disability Status Scale (EDSS). At follow-up, 32 had developed MS, and 9 still had CIS. Compared with controls, MS patients demonstrated significantly higher concentrations of myo-inositol (Ins) in normal appearing white matter (NAWM) and lesions. Lesions also demonstrated a reduced N-acetyl-aspartate (NAA) level and an increase in choline-containing compounds (Cho). The NAWM Ins concentration was correlated with EDSS (r = 0.48, p = 0.005). MS normal appearing cortical grey matter (CGM) exhibited a decreased NAA. Patients who remained CIS did not differ significantly from controls in any MRS measure. Metabolite changes in normal appearing white and grey matter in MS indicate diffuse involvement of the entire MS brain, which was not seen in the persisting CIS patients. Elevated Ins in MS NAWM appeared functionally relevant It may indicate glial cell proliferation or gliosis.

Adult↗