Biomedical subjects

Mark A Horsfield

Publications and source records attributed to Mark A Horsfield.

16 recordsLinked to original sources

PubMed2006

Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia.

Diffusion tensor magnetic resonance imaging (DT-MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results. The aim of the study was to use a novel method for tract-specific measurements of fronto-temporal fasciculi in early-onset schizophrenia. We hypothesized that by making tract-specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia. Measurements of diffusion anisotropy and mean diffusivity were localized within fronto-temporal fasciculi by forming 3-D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto-occipital fasciculi using diffusion tensor tractography. We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT-MRI-based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus. The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age-matched comparison subjects, but this difference diminished with increasing age. The main conclusion of this study was that direct comparisons of absolute DT-MRI-based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age-related differences in brain maturation between groups.

Adult↗

PubMed2006

A magnetization transfer MRI study of deep gray matter involvement in multiple sclerosis.

BACKGROUND/PURPOSE: Gray matter involvement in multiple sclerosis (MS) is of growing interest with respect to disease pathogenesis. Magnetization transfer imaging (MTI), an advanced MRI technique, is sensitive to disease in normal appearing white matter (NAWM) in patients with MS. DESIGN/METHODS: We tested if MTI detected subcortical (deep) gray matter abnormalities in patients with MS (n= 60) vs. age-matched normal controls (NL, n= 20). Magnetization transfer ratio (MTR) maps were produced from axial proton density, conventional spin-echo, 5 mm gapless slices covering the whole brain. Region-of-interest-derived MTR histograms for the caudate, putamen, globus pallidus, thalamus, and NAWM were obtained. Whole brain MTR was also measured. RESULTS: Mean whole brain MTR and the peak position of the NAWM MTR histogram were lower in patients with MS than NL (P < .001) and mean whole brain MTR was lower in secondary progressive (SP, n= 10) than relapsing-remitting (RR, n= 50, P < .001) patients. However, none of the subcortical gray matter nuclei showed MTR differences in MS vs. NL, RR vs. SP, or SP vs. NL. CONCLUSIONS: The MTI technique used in this cohort was relatively insensitive to disease in the deep gray matter nuclei despite showing sensitivity for whole brain disease in MS. It remains to be determined if other MRI techniques are more sensitive than MTI for detecting pathology in these areas.

Adult↗

PubMed2005

Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer.

PURPOSE: PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. PATIENTS AND METHODS: Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. RESULTS: At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease. CONCLUSION: The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.

Administration, Oral↗

PubMed2005

Mean diffusivity and fractional anisotropy histogram analysis of the cervical cord in MS patients.

The spinal cord is frequently involved in multiple sclerosis (MS), and cord damage may be an important contributor to disability. Diffusion tensor magnetic resonance imaging (DT-MRI) provides quantitative information about the structural and orientational features of the central nervous system. In order to assess whether diffusion tensor-derived measures of cord tissue damage are related to clinical disability, mean diffusivity (MD) and fractional anisotropy (FA) histograms from the cervical cord were acquired from a large cohort of MS patients. Diffusion-weighted sensitivity-encoded (SENSE) echo planar images of the cervical cord, and brain dual-echo and diffusion-weighted scans were acquired from 44 patients with MS and 17 healthy controls. Cord and brain MD and FA histograms were produced. An analysis of variance model, adjusting for cord volume and patient age, was used to compare cord DT-MRI parameters from controls and patients. A multivariate linear regression model was used to identify DT-MRI variables independently associated with disability. Average cervical cord FA was significantly lower in MS patients compared to controls. Cord cross-sectional area, average FA and average MD were all significantly correlated with the degree of disability (r values ranging from 0.36 to 0.51). The multivariate linear regression model retained average cord FA and average brain MD as variables independently associated with disability, with a correlation coefficient of 0.73 (P < 0.001). DT-MRI reveals a loss of cervical cord tissue structure in MS patients. The strong correlation found between a composite DT-MRI score and disability suggests that a full and accurate assessment of cervical cord damage in MS provides information that usefully contributes to an explanation of the clinical manifestations of the disease.

Adult↗

PubMed2005

Effect of device inhalational resistance on the three-dimensional configuration of the upper airway.

Entrainment and de-aggregation of aerosol particles from dry powder inhalers (DPIs) is achieved by a forceful inhalation from the device by the patient and by the airflow resistance built into the device. The aerodynamic shear stress imposed by the upper airway also plays an important role in the de-aggregation process. In this study the effect of device airflow resistance on the upper airway shape is determined. Seven healthy subjects inhaled via a test inhaler of different resistances (0.2 x 10(5) to 2.2 x 10(5) N(0.5).s.m(-4)) while the upper airway was imaged using magnetic resonance imaging. Decreasing the test inhaler resistance led to an increase in the cross-sectional areas of the upper airway at the oral cavity, oropharynx and larynx, while the cross-sectional areas of the upper trachea remained rather constant. The mean volume of the upper airway also increased from 72 (22) cm3 (mean (SD)) to 101 (25) cm3 by decreasing device airflow resistance from 2.2 x 10(5) to 0.2 x 10(5) N(0.5).s.m(-4). In conclusion, this study shows a significant variation in the shape of the upper airway during inhalation via devices with different resistances. This may aid understanding of drug deposition in the lungs from DPIs.

Adult↗

PubMed2005

A diffusion tensor magnetic resonance imaging study of frontal cortex connections in very-late-onset schizophrenia-like psychosis.

OBJECTIVE: Onset of psychosis after the age of 60 may be associated with structural abnormalities within cerebral white matter. The authors looked within white-matter tracts, which mediate connectivity of the frontal lobes, in psychotic patients for evidence of loss of fiber integrity consistent with degenerative damage. METHODS: Fourteen patients with very-late-onset schizophrenia-like psychosis and an age-matched control group underwent diffusion tensor magnetic resonance imaging. Tract maps were constructed for each subject from the imaging data, and measurements of fractional anisotropy and mean diffusivity were made within the uncinate, superior longitudinal, and inferior occipito-frontal fasciculi, and the cingulum. RESULTS: There were no significant differences in fractional anisotropy, a measure of the ordering of axons within fiber tracts, nor in mean diffusivity, an orientationally-averaged measure of the bulk diffusivity within each voxel, between patients and control subjects. CONCLUSION: The lack of difference in fractional anisotropy and mean diffusivity measures between patients and controls argues against the presence of structural abnormalities within these tracts and the notion that a focal white-matter abnormality within the tracts investigated underpins the onset of psychosis.

Age of Onset↗

PubMed2005

Magnetization transfer imaging in multiple sclerosis.

Magnetization transfer (MT) is a relatively new way of generating contrast in magnetic resonance (MR) images that is sensitive to the density of the macromolecules found throughout tissue structures such as membranes, myelin, and organelles. MT imaging (MTI) can provide a quantitative measure of macromolecular density, and therefore of tissue damage, and has been applied in the central nervous system in multiple sclerosis (MS) and other diseases. This article introduces the contrast mechanisms behind MTI and gives some practical guidance about implementing MTI and about quantitative analysis of the MT scans. An overview of MT measurements made in animal studies, in postmortem tissue samples, and in other demyelinating diseases attempts to rationalize the pathological basis of changes in MT contrast in MS. The application of MTI to MS is reviewed, with emphasis on the contribution that MTI has made to the current understanding of the MS disease process, both its natural history and the response to treatment. The pathological basis of abnormal MT contrast is still open to debate, with many conflicting reports; indeed, it is unlikely that a simple measure of MT effect will reveal the details of pathology that is a combination of inflammation, demyelination, remyelination, and axonal loss. There is no doubt, however, that MT measurements have contributed to the current understanding of both disease progression and the response to treatment and will prove to be a valuable tool in the future, particularly if more refined techniques can be applied practically in multicenter studies.

Brain↗

PubMed2005

Interhemispheric asymmetry of brain diffusivity in normal individuals: a diffusion-weighted MR imaging study.

BACKGROUND AND PURPOSE: Previous neuroimaging studies have suggested asymmetries in brain diffusivity may exist. The purpose of this study was to assess whether water diffusivity in deep gray matter structures shown by diffusion-weighted (DW) imaging differs between the right and left cerebral hemispheres in normal individuals. METHODS: Brain MR imaging was obtained in 23 healthy volunteers. A multisection image without diffusion weighting, and images with weighting applied in the read, phase, and section directions with a b-factor of 1000 s/mm(2) were collected. Diffusivity was computed separately in each direction, and the results were averaged to form mean diffusivity maps. Quantitative diffusivity values were obtained from the globus pallidus, putamen, caudate, thalamus, white matter, and CSF by using a standardized region of interest template. Interhemispheric differences were assessed by using a paired sample t test. RESULTS: Mean diffusivity was higher in the: left (mean +/- SD: 0.689 x 10(-3)+/- 0.069 x 10(-3)mm(2)/s) versus right (0.642 x 10(-3)+/- 0.071 x 10(-3)mm(2)/s) caudate (% difference, P value: 7.0%, P = .001); right (0.745 x 10(-3)+/- 0.053 x 10(-3)mm(2)/s) versus left (0.706 x 10(-3)+/- 0.050 x 10(-3)mm(2)/s) globus pallidus (5.2%, P < .001); left (0.720 x 10(-3)+/- 0.059 x 10(-3)mm(2)/s) versus right (0.674 x 10(-3)+/- 0.052 x 10(-3)mm(2)/s) putamen (6.4%, P < .001); right (0.750 x 10(-3)+/- 0.040 x 10(-3)mm(2)/s) versus left (0.716 x 10(-3)+/- 0.031 x 10(-3)mm(2)/s) thalamus (4.5%, P < .001). No significant right versus left difference was seen in the CSF (P = .291), anterior frontal white matter (P = .834), or centrum semiovale (P = .320). CONCLUSION: Gray matter diffusivity may differ between hemispheres of the brain in healthy individuals. Analysis of deep gray matter lesions requires caution, as statistically significant interhemispheric differences may not always be indicative of disease.

Adult↗

PubMed2004

Algorithms for calculation of kinetic parameters from T1-weighted dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: To quantify the errors involved in calculating dynamic parameters (K(trans) and ve) from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans, and to develop alternative analyses to improve accuracy or increase processing speed. MATERIALS AND METHODS: This paper presents three different ways of handling the discrete samples of the arterial input and tissue response data with increasing fidelity, with which this continuous arterial input function (AIF) is represented. Also, a new noniterative approach to parameter estimation was developed from one used previously for analysis of radioactive tracer concentrations in radioangiography. The analysis methods were tested using simulated data. RESULTS: The more sophisticated schemes for data processing give more accurate parameter estimates when data are sparsely sampled, at least for the AIF that we modeled. The noniterative algorithm is very rapid in execution, but was more susceptible to measurement errors. CONCLUSION: The improved algorithms presented should be useful when the AIF and tissue response are sparsely sampled. The noniterative approach may be suitable for semiquantitative visualization, or where the AIF and tissue response are sampled accurately and with a small time interval between samples.

Algorithms↗

PubMed2004

The role of imaging in the clinical development of antiangiogenic agents.

Early clinical development of novel antiangiogenesis agents is hampered by the fact that classic response end points are unlikely to be relevant and there is a lack of validated surrogate markers of efficacy. Toxicity-based decisions for dose setting and tumor size measurements by standard imaging probably are not be applicable. Because these agents modify a multitude of biologic processes that may cause early measurable effects, there is great interest in developing imaging tests that are sensitive to changes in tissue function. This article discusses the development of such "functional" clinical imaging and attempts to address the questions that are being asked of imaging departments by oncologists and pharmaceutical companies.

Angiogenesis Inhibitors↗

PubMed2004

Dynamic change of the upper airway during inhalation via aerosol delivery devices.

Although it is likely that the upper airway is a major factor in the large inter- and intra-subject variation in deposition of inhaled drug aerosols in the lung, data on the configuration of the upper airway during inhalation is sparse. We have developed a unique method, using magnetic resonance imaging, to reconstruct the upper airway in three dimensions during inhalation from aerosol devices used to deliver medication to patients with asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Ten healthy adults were imaged while inhaling from a pressurized metered dose inhaler (pMDI), a spacer used with pMDI (spacer), and a high-resistance dry powder inhaler, the Turbuhaler (DPI). The mean cross-sectional area of the oropharyngeal region was significantly larger (Wilcoxon's signed-rank test with Bonferroni correction, p < 0.0167) when the DPI (281 [143] mm2, mean [SD]) was used compared to the spacer (205 [32] mm2, p = 0.016) or pMDI (152 [48] mm2, p = 0.013). Considerable variations in the cross-sectional areas of the oral cavity, oropharynx, and larynx were seen when compared to the upper trachea. The main cause for this was the varying position of the tongue during inhalation via the devices. Although differences were observed when comparing the total volume of the upper airway during inhalation via the DPI (70 [17] cm3) to the pMDI (56 [20] cm3, p = 0.037) or spacer (59 [12] cm3, p = 0.022), these did not reach significance. This study shows that there are very significant variations in the configuration of the upper airway when different devices are used for inhalation. These changes are likely to be produced by a number of factors, including tongue position, device airflow resistance, and patient effort.

Administration, Inhalation↗

PubMed2003

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.

PURPOSE: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. PATIENTS AND METHODS: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. RESULTS: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. CONCLUSION: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.

Administration, Oral↗

PubMed2003

Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis.

Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future.

Brain↗

PubMed2002

Spatial normalization and averaging of diffusion tensor MRI data sets.

Diffusion tensor magnetic resonance imaging (DT-MRI) is unique in providing information about both the structural integrity and the orientation of white matter fibers in vivo and, through "tractography", revealing the trajectories of white matter tracts. DT-MRI is therefore a promising technique for detecting differences in white matter architecture between different subject populations. However, while studies involving analyses of group averages of scalar quantities derived from DT-MRI data have been performed, as yet there have been no similar studies involving the whole tensor. Here we present the first step towards realizing such a study, i.e., the spatial normalization of whole tensor data sets. The approach is illustrated by spatial normalization of 10 DT-MRI data sets to a standard anatomical template. Both qualitative and quantitative approaches are described for assessing the results of spatial normalization. Techniques are then described for combining the spatially normalized data sets according to three definitions of average, i.e., the mean, median, and mode of a distribution of tensors. The current absence of, and hence need for, appropriate statistical tests for comparison of results derived from group-averaged DT-MRI data sets is then discussed. Finally, the feasibility of performing tractography on the group-averaged DT-MRI data set is investigated and the possibility and implications of generating a generic map of brain connectivity from a group of subjects is considered.

Adult↗

PubMedDate not supplied

Applications of diffusion-weighted and diffusion tensor MRI to white matter diseases - a review.

This paper reviews the current applications of diffusion-weighted and diffusion tensor MRI in diseases of the brain white matter. The contribution that diffusion-weighted imaging has made to our understanding of white matter diseases is critically appraised. The quantitative nature of diffusion MRI is one of its major attractions; however, this is offset by the more advanced hardware required to collect diffusion-weighted images reliably, and the more complex processing to produce quantitative parametric diffusion images. With the now common availability of scanners equipped to perform echo-planar imaging, the acquisition of diffusion tensor images is sure to become more widespread and routine.

Alzheimer Disease↗

PubMedDate not supplied

Sensitivity-encoded diffusion tensor MR imaging of the cervical cord.

The aim of this study was to apply sensitivity-encoding (SENSE) echo-planar imaging (EPI) to diffusion tensor MR imaging of the cervical cord, an anatomic region where MR imaging is particularly challenging. This technique was implemented with a SENSE reduction factor of 2 and used for imaging a water phantom and five healthy volunteers. Off-resonance artifacts were notably reduced compared with those of full-FOV EPI sequences. This approach to diffusion tensor MR imaging of the cervical cord is promising for future, more extensive clinical applications.

Adult↗