Mark A. Horsfield

Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging.

The optimization of acquisition parameters for precise measurement of diffusion in anisotropic systems is described. First, an algorithm is presented that minimizes the bias inherent in making measurements with a fixed set of gradient vector directions by spreading out measurements in 3‐dimensional gradient vector space. Next, it is shown how the set of b—matrices and echo time can be optimized for estimating the diffusion tensor and its scalar invariants. The standard deviation in the estimate of the tensor trace in a water phantom was reduced by more than 40% and the artefactual anisotropy was reduced by more than 60% when using the optimized scheme compared with a more conventional scheme for the same scan time, and marked improvements are demonstrated in the human brain with the optimized sequences. Use of these optimal schemes results in reduced scan times, increased precision, or improved resolution in diffusion tensor images. Magn Reson Med 42:515–525, 1999.

Non-invasive assessment of axonal fiber connectivity in the human brain via diffusion tensor MRI

A technique for assessing in vivo fiber connectivity in the human brain is presented. The method utilizes a novel connectivity algorithm that operates in three spatial dimensions and uses estimates of fiber tract orientation and tissue anisotropy, obtained from diffusion tensor magnetic resonance imaging, to establish the pathways of fiber tracts. Sample in vivo connectivity images from healthy human brain are presented that demonstrate connections in the white matter tracts. White matter connectivity information is potentially of interest in the study of a range of neurological, psychiatric, and developmental disorders and shows promise for following the natural history of disease. Magn Reson Med 42:37–41, 1999.

Diffusion tensor magnetic resonance imaging in multiple sclerosis

Objectives: To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. Methods: Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity () and fractional anisotropy (FA) images and image coregistration, and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. Results: The average lesion was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = −0.50). Conclusions The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.

Diffusion tensor MRI assesses corticospinal tract damage in ALS

Background: A number of neurophysiologic and neuroimaging techniques have been evaluated in the research setting to assess upper motor neuron (UMN) damage in ALS. Changes in tissue structure in the CNS modify the diffusional behavior of water molecules, which can be detected by diffusion tensor MRI. Objectives: To explore the hypothesis that degeneration of the motor fibers in ALS would be reflected by changes in the diffusion characteristics of the white matter fibers in the posterior limb of the internal capsule and that these changes could be detected by diffusion tensor MRI. Methods: We studied 22 patients with El Escorial definite, probable, or possible ALS—11 with limb onset (mean age 54.5 ± 10.7 years) and 11 with bulbar onset (mean age 49.6 ± 11.7 years)—and compared them with 20 healthy, age-matched controls (mean age 46.0 ± 12.6 years). We assessed central motor conduction time (CMCT), threshold to stimulation, and silent period using transcranial magnetic stimulation. Diffusion tensor MRI was performed using a 1.5-T GE Signa system (Milwaukee, WI) fitted with Advanced NMR hardware and software capable of producing echo planar MR images. Data were acquired from seven coronal slices centered to include the posterior limb of the internal capsule. Maps of the mean diffusivity, fractional anisotropy, and T2-weighted signal intensity were generated. Results: There were no differences between the subject groups on measures of CMCT, threshold to stimulation, and silent period. However, the CMCT correlated with clinical measures of UMN involvement. We found a significant increase in the mean diffusivity and reduction in fractional anisotropy along the corticospinal tracts between the three subject groups, most marked in the bulbar-onset group. The fractional anisotropy correlated with measures of disease severity and UMN involvement, whereas the mean diffusivity correlated with disease duration. Conclusion: The results support the use of diffusion tensor MRI in detecting pathology of the corticospinal tracts in ALS.

Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis

We performed semiautomated quantitative measurement of brain magnetic resonance imaging (MRI) abnormalities seen at presentation and at 5-year follow-up in 84 patients presenting with an acute clinically isolated syndrome of the optic nerves, brainstem, or spinal cord suggestive of multiple sclerosis (MS). At follow-up, 34 (40%) had developed clinically definite and four (5%) clinically probable MS. Patients who developed MS during follow-up had a higher lesion load at presentation than those who did not. There was a strong correlation of the MRI lesion load at presentation with both the increase in lesion load over the next 5 years and disability at follow-up. Increasing initial lesion load correlated with a decreasing time to development of MS clinically (r = −0.328, p <0.05). At follow-up, disability and brain lesion load were strongly correlated in patients who had developed MS. These results establish that MRI at presentation with clinically isolated syndromes suggestive of MS is useful in predicting the subsequent clinical course and the development of new MRI lesions. This suggests that quantitative brain MRI will be helpful in selecting patients with early clinical MS for treatment trials and for subsequent monitoring of their response to treatment.

MRI in multiple sclerosis: current status and future prospects

Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.

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.

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. Hum Brain Mapp, 2005.

Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI.

Objective: To identify differences in pathology between the principal clinical phenotypes of MS using conventional and magnetization transfer (MT) MRI. Methods: T1-weighted and T2-weighted images as well as MT scans were obtained from 20 controls, 21 patients presenting with clinically isolated syndromes suggestive of MS, and 93 MS patients with relapsing-remitting, secondary progressive, benign, or primary progressive course. Metrics considered: hypointense T1 and T2 lesion volumes, average lesion MT ratio, average brain MT ratio, peak height and position from MT histograms. Results: MS patients had lower MT metrics than controls. Patients with clinically isolated syndromes had MT measures similar to controls, whereas primary progressive MS patients had lower histogram peak height with normal peak position. Relapsing-remitting MS patients had lower MT measures, higher T2 lesion load and ratio of hypointense T1 to T2 lesion volumes than patients with clinically isolated syndromes, and lower MT ratio and peak height than benign MS patients. Benign MS patients were similar to controls and patients with clinically isolated syndromes. Secondary progressive MS patients had the lowest MT measures and highest lesion loads. Conclusions: Pathology in patients with clinically isolated syndromes is confined to modest tissue damage in the lesions seen on T2-weighted scans. Severe damage is important for the later development of disability. However, microscopic damage in normal-appearing white matter may be a major contributor to disability in primary progressive MS.

Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI

Objective: To compare diffusion characteristics of MS lesions, normal-appearing white matter (NAWM) from patients, and normal white matter from control subjects, and to investigate the correlations between the magnetization transfer ratio (MTR) and a directionally averaged tissue water diffusion coefficient (D¯) in patients. Background: MS and other pathologic processes that modify tissue integrity can result in abnormal diffusion of water molecules detectable by diffusion-weighted imaging (DWI). Methods: Conventional dual-echo and DWI scans were obtained from 35 patients with relapsing-remitting MS and 24 healthy control subjects. MT scans were also obtained from the patients. After coregistration of all scans, MTR and D¯ values from MS lesions and NAWM in different regions were marked using the dual-echo scans as a reference. D¯ values from the same brain regions in control subjects were acquired. Histograms of MTR and D¯ were also produced. Results: Patients with MS had significantly higher D¯ values in all the areas studied. Moreover, histogram metrics (peak height, peak site, and average D¯) from patients were substantially different from those of control subjects. In patients, average lesion D¯ and MTR were markedly different from those in the NAWM. There was an inverse correlation between average lesion MTR and D¯ inside lesions, whereas no correlation was found for average MTR and D¯ taken from the histograms. Conclusions: DWI detects severe tissue disruption inside lesions and subtle widespread abnormalities in NAWM in patients with relapsing-remitting MS. MT and DWI may provide information about different aspects of brain pathology in MS.