Biomedical subjects

D H Miller

Publications and source records attributed to D H Miller.

At least 73 records · Page 4Linked to original sources

PubMed2004

Cervical spinal cord MTR histogram analysis in multiple sclerosis using a 3D acquisition and a B-spline active surface segmentation technique.

The application of a three-dimensional magnetization transfer (MT) sequence and B-spline active surface segmentation method to produce MT histograms of the cervical spinal cord in a pilot study of controls and multiple sclerosis (MS) patients is presented. Subjects' cervical spinal cords were imaged with (a) a volume-acquired inversion-prepared fast spoiled gradient echo sequence and (b) a volume-acquired noninversion-prepared fast spoiled gradient echo MT sequence. The images were segmented using the B spline active surface technique and MT histograms were produced from the MT images. The method was sensitive enough to detect differences between seven MS patients and 10 controls in mean MT ratio (42.4 pu versus 44.0 pu, p = 0.03) and peak location (45.2 versus 46.8, p = 0.03). The spinal cord volumes obtained from the two sequences were associated with each other (parameter estimate 0.972, 95% confidence intervals 0.742, 1.202, p < 0.001).

Adult↗

PubMed2004

Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis.

OBJECTIVES: To establish whether magnetisation transfer ratio (MTR) histograms are sensitive to change in normal appearing grey matter (NAGM) in early relapsing-remitting multiple sclerosis (RRMS) in the absence of significant disability; and to assess whether grey or white matter MTR measures are associated with clinical measures of impairment in early RRMS METHODS: 38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined from proton density weighted images with and without MT presaturation. SPM99 was used to generate normal appearing white matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls. RESULTS: Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005). CONCLUSIONS: In early RRMS, grey matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.

Adult↗

PubMed2004

Abnormalities of cerebral perfusion in multiple sclerosis.

BACKGROUND: Measuring perfusion provides a potential indication of metabolic activity in brain tissue. Studies in multiple sclerosis (MS) have identified areas of decreased perfusion in grey matter (GM) and white matter (WM), but the pattern in clinical subgroups is unclear. OBJECTIVES: This study investigated perfusion changes in differing MS clinical subgroups on or off beta-interferon therapy using a non-invasive MRI technique (continuous arterial spin labelling) to investigate whether different clinical MS subtypes displayed perfusion changes and whether this could give a further insight into the pathological mechanisms involved. METHODS: Sixty patients (21 relapsing remitting, 14 secondary progressive, 12 primary progressive, 13 benign) and 34 healthy controls were compared. Statistical parametric mapping (SPM '99) was used to investigate regional variations in perfusion in both GM and WM. Global WM perfusion was derived by segmenting WM from images using T(1) relaxation times. RESULTS: Regions of lower perfusion in predominantly GM were observed in the primary and secondary progressive cohorts, particularly in the thalamus. Increased WM perfusion was seen in relapsing remitting and secondary progressive cohorts. CONCLUSIONS: Low GM perfusion could reflect decreased metabolism secondary to neuronal and axonal loss or dysfunction with a predilection for progressive forms of MS. Increased WM perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation. Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and cognitive impairment.

Adolescent↗

PubMed2004

Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis.

Brain atrophy appears to occur in patients with multiple sclerosis (MS) in excess of that associated with normal ageing, and may be observed early in the clinical course of the disease. The dynamics and tissue specificity of this process remain unclear This preliminary study explored the evolution of brain grey matter (GM) and white matter (WM) volume loss (as fractions of total intracranial volumes) in 13 subjects with relapsing-remitting MS (mean disease duration 1.9 years at first scan), compared with nine normal control (NC) subjects. Subjects were scanned every six months for 18 months. In MS compared with NC subjects, significant differences in WM fractional volumes were observed at baseline (mean - 5.8%, P = 0.008) but no apparent progressive WM tissue loss was detected. In contrast, while no significant differences in GM fractional volumes were observed at baseline, there was significantly greater time-related volume loss in MS compared with NC subjects over the follow-up period (circa - 0.0086 per year in MS subjects, - 0.0021 per year in the NC subjects, difference P = 0.010). These results suggest that while both GM and WM atrophy are seen early in the clinical course of MS, they may not occur concurrently and may evolve at different rates.

Adult↗

PubMed2004

Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study.

Magnetic resonance imaging (MRI) has become an accepted tool for monitoring therapeutic trials in relapsing-remitting and secondary progressive multiple sclerosis (MS); it is however unclear whether such MRI markers are equally applicable to primary progressive MS (PPMS). Forty-two patients with PPMS were reviewed five years after commencing a two-year MRI and clinical study. Clinical measures recorded at baseline and five years included both the Expanded Disability Status Scale and the MS functional composite. MRI data collected at baseline and two years included T1 and T2 lesion loads, the number of new brain and cord lesions, and measures of both brain and cord atrophy. The study demonstrated that both the number of new T2 lesions and rate of increase in ventricular volume over two years were modestly predictive of subsequent disease progression and therefore may be useful tools in the testing of new therapeutic agents in PPMS.

Atrophy↗

PubMed2004

Estimation of the macromolecular proton fraction and bound pool T2 in multiple sclerosis.

This study used a model for magnetization transfer (MT) to estimate two underlying parameters: the macromolecular proton fraction (f) and the bound pool T2 (T2b) in patients with multiple sclerosis (MS). Sixty patients with clinically definite MS and 27 healthy controls were imaged using: (1) a dual echo fast spin echo sequence, (2) a MT sequence (with ten MT power and offset frequency combinations) and (3) proton density and T1 weighted sequences (for T1 relaxation time estimation). Fourteen normal-appearing white matter (NAWM) regions of interest (ROI) and six normal-appearing gray matter (NAGM) ROIs were outlined in all subjects. Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f. Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in secondary progressive MS. NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.

Adult↗

PubMed2004

Diffusion tensor imaging of early relapsing-remitting multiple sclerosis with histogram analysis using automated segmentation and brain volume correction.

Diffusion tensor magnetic resonance imaging (DTI) reveals measurable abnormalities in normal-appearing brain tissue (NABT) in established multiple sclerosis (MS). However, it is unclear how early this occurs. Recent studies have employed whole brain histogram analysis to improve sensitivity, but concern exists regarding reliability of tissue/cerebrospinal fluid segmentation and possible intersubject brain volume differences, which can introduce partial volume error: To address this, 28 early relapsing-remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5] and 20 controls were compared with whole brain histogram analysis using an automated segmentation algorithm to improve reproducibility. Brain parenchymal volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI parameters [fractional anisotropy (FA), mean diffusivity and volume ratio]. An increased FA peak height in MS subject NABT was observed (P = 0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT. The main conclusions are i) FA peak height is increased in NABT in early MS, ii) partial volume edge effects may contribute to apparent NABT histogram abnormalities, and iii) correction for brain volume differences should reduce potential partial volume edge effects.

Adult↗

PubMed2003

Primary progressive multiple sclerosis: a 5-year clinical and MR study.

Longitudinal imaging studies of primary progressive multiple sclerosis (PPMS) have shown significant changes in MR measures over 1 to 2 years. Correlation with clinical change over the same period has not been evident; we investigated the possibility that this is because the period of observation was insufficient for these associations to become apparent. Forty-one patients with PPMS were followed prospectively for 5 years. Patients had clinical [Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite Measure (MSFC)] and MRI assessment (brain and spinal cord) at baseline, 1, 2 and 5 years. At 5 years, significant deterioration was seen in all clinical and MRI measures (P<0.01, P<0.001 respectively). Associations were seen between increase in EDSS score and decrease in cord area (r=0.31, P<0.05) and between increase in MSFC and both rate of ventricular enlargement (r=0.31, P<0.05) and increase in T2 load (r=0.31, P<0.05). The rates of change of MR measures were not associated with age or disease duration and were more consistent within than between patients. Longer duration of follow-up demonstrates modest associations between change in clinical and MR measures and provides new insights into the pattern of change within and between individuals with PPMS.

Brain↗

PubMed2003

MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b.

BACKGROUND: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. METHODS: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. RESULTS: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. CONCLUSIONS: This study shows that the beneficial effect of IFNbeta-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNbeta in secondary progressive MS.

Biomarkers↗

PubMed2003

Branching fractions of tau leptons to three charged hadrons.

From electron-positron collision data collected with the CLEO detector operating at Cornell Electron Storage Ring near sqrt[s]=10.6 GeV, improved measurements of the branching fractions for tau decays into three explicitly identified hadrons and a neutrino are presented as B(tau(-)-->pi(-)pi(+)pi(-)nu(tau))=(9.13+/-0.05+/-0.46)%, B(tau(-)-->K-pi(+)pi(-)nu(tau))=(3.84+/-0.14+/-0.38) x 10(-3), B(tau(-)-->K-K+pi(-)nu(tau))=(1.55+/-0.06+/-0.09) x 10(-3), and B(tau(-)-->K-K+K-nu(tau))<3.7 x 10(-5) at 90% C.L., where the uncertainties are statistical and systematic, respectively.

Journal Article↗

PubMed2003

The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS.

BACKGROUND: Magnetization transfer (MT) MRI can provide in vivo markers reflecting the severity of irreversible, MS-related brain damage occurring within and outside T2-visible lesions. OBJECTIVE: To assess the effect of interferon (IFN) beta-1b treatment on the accumulation of brain damage in patients with secondary progressive (SP) MS, measured using MT MRI. METHODS: Eighty-two patients with SPMS from five centers participating in a European, multicenter, double-blind, placebo-controlled trial of IFNbeta-1b in SPMS underwent brain T2-weighted and MT MRI at baseline. Evaluable follow-up data were available for 75 patients at 12 months, 54 at 24 months, and 47 at 36 months. MT MRI scans were postprocessed and analyzed to obtain histograms of MT ratio (MTR) values from the whole brain. A region of interest-based analysis of MTR values from the normal-appearing white matter (NAWM) was also performed. RESULTS: In both the treatment arms, there was a decrease of average brain MTR values from baseline to month 24 (mean change -4.9%) and month 36 (mean change -4.3%). These changes were significant for the placebo group at both timepoints and for the IFNbeta-1b group at month 24 only, with no significant treatment effect. A decrease of NAWM MTR was also observed, with no significant difference between the two treatment arms. CONCLUSION: In this cohort of patients with secondary progressive MS, interferon beta-1b did not show an overall effect on the worsening of magnetization transfer MRI measures, when compared with placebo. The data show that change in magnetization transfer ratio is a promising tool for monitoring disease evolution in secondary progressive MS and that the information obtained from magnetization transfer MRI complements that obtained from MRI measures of lesion load and inflammation.

Adult↗

PubMed2003

Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial.

BACKGROUND: Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. METHODS: Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. RESULTS: The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). CONCLUSIONS: This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.

Adult↗

PubMed2003

Quantitative magnetization transfer mapping of bound protons in multiple sclerosis.

Quantitative analysis of magnetization transfer images has the potential to allow a more thorough characterization of the protons, both bound and free, in a tissue by extracting a number of parameters relating to the NMR properties of the protons and their local environment. This work develops previously presented techniques to produce estimates of parameters such as the bound proton fraction, f, and the transverse relaxation time of the bound pool, T(2B), for the whole brain in a clinically acceptable imaging time. This is achieved by limiting the number of data collected (typically to 10); to collect 28 5-mm slices with a reconstructed resolution of 0.94 x 0.94 mm. The protocol takes 82 sec per data point. The fitting technique is assessed against previous work and for fitting failures. Maps and analysis are presented from a group of seven controls and 20 multiple sclerosis patients. The maps show that the parameters are sensitive to tissue-specific differences and can detect pathological change within lesions. Statistically significant differences in parameters such as T(2B) and f are seen between normal-appearing white matter, multiple sclerosis lesions, and control white matter. Whole-brain histograms of these parameters are also presented, showing differences between patients and controls.

Adolescent↗

PubMed2003

High field MRI correlates of myelin content and axonal density in multiple sclerosis--a post-mortem study of the spinal cord.

Different MRI techniques are used to investigate multiple sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to demyelination and axonal loss. The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) spinal cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine. Quantitative MRI maps (PD; T2; T1; magnetization transfer ratio, MTR; diffusion weighted imaging) were obtained. After scanning, the myelin content and the axonal density of the specimens were evaluated neuropathologically using quantitative techniques. Myelin content and axonal density correlated strongly with MTR, T1, PD, and diffusion anisotropy, but only moderately with T2 and weakly with the apparent diffusion coefficient. Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful. Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between axonal loss and demyelination and between demyelinated and remyelinated lesions.

Aged↗

PubMed2003

Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis.

Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patient's functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.

Brain↗

PubMed2003

The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study.

BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.

Adult↗

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↗