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Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

We performed a prospective multi-centre study using functional magnetic resonance imaging (fMRI) to better characterize the relationships between clinical expression and brain function in patients with multiple sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls). Patients showed greater task-related activation bilaterally in brain regions including the pre- and post-central, inferior and superior frontal, cingulate and superior temporal gyri and insula (P < 0.05, all statistics corrected for multiple comparisons). Both patients and healthy controls showed greater brain activation with increasing age in the ipsilateral pre-central and inferior frontal gyri (P < 0.05). Patients, but not controls, showed greater brain activation in the anterior cingulate gyrus and the bilateral ventral striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found. This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater cognitive 'resource allocation' and suggests age-related differences in brain responses to the disease. These observations add to evidence that brain functional responses (including potentially adaptive brain plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.

Purpose: To investigate intercenter agreement of brain volume (change) measurement in multiple sclerosis (MS) using structural image evaluation using normalization of atrophy (SIENA) and the cross-sectional version of SIENA (SIENAX) with additional manual editing to correct for inadequate brain extraction., Materials and Methods: Baseline and follow-up T1-weighted MR images of 20 MS patients were dispatched to five centers. Each center performed fully-automated and manually-edited analyses for SIENAX, yielding normalized brain volume (NBV), and SIENA, yielding percentage brain volume change (PBVC). Intercenter agreement was assessed with the concordance correlation coefficient (CCC)., Results: Intercenter agreement was perfect for fully automated NBV and PBVC (both CCC = 1.0), and remained substantial upon manual editing (CCC = 0.94 for NBV, CCC = 0.95 for PBVC). Mean NBV values for each center decreased significantly after manual editing (overall mean NBV = 1605.3 cm(3) vs. 1651.1 cm(3) without manual editing; t = -4.58, P < 0.001). Total variance in PBVC decreased significantly by a factor of 1.8 after manual editing (sigma(2) = 2.82 before, and sigma(2) = 1.54 after manual editing, P < 0.05)., Conclusion: Substantial intercenter agreement was found for manually-edited SIENAX and SIENA, suggesting that measurements from multiple centers may be pooled. Manual editing reduces overestimation of NBV, and is likely to increase statistical power for PBVC., ((c) 2007 Wiley-Liss, Inc.)

We investigated the magnetization transfer ratio (MTR) of normal-appearing white (NAWM) and grey matter (NAGM) in a relatively large group of multiple sclerosis (MS) patients, and the relations of MTR changes with clinical disability. MTR was measured in 66 MS patients (12 PP, 35 RR, 19 SP) and 23 healthy controls, using a whole-brain 3D-FLASH technique corrected post-hoc for B1-induced variation. Histogram parameters of conservatively selected NAWM and cortical NAGM were analysed using Bonferroni-corrected ANOVA with age as covariate. Additionally, manually outlined regions of interest were analysed using a multilevel method. Lesions had low MTR (mean 22.7+/-6.9%), but NAWM exhibited limited changes: MTR histogram peak position was 32.8+/-1.0% in controls and 32.4+/-0.9% in MS patients, with a significant decrease compared to controls only in SPMS patients (31.9+/-1.1%, p=0.045). Cortical NAGM histograms did not differ significantly between patients and controls. In SPMS, regional mean MTR was significantly decreased in corpus callosum and hippocampus. MTR histogram parameters of NAGM and NAWM were correlated with EDSS and MSFC scores, with lesion volume and with normalized brain volume. We conclude that disease-induced MTR changes were small in MS NAWM and NAGM, but did correlate with clinical decline, lesion volume and overall cerebral atrophy.

More than half of all elderly have some degree of white matter lesions (WML) on MRI of the brain. Until recently, the rate of progression of WML was unknown. Recent work within several population based large scale studies was devoted to tackle this question, to identify factors related to WML progression and to establish a relationship with clinical variables and cognitive changes. There is converging evidence that at least a subset of WML demonstrates considerable progression over time. Increases in WML volume have been correlated with increased loss of brain volume and decline in cognitive and motor performance, indicating that progression of WML harbors clinical relevance. Correlative MRI-histopathologic studies and the clustering of vascular risk factors in subjects with progressive WML support a vascular aetiology of WML, particularly in "confluent" MRI phenotypes. Although specific rating scales have been proposed to detect WML progression, quantitative measurements appear superior given their objective and reproducible nature and regarding possibilities of statistical analyses. Measuring changes in the progression of WML may provide a valid surrogate marker in future clinical trials on cerebral small-vessel disease. Power calculations based on quantitative data of the Austrian Stroke Prevention Study (ASPS) suggest that such studies would be feasible.

Objective: White matter hyperintensities (WMH) are common on brain MRI of the elderly. Their size ranges from punctate to early confluent to confluent lesions. While this increase in extension is frequently seen as evidence for a continuum of changes, histological data and clinical follow-up suggest differences in underlying pathology and their progression., Methods: We tested this hypothesis by exploring the distributions of punctuate and confluent lesions using lesion probability maps (LPM) generated from MRI scans of 189 participants (mean age 60.8+/-6.2 years) in the Austrian Stroke Prevention Study. We dichotomised WMH according to the classification by Fazekas et al. [punctate (n=143) vs. early confluent and confluent (n=33)] to run voxel-based t-tests using permutation-based nonparametric inference. To test alternative hypotheses, we created similar LPM for age and arterial hypertension., Results: We observed significant differences in the spatial distribution of lesions for the two WMH groups (p<0.01). Punctate lesions were more diffusely distributed throughout the cerebral white matter (peak probability approximately 5%) relative to confluent lesions (peak probability 45%). Confluent lesions had greatest likelihood of being found in perfusion "watershed" regions. These differences in distribution could not be explained by differences in age or hypertension only, as both greater age and the diagnosis of hypertension were associated with WMH abutting the occipital horns., Conclusions: Punctate and early confluent to confluent WMH show distinguishable differences in their spatial distribution within a normal elderly population. The pattern of punctate WMH is probably a consequence of mixed etiologies. Preferential localization of the more confluent WMH with arterial watershed areas implies a stronger ischemic component in their development.

A new magnetic resonance (MR) method for measuring T2 relaxation times in tissues is proposed. The method is based on a T2 selective saturation period followed by sampling of the remaining longitudinal magnetization. Saturation of the longitudinal magnetization is accomplished by a single binomial RF pulse of zeroth order with a constant flip angle. The T2 selectivity is controlled by the RF pulse duration. A full T2 spectrum can be obtained by performing a series of measurements with varying RF pulse duration. On a conventional 1.5 T system this approach allows detection of T2 components as short as several hundred microseconds. A major limitation is the method's susceptibility to resonance offsets. At typical offsets of 0.1-0.2 ppm the sensitivity of the method is limited to a T2 range below 20 ms, which corresponds to an RF pulse duration shorter than 50 ms. The new method was used to acquire T2 spectra from the liver of pigs in vitro on a conventional 1.5 T system. We observed a short T2 component around 17 ms and an ultrashort T2 component in the range of 0.9-1.1 ms. Numerical simulations and in vitro measurements suggest that resonance offsets have effects that require further investigation., (Copyright 2006 Wiley-Liss, Inc.)

Subcortical vascular cognitive impairment is caused by lacunes and widespread ischemic white matter damage which closely resembles white matter abnormalities seen in multiple sclerosis. Recent evidence suggests that the progression rate of ischemic white matter lesions on MRI is very similar to that observed in multiple sclerosis. Consequently, it has been proposed to use MRI for monitoring disease activity not only in multiple sclerosis but also in vascular dementia trials. There is first evidence from magnetization transfer imaging studies that other than in MS normal appearing white matter is not affected in cerebral small vessel disease. This contrasts the hypothesis that ischemic white matter damage extends far beyond changes visible on conventional MR. The cognitive consequences of both diseases are strikingly similar which is at least partly caused by damage to frontal-subcortical circuits. Involvement of these common functional anatomical structures and their modulatory transmitter systems has now led to common interventional approaches such as the use of cholinesterase inhibitors.

Epidemiological studies provide strong evidence that susceptibility to multiple sclerosis (MS) is in part genetically determined. Likewise the heterogeneity in clinical manifestations, temporal course, severity, and in the pathological processes of MS are probably also influenced by our genes. Apolipoprotein E (apoE) polymorphism has been considered a candidate for impacting on MS because of its numerous functions related to brain tissue and evidence for an association with a variety of cerebral disorders, specifically Alzheimer's disease (AD). The apoE alleles epsilon2, epsilon3, and epsilon4 are known to impact differently on aspects such as neuronal growth and repair, neuroprotection and inflammation. After a review of the strong association of the apoE polymorphism with AD, we review the results on MS. These are far less homogenous but have gained support from morphologic and metabolic measures obtained with magnetic resonance imaging indicating a greater extent of brain destruction with the apoE epsilon4 allele. Evidence for a protective role of the epsilon2 allele in MS is weak. In view of the association with AD it is tempting to speculate that neuropsychologic functioning in MS might be even more strongly related to the apoE polymorphism and especially to the epsilon4 allele than other deficits, but few data on this issue are yet available. While part of the association of the apoE polymorphism with AD is supposed to be caused by apoE-isoform dependent effects on amyloid-beta deposition, no single pathogenetically relevant mechanism has yet been confirmed for MS. In summary we presently may assume only subtle effects of the apoE polymorphism on the course of MS. These effects are probably further modulated by other genes and need further investigation.

We performed a functional MRI (fMRI) study during the execution of the Paced Visual Serial Addition Task (PVSAT) in 9 patients with a clinically isolated syndrome suggestive of multiple sclerosis (CIS), 9 patients with clinically definite multiple sclerosis (CDMS), and 18 matched healthy control subjects. In controls, the PVSAT elicited a fronto-parietal network with cerebellar activation which we expected for this kind of working memory test and which indicates that this PVSAT version is an appropriate tool for measuring functional changes during a cognitive task. Although there were no significant differences in the actual test results of patients vs. controls, CDMS and CIS patients activated distinct cerebral networks in their attempt to solve the fMRI-PVSAT. Compared to CIS patients, CDMS patients showed increased hippocampal and parahippocampal activation, suggesting the need to additionally support their working memory. In contrast, compared to CDMS patients and healthy controls, CIS patients demonstrated stronger activation of the anterior cingulate cortex, which might indicate focused involvement of executive processes. On the PASAT (Paced Auditory Serial Addition Task) patients also performed similarly to controls but they showed decreased scores on most of the sub-tests of the Wechsler Memory Scale. Based on our observations using the fMRI-PVSAT, we hypothesize that distinct differences in cognitive processing occur with the evolution of MS and that, at these early stages of the disease, they cannot be detected with sufficient sensitivity using only the PASAT.

The severity of tissue changes associated with incidental white matter hyperintensities (WMH) in the elderly cannot be sufficiently determined by conventional MRI. We, therefore, performed a regional analysis of the magnetization transfer ratio (MTR) maps obtained on a 1.5 T scanner from 198 neurologically asymptomatic participants of the Austrian Stroke Prevention Study (mean age 70, age range 52-87 years) in regard to WMH and predefined areas of normal appearing brain tissue. Fluid attenuated inversion recovery MRI was used to grade lesion severity and for lesion volume measurements. The MTR of WMH was always significantly lower than that of normal appearing white matter (NAWM) with an overall relative reduction of approximately 10% and decreased significantly with increasing scores of WMH severity (P = 0.02) and WMH volume (r = -0.24, P = 0.0016). NAWM MTR was not different between subjects with very few and extensive WMH and the WMH volume was associated with NAWM MTR of the frontal lobes only. Concerning a possible impact on cerebral functioning the MTR of the frontal NAWM was significantly associated with fine motor dexterity (P = 0.04) but not with cognitive performance. A significant decline of the MTR with aging was seen in both NAWM and cortex but not in WMH. We conclude that MTR measurements can serve to quantify WMH associated tissue damage. It is predominantly focal, relatively mild, increases with lesion size and may have remote effects on the frontal white matter.

Multiple sclerosis (MS) plaques and age related white matter lesions (WML) are of similar morphological appearance on T2 weighted MRI. Therefore their differentiation is sometimes crucial. Proton magnetic resonance spectroscopy ((1)H-MRS) adds metabolic information to conventional imaging and may help to distinguish inflammatory MS plaques from vascular related WML. This study was performed to evaluate the metabolite pattern in MS plaques and WML. 15 MS patients, 14 elderly individuals with WML and 16 controls were investigated by conventional MRI and short echo quantitative (1)H-MRS (TE: 30ms, TR: 3000ms). The mean metabolite concentrations in normal control white matter (NCWM), MS plaques and WML were: t-NAA: 8.96 mmol/l (SD: 0.93) vs 6.79 mmol/l (SD: 1.99) vs 7.18 mmol/l (SD: 1.41); Cho:1.66 mmol/l (SD: 0.4) vs 1.49 mmol/l (SD: 0.45) vs 1.46 mmol/l (SD: 0.34); PCr:5.64 mmol/l (SD: 0.83) vs 4.9mmol/l (SD: 1.3) vs 4.95 mmol/l (SD: 0.86); myo-Ins: 4.57 mmol/l (SD:1.05) vs 6.34 mmol/l (SD: 2.03) vs 4.5 mmol/l (SD: 0.96). t-NAA reduction in MS plaques and WML was significant compared with controls (p

Acute transverse myelitis (ATM) not related to systemic disease may present in a relapsing manner. Data in the literature about this condition are scarce. We describe three patients suffering from relapsing myelitis in whom no association with systemic disease, i.e. infectious or connective tissue disease was found. Magnetic resonance imaging (MRI) findings were also distinctly different from multiple sclerosis and consistent with a necrotizing type of inflammation. Despite various treatment strategies, all patients became severely disabled. Relapsing ATM not related to systemic disease appears to be a specific entity which accounts for severe disability and currently lacks effective treatment.

Objectives: To determine the rate of brain atrophy in neurologically asymptomatic elderly and to investigate the impact of baseline variables including conventional cerebrovascular risk factors, APOE epsilon4, and white matter hyperintensity (WMH) on its progression., Methods: We assessed the brain parenchymal fraction at baseline and subsequent annual brain volume changes over 6 years for 201 participants (F/M = 96/105; 59.8 +/- 5.9 years) in the Austrian Stroke Prevention Study from 1.5-T MRI scans using SIENA (structural image evaluation using normalization of atrophy)/SIENAX (an adaptation of SIENA for cross-sectional measurement)(www.fmrib.ox.ac.uk/fsl). Hypertension, cardiac disease, diabetes mellitus, smoking, and regular alcohol intake were present in 64 (31.8%), 60 (29.9%), 5 (2.5%), 70 (39.3%), and 40 (20.7%) subjects, respectively. Plasma levels of fasting glucose (93.7 +/- 18.6 mg/dL), glycated hemoglobin A (HbA1c; 5.6 +/- 0.7%), total cholesterol (228.3 +/- 40.3 mg/dL), and triglycerides (127.0 +/- 75.2 mg/dL) were determined. WMH was rated as absent (n = 56), punctate (n = 120), early confluent (n = 14), and confluent (n = 11)., Results: The baseline brain parenchymal fraction of the entire cohort was 0.80 +/- 0.02 with a mean annual brain volume change of -0.40 +/- 0.29%. Univariate analysis demonstrated a higher rate of brain atrophy in older subjects (p = 0.0001), in those with higher HbA1c (p = 0.0001), higher body mass index (p = 0.02), high alcohol intake (p = 0.04), severe WMH (p = 0.03), and in APOE epsilon4 carriers (p = 0.07). Multivariate analysis suggested that baseline brain parenchymal fraction, HbA1c, and WMH score explain a major proportion of variance in the rates of brain atrophy in the cohort (corrected R2 = 0.27; p = 0.0001)., Conclusions: Neurologically asymptomatic elderly experience continuing brain volume loss, which appears to accelerate with age. Glycated hemoglobin A (HbA1c) was identified as a risk factor for a greater rate of brain atrophy. Clustering of factors associated with the so-called metabolic syndrome in subjects with high HbA1c suggests a link between this syndrome and late-life brain tissue loss.

In rare instances, demyelinating disorders present with radiological features that mimic a brain tumour. This often leads to biopsy, which--apart from carrying significant morbidity--frequently turns out as nondiagnostic or dispensable. We therefore set out to assess the contribution of repeated conventional magnetic resonance imaging (MRI), 1H-MR spectroscopy and magnetization transfer imaging in establishing a correct diagnosis of tumefactive demyelinating lesions (TDLs). We studied two females and one male, who presented with TDLs that led to brain biopsy in two cases, for up to three years. TDLs were characterized by the following features: (a) delayed or absent response to high-dose steroids together with progressive lesion growth over several weeks; (b) late or sparse enhancement, ill-defined borders, signal inhomogeneity and considerable concomitant oedema; and (c) normalization of initial increases in lipid and lactate peaks within three to four weeks, followed by persistent, marked reductions of the neuronal marker NAA and MTR values around or below 30%. These imaging characteristics reflected the histological correlate of marked demyelination in the absence of significant inflammation. MRI techniques thus appear to have the potential to establish a correct diagnosis of this subtype of TDLs. Awareness of these possibilities might obviate the need for biopsy at least in some cases in future.

During the past decade, major breakthroughs in magnetic resonance imaging (MRI) quality were made by means of quantum leaps in scanner hardware and pulse sequences. Some advanced MRI techniques have truly revolutionized the detection of disease states and MRI can now-within a few minutes-acquire important quantitative information noninvasively from an individual in any plane or volume at comparatively high resolution. This article provides an overview of the most common advanced MRI methods including diffusion MRI, perfusion MRI, functional MRI, and the strengths and weaknesses of MRI at high magnetic field strengths.

The magnetization transfer ratio (MTR) is strongly related to the field strength (B(1)) of the saturation pulse. B(1) variations therefore can result in significant MTR variations and can affect histogram analysis, particularly if data from a large volume of interest are included. A multicenter study was performed to determine the typical range of B(1) errors and the corresponding MTR variations in brain tissue of healthy volunteers. Seven subjects were included at each center resulting in a total cohort of 28 subjects. Additionally, numerical simulations were done to study this relationship more generally for pulsed saturation. It could be demonstrated, both theoretically and empirically, that for typical B(1) errors there is a linear relationship between B(1) error and the corresponding MTR change. In addition, for proton density-weighted sequences, this relationship seems to be largely independent of the underlying relaxation properties. Mean B(1) errors in the entire brain were typically in the range between -3% and -7%. Due to different coil characteristics, significant MTR differences between different scanners and sites were observed. Using a simple correction scheme that is based on a linear regression analysis between MTR and B(1) data it was possible to reduce the intersubject variation by approximately 50%. Furthermore, interscanner variation could be reduced such that no significant differences between scanners could be detected. The correction scheme may be useful when investigating MTR as an outcome measure in single or multicenter studies., (Copyright 2004 Wiley-Liss, Inc.)

Background: Magnetization transfer magnetic resonance imaging (MT MRI) can provide in vivo markers reflecting the severity of multiple sclerosis-related brain damage occurring within and outside T2-visible lesions., Objective: To investigate the effect of intravenous immunoglobulin (IVIG) treatment on the accumulation of brain damage in patients with secondary progressive multiple sclerosis (SPMS), measured using MT MRI.Design, Patients, and Intervention Seventy patients with SPMS participating in the European, multicenter, randomized, double-blind, placebo-controlled trial of IVIG in SPMS underwent brain T2-weighted and MT MRI at baseline and after 12 and 24 months. The MT MRI scans were post-processed and analyzed to obtain MT ratio values from T2-visible lesions and MT ratio histograms from the normal-appearing brain tissue (NABT)., Results: At baseline, a significant difference was found for NABT MT ratio histogram peak height (P =.003) between treated patients and patients receiving placebo. No significant differences between treated patients and those receiving placebo were found for any of the considered MT MRI-derived metrics in terms of treatment x time interaction. Nevertheless, over the 24-month period, the placebo patients experienced a 6.75% reduction of the NABT MT ratio histogram peak height, whereas treated patients experienced only a 0.92% reduction of the NABT MT ratio histogram peak height., Conclusions: This study did not show any statistically significant effect of IVIG on MT MRI quantities. Nevertheless, the markedly different percentage change of the NABT MT ratio histogram peak height over time between patients receiving placebo and treated patients suggests a possible role of IVIG treatment in preventing the loss of "truly" normal brain tissue in SPMS patients.

Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4.

Background: Conventional magnetic resonance imaging may fail to identify very small but clinically relevant acute subcortical brain infarcts. Diffusion-weighted magnetic resonance imaging (DWI) is very sensitive and specific for acute cerebral ischemia and should contribute to the early detection of such lesions., Methods: We analyzed 6 patients who presented with acute vertical gaze palsy and in whom DWI was performed within 1-6 days from symptom onset., Results: DWI accurately identified ischemia in an area supplied by the posterior thalamosubthalamic paramedian artery in all patients. T(2)-weighted and FLAIR imaging failed to identify the clinically relevant lesion in 2 and 3 patients, respectively., Conclusion: DWI improves the clinicoanatomical correlation in patients presenting with supranuclear oculomotor disturbances., (Copyright 2004 S. Karger AG, Basel)

Acupuncture using laser needles is a new totally painless stimulation method which has been described for the first time. This paper presents an experimental double-blind study in acupuncture research in healthy volunteers using a new optical stimulation method. We investigated 18 healthy volunteers (mean age +/- SD: 25.4 +/- 4.3 years; range: 21-30 years; 11 female, 7 male) in a randomized controlled cross-over trial using functional multidirectional transcranial ultrasound Doppler sonography (fTCD; n = 17) and performed functional magnetic resonance imaging (fMRI) in one volunteer. Stimulation of vision-related acupoints resulted in an increase of mean blood flow velocity in the posterior cerebral artery measured by fTCD [before stimulation (mean +/- SE): 42.2 +/- 2.5; during stimulation: 44.2 +/- 2.6; after stimulation: 42.3 +/- 2.4 cm/s, n.s.]. Mean blood flow velocity in the middle cerebral artery decreased insignificantly. Significant changes (p < 0.05) of brain activity were demonstrated in the occipital and frontal gyrus by fMRI. Optical stimulation using properly adjusted laser needles has the advantage that the stimulation cannot be felt by the patient (painless and no tactile stimulation) and the operator may also be unaware of whether the stimulation system is active. Therefore true double-blind studies in acupuncture research can be performed.

More than half of all elderly people have some degree of cerebral white matter lesions. However, the rate of progression of these lesions is uncertain. We aimed to assess the progression of lesions in community-dwelling volunteers aged 50-75 years without neuropsychiatric disease. We used MRI to grade and measure the total volume of white matter lesions in 296 volunteers at baseline, 3 years, and 6 years. 58 participants with no lesions and 123 with punctate abnormalities at baseline had a low tendency for lesion progression, whereas 14 participants with early confluent and nine with confluent lesions underwent median increases of 2.7 cm(3) (IQR 0.5-5.9) and 9.3 cm(3) (7.1-21.0), respectively, in lesion volume at 6 years. Lesion grade at baseline was the only significant predictor of lesion progression (p<0.0001). Punctate white matter lesions are not progressive and are thus benign, whereas early confluent and confluent white matter abnormalities are progressive, and thus malignant.

A new method was developed for mapping the relative density of the macromolecular protons involved in magnetization transfer (MT). This method employs a stimulated echo preparation scheme in order to modulate the phase distribution within a spin ensemble. This labeled spin ensemble is then used as an intrinsic indicator, which is diluted due to magnetization exchange with macromolecular protons. A pulse sequence is presented which compensates for longitudinal relaxation, allows observation of the dilution effect only, and provides for calculation of parameter maps using indicator dilution theory. Compared to other quantitative MT techniques, neither additional relaxation time measurements nor knowledge regarding the lineshape of the macromolecular proton pool are required. Moreover, the inherent low specific absorption rate and the low sensitivity for B(1) errors make this method favorable in a clinical setting. This sequence was used to measure the macromolecular proton density in cross-linked bovine serum albumin. Using a navigated echo planar readout, the sequence was also employed to visualize the macromolecular content of human brain in vivo., (Copyright 2003 Wiley-Liss, Inc.)

Background: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging., Objective: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4., Design: A 2-year clinical and (1)H-MRS follow-up cohort study., Setting: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University., Patients: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months., Main Outcome Measure: Levels of N-acetylaspartate as measured by (1)H-MRS., Results: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19)., Conclusions: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.

Objective: Previous magnetization transfer (MT) studies in multiple sclerosis (MS) suggest a reduction of the MT ratio (MTR) precedes new lesion development. To gain further insight into pre-lesional tissue abnormalities, we investigated the time course of additional quantitative MT parameters., Methods: Serial magnetic resonance imaging (MRI), including a gadolinium-enhanced T1 scan and MT imaging by means of a FastPACE sequence, was performed on 12 patients (4 males, 8 females) with relapsing-remitting MS. Quantitative MT values including the magnetization exchange rate (kfor) and the native relaxation time (T1free were analysed in the six months prior to the appearance of 44 enhancing lesions and in 88 control regions of persistently normal-appearing white matter (NAWM)., Results: Appearance of new active lesions was preceded by a significant decrease of the MTR (F7,166=91.5; p<0.0001) and of kfor (F7,166=105.2; p<0.0001), and by an increase of T1free (F7,166=57.3; p<0.0001). The drop of kfor was the most pronounced pre-lesional change and together with the MTR was statistically significant already four months before the appearance of new lesion. The observed increase of T1free was relatively small. MT variables of reactivated lesions were always different from NAWM but showed no characteristic time course., Conclusions: Multiparametric MT measurements suggest both a reduction of macromolecular material and a focal increase of free water to occur several months before the appearance of an active lesion. Reduction of the magnetization exchange rate, which may result from primary damage to myelin, appears to be the leading event

Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of multiple sclerosis (MS). It has to be released from its cell membrane-bound precursor by proteolytic cleavage. This is mainly performed by a member of the ADAM (a disintegrin and metalloproteinase) family of enzymes, TNF-alpha-converting enzyme (TACE, ADAM 17). In a longitudinal study on 11 relapsing-remitting MS patients, we qualitatively determined mRNA expression of TNF-alpha and TACE in peripheral blood mononuclear cells (PBMCs) without ex vivo stimulation. mRNA expression was related to disease activity as assessed by monthly gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI). Patients found positive for TACE mRNA in PBMCs showed a significantly higher mean number of new Gd-enhancing lesions per scan one month following PBMC sampling.

The rate and extent of progression of white matter hyperintensities (WMH) over time in elderly subjects is yet unclear. These abnormalities may represent an early form of subcortical vascular dementia. As to whether such changes could be used, as a surrogate marker for this subtype of vascular dementia remains to be determined. So far there exists only a very limited number of studies determining the rate, clinical predictors and cognitive consequences of WMH evolution. There is evidence that these changes do progress over time, however the results of the different studies cannot be compared due to methodological differences. The Austrian Stroke Prevention Study reported that 17.9% of normal individuals show progression over time. The only published quantitative data demonstrated an absolute increase of 1.1 cm(3) over an observational period of 4 years in healthy subjects. Diastolic blood pressure, early confluent or confluent WMH at baseline and genetic variants in the angiotensinogen gene are so far the only known predictors of WMH progression. The Austrian Stroke Prevention Study did not find an association between the evolution of WMH and cognitive functioning but the statistical power of this analysis was small and the relationship needs to be further explored.

Clinical scales for measuring the effectiveness of disease-modifying therapies in patients with vascular dementia are of limited sensitivity. Moreover, they cannot serve to directly probe the potential of a drug in slowing further progression of vascular damage. Assessment of morphologic abormalities that reflect ischemia-related cerebral tissue changes and have a bearing on cognitive function could serve to address both of these aspects and, if sensitive enough, could constitute an ideal surrogate for measuring progression of the disease. For drug licensing agencies a validated surrogate has to meet several requirements: First, the surrogate must predict the future clinical course. Second, the effect of treatment on the disease must be explained by the effect of the treatment on the surrogate; the treatment needs to affect clinical outcome by working through mechanisms related to the surrogate. Third, evidence must exist that treatments of various classes affect the surrogate in the same and predictable manner. Apart from these requirements, regulatory guidelines may also allow the use of even an unvalidated surrogate if it is considered reasonably likely to predict future clinical outcome or disease activity. Various morphologic measures, particularly those using conventional or more sophisticated MRI techniques have already shown a close correlation to neuropsychologic functions. If these associations can also be confirmed in longitudinal studies and following specific treatments, morphologic markers will play a major role in future clinical trials of vascular dementia.

The impact of white matter changes (WMC) detectable on CT or MRI on various diseases like ischemic stroke and intracerebral hemorrhage and their association with cognitive impairment was and still is under debate. To assess WMC in a qualitative and/or semiquantitative fashion rating scales have been developed. For MRI most widely used scales are the scales of Manolio, Fazekas, Schmidt, and Scheltens. Most recently a new scale extending earlier suggestions has been introduced by Wahlund et al. applicable for both CT and MRI. This article will review strengths and weaknesses of these rating scales and will discuss further requirements and future perspectives.

A three year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides first information on the rate and clinical predictors of progression of small vessel disease related cerebral abnormalities including white matter changes and lacunes. White matter hyperintensity progression was found in 17.9% of individuals over the 3 year period. New lacunes occurred in 2.2% of subjects. The overall frequency of progression of small vessel disease related brain changes was 19%. Diastolic blood pressure and early confluent or confluent white matter hyperintensities at baseline predicted lesion progression. Genetic association studies in the setting of the Austrian Stroke Prevention Study described that polymorphisms in the renin angiotensin system (RAS) increase the susceptibility for progression of cerebral small vessel disease. Homozygosity for the T allele of the M235T polymorphism of the angiotensinogen gene was associated with a 3.19-fold increased risk for lesion progression independently of arterial hypertension. These data suggest that drugs influencing the RAS system may allow to intervene with an unfavorable course of cerebral small vessel disease.

A new pulse sequence for fast multislice T1 mapping is presented. This method is based on calculating T1 from spin echo (SE) and stimulated echo (STE) images obtained with different degrees of T1 weighting, and uses the interleaved acquisition scheme of the fast phase acquisition of composite echoes (FastPACE) technique. In contrast to the FastPACE technique, the two echoes are sampled separately. Experimental comparisons confirm that the new sequence layout overcomes most of the FastPACE restrictions, such as its motion sensitivity and the need for a fully complex data set. Moreover, this method offers a higher precision for long T1 values and a further reduction of acquisition time., (Copyright 2001 Wiley-Liss, Inc.)

Background and Purpose: Magnetization transfer (MT) imaging and measurements of the magnetization transfer ratio (MTR) have extended our capability to depict and characterize pathologic changes associated with multiple sclerosis (MS). We wanted to investigate whether the analysis of other MT parameters, such as magnetization transfer rate (k(for)) and relative measure of water content (T1(free)), adds insight into MS-related tissue changes., Methods: Quantitative MT imaging by use of phase acquisition of composite echoes was performed in nine patients with clinically definite relapsing-remitting MS and eight healthy control subjects on a 1.5-T MR system. We analyzed a total of 360 regions of interest and compared control white matter with various types of lesions and normal-appearing white matter in MS., Results: We found a strong correlation between the MTR and k(for), but this relation was non-linear. A slight but significant reduction of the MTR in normal-appearing white matter of patients with MS was attributable to a reduced transfer rate only, whereas a lower MTR was associated with both a reduction of k(for) and an increase of T1(free) in regions of dirty white matter. Moreover, areas such as edema and T1-isointense lesions had a similar MTR but could be differentiated on the basis of Tl(free)., Conclusion: Estimates of k(for) and T1(free) appear to complement MTR measurements for the understanding of MT changes that occur with different types of MS abnormalities in the brain.

Introduction of magnetic resonance imaging (MRI) has opened new possibilities for detecting age-related brain tissue changes. The majority of these abnormalities consists of hyperintense foci in the deep and subcortical white matter probably related to microvascular disturbances and of signal hyperintensities around the lateral ventricles. It has also been suggested that these abnormalities may contribute to the development of cognitive impairment. The correlation between age-related signal abnormalities on conventional MRI and neuropsychologic dysfunction is limited, however, and a threshold beyond which such a relation may come into existence has not yet been defined. Poor tissue characterisation by conventional MRI may be one explanation. Therefore, new pulse sequences are expected not only to provide a higher lesion contrast such as the fluid attenuated inversion recovery (FLAIR) technique but also to offer new insights concerning the composition of incidental brain lesions. In this context both magnetisation transfer imaging (MTI) and diffusion weighted imaging (DWI) may serve to gain information about the integrity of cell membranes and organelles and the preservation of axons and fibre tracts. We will review the technical background of these recently developed MR sequences and their first applications to age-associated brain abnormalities.

An optimized multislice data acquisition scheme for phase acquisition of composite echoes (PACE) imaging is presented. This new scheme uses a repetition time equal to the mixing time and an appropriate phase cycling scheme, which allows for more efficient exploitation of all composite echoes. These modifications provide true multislice capability in parallel to a reduction of the acquisition time by a factor >2 compared with the original PACE method. Moreover, T(1) values can be obtained directly from phase images without the use of a lookup table. Because of the symmetrical application of the radio frequency pulses, this method is also well suited for T(1sat) imaging. Phantom studies showed a significantly better accuracy of the multislice fast PACE technique compared with a conventional two-point method in multislice acquisition mode, although precision was limited at high T(1) values. T(1) and T(1sat) measurements in brain tissue of eight healthy volunteers confirmed the stability of the fast PACE technique in a clinical setting. Magn Reson Med 42:1089-1097, 1999., (Copyright 1999 Wiley-Liss, Inc.)

Purpose: To demonstrate the technical feasibility and precision of a navigated diffusion-weighted (DW) MR imaging method with interleaved echo-planar imaging and test its diagnostic sensitivity for detection of ischemic stroke., Materials and Methods: Apparent diffusion coefficient (ADC) measurements were performed in phantoms, and six healthy adult volunteers were examined to determine intrasubject (precision) and intersubject (reference range) variations in absolute ADC and relative ADC (rADC) measurements. DW imaging maps and lesion rADC values were also obtained in 34 consecutive stroke patients to evaluate the sensitivity and reliability of DW-interleaved echo-planar imaging for detection of ischemic brain damage., Results: Phantom and volunteer ADC values were in excellent agreement with published data. The intrasubject variation of rADC was 6.2%. The ADC precision ranged from 6.5% in the subcortical white matter in the frontal lobe to 12.9% in the head of the caudate nucleus. Interleaved echo-planar imaging enabled rapid acquisition of high-quality images of the entire brain without substantial artifacts. Within the 1st week, the sensitivity of DW-interleaved echo-planar imaging for detection of acute infarction was 90% (18 of 20 true-positive studies) and independent of lesion location., Conclusion: DW-interleaved echo-planar imaging with phase navigation and cardiac triggering is robust, reliable, and fast. With high sensitivity for detection of early ischemic infarction, it is useful for examining stroke patients by using MR systems with conventional gradient hardware.

A new magnetic resonance method for T1 imaging is presented. It is based on the simultaneous acquisition of a spin echo and a phase-shifted, stimulated echo. The phase of this composite echo image is modulated heavily by the spin-lattice relaxation time T1, whereas spin density and T2 do not influence the phase information. This phase information can be assigned easily to corresponding T1 values. Although this method is sensitive to radiofrequency inhomogenities, phantom studies showed that high precision and reasonable accuracy of T1 determination can be achieved. Moreover, this method was found to be very robust, because no fitting is required. T1 imaging of the human brain was performed to confirm the in vivo utility of this method.