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To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS).The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68).There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.

BACKGROUND AND PURPOSE: GM is typically affected in HD since the presymptomatic stage. Our aim was to investigate with MT MR imaging the microstructural changes of the residual brain subcortical and cortical GM in carriers of the HD gene and to preliminarily assess their correlation with the clinical features. MATERIALS AND METHODS: Fifteen HD gene carriers with a range of clinical severity and 15 age- and sex-matched healthy controls underwent MT MR imaging on a 1.5T scanner. The MT ratio was measured automatically in several subcortical and cortical GM regions (striatal nuclei; thalami; and the neocortex of the frontal, temporal, parietal, and occipital lobes) by using FLS tools. RESULTS: The MT ratio was significantly (P < .05 with Bonferroni correction for multiple comparison) decreased in all subcortical structures except the putamen and decreased diffusely in the cerebral cortex of HD carriers compared with controls. Close correlation was observed between the subcortical and cortical regional MT ratios and several clinical variables, including disease duration, motor disability, and scores in timed neuropsychological tests. CONCLUSIONS: MT imaging demonstrates degeneration of the subcortical and cortical GM in HD carriers and might serve, along with volumetric assessment, as a surrogate marker in future clinical trials of HD.

1477-0970 (Electronic) 1352-4585 (Linking) Journal Article; This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing-remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (-0.02% per visit; p = 0.14), and MTR peak height (-0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (-0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from -0.54 to -0.28, and p-values from

In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imaging-based techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.

To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures.CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution.24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2 years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS).Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p0.0001), RS (r=-0.65, p0.001) and MMSE (r=-0.60, p0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1 ± 0.2%.Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients.

Background: The presence of cortical lesions (CLs) and their topographic distribution in the brains of patients with multiple sclerosis (MS) have been clearly shown by recent histopathologic studies. CLs can also be assessed in vivo, with less sensitivity, by using specific MRI sequences. MRI-based lesion probability maps (LPMs) may partially overcome this lack of sensitivity and provide unique information on the spatial distribution and frequency of CLs in MS. Methods: A total of 149 patients with MS (103 relapsing-remitting [RR] and 46 primary progressive [PP]) underwent an MRI examination, which included the double inversion recovery (DIR) sequence for CL assessment. CL masks were then obtained for each patient and a cortical LPM (cLPM) was created for each MS subtype. Results: CLs were mainly distributed in the frontal (RR = 51.8%; PP = 50.5%) and temporal (RR = 30.4%; PP = 35.5%) lobes, with a prominent involvement of the motor (RR = 37.8%; PP = 30.6%) and anterior cingulate (RR = 9.2%; PP = 10.6%) cortices. The extent of brain lobe affected by CLs was higher in RR than in PP patients. The frequency of CL occurrence was higher in PP than in RR patients. Both measurements, however, did not show differences between the 2 MS subtypes at voxel-wise analysis. Conclusions: Patients with RRMS and PPMS share more similarities than differences in terms of CL number, volume, topographic distribution, and frequency. The similarities between histopathologic data and the findings reported here suggest that DIR images can accurately illustrate the focal pathology occurring in the cortical regions of patients with MS, providing clinically relevant information.

Objective: To assess whether neuropsychological tests and MRI measures could be used as predictors of short-term disease evolution in a population of patients with benign multiple sclerosis (B-MS). Background: The definition of B-MS is controversial. Recent data suggest that neuropsychological tests and MRI measures can provide valuable information for a more correct definition and interpretation of B-MS. Methods: Sixty-three patients with B-MS (Expanded Disability Status Scale [EDSS] ≤3.0 and disease duration ≥15 years) underwent neuropsychological assessment using the Rao9s Brief Repeatable Neuropsychological Battery and the Stroop Test. At that time, conventional brain MRI and magnetization transfer (MT) imaging was performed. White matter lesion load, global and regional brain volumes, and MT ratio in lesions and normal-appearing brain were measured. After a mean follow-up of 5 years, patients still having an EDSS score ≤3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score ≥4.0 were defined as no longer benign (NLB). Results: At end of follow-up, 29% of patients were classified as NLB. Male gender (hazard ratio [HR] = 2.9; 95% confidence interval [CI] 1.2–7.5; p = 0.02), number of neuropsychological tests failed (HR = 1.4; 95% CI 1.1–1.7; p = 0.003), and T1-weighted lesions (HR = 1.3; 95% CI 1.1–1.5; p = 0.002) were related to NLB status. In a model including these 3 variables, the NLB status was predicted with an accuracy of 82%. Conclusions: Cognitive assessment and MRI metrics can predict short-term disease evolution in benign multiple sclerosis (B-MS). This information can be useful to correctly identify patients with B-MS.

It is well known that the current classification of patients with benign multiple sclerosis (BMS), i.e., those with absent or minimal locomotor disability several years after disease onset, suffers from not having any prognostic value for the subsequent evolution of multiple sclerosis (MS). The identification of markers predictive of the longer-term course of MS will help define BMS more reliably and would allow better counseling of patients, particularly when advising on the initiation of a disease-modifying treatment. MRI-based evidence suggests that there are three potential, but not mutually exclusive, explanations for the scarce clinical impact of BMS: 1) the paucity of tissue damage within and outside MS lesions; 2) the relative sparing of clinically eloquent regions; and 3) the presence of effective compensatory mechanisms. In addition, the results of correlative MRI/neuropsychology studies underpin the need for a new definition of BMS, which should consider the maintenance of a normal cognitive profile as an additional criterion.

We report the clinical, neurophysiological (comprehending electromyography, nerve conduction velocities, and multimodal evoked potentials), histological study of the nerve and muscle and the effect of vitamin E supplement in a 32-year-old case with chronic vitamin E deficiency subsequent to acquired intestinal malabsorption. An early diagnosis for an early treatment is essential in preventing severe neurological deterioration.

Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer’s disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.

BACKGROUND: Idiopathic inflammatory demyelinating lesions (IIDL) of the brain usually present with a morphologic pattern characteristic of multiple sclerosis (MS). Atypical appearances of IIDLs also exist, however, and can pose significant diagnostic problems and uncertainty regarding prognosis and adequate therapy. We attempted to improve upon this situation by reviewing the literature. METHODS: We performed a PubMed search from January 1984 through December 2004 for articles in English reporting on IIDLs which had been considered as morphologically atypical (66 articles; 270 cases reported). From these publications 69 individual patient reports allowed the extraction of adequate information on magnetic resonance imaging (MRI) and associated disease characteristics. RESULTS: Reported atypical IIDLs most frequently manifested as large ring-like lesions (n = 27) which are now considered quite suggestive of an antibodymediated form of MS. Truly atypical IIDLs were less common and exhibited appearances which we termed megacystic (n = 8), Balolike (n = 11) and diffusely infiltrating (n = 11). Despite limitations imposed by the absence of original data the inter-rater agreement in defining these subtypes of atypical IIDLs was moderate to substantial (kappa 0.48-0.68) and we noted trends for their association with certain demographic, clinical and paraclinical variables. INTERPRETATION: We suggest that IIDLs reported as atypical in the literature can be segregated into several distinct subtypes based on their MRI appearance. The recognition of these patterns may be useful for the differential diagnosis and for a future classification. Because of the limitations inherent in our review this will have to be confirmed by a prospective registry.

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.

Background and purpose: Although sudden death (SD) accounts for numerous cases of premature mortality in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the risk factors responsible for this dramatic event remain unclear. We sought possible differences in the QT variability index (QTVI) – a well-known index of temporal dispersion in myocardial repolarization strongly associated with the risk of SD – between a group of patients with CADASIL and healthy controls. Methods: A total of 13 patients with CADASIL and 13 healthy volunteers underwent a 5-min electrocardiogram recording to calculate the QTVI. All the patients also underwent a clinical assessment, including functional status by Rankin score, and a magnetic resonance imaging (MRI) brain scan for quantitative analysis of T2-weighted (T2-W) and T1-weighted (T1-W) lesion volume (LV). Results: Short-term QT-interval analysis showed significantly higher QTVI (P = 0.029) in patients than in controls. In patients, notwithstanding the limitations of the small sample size, QTVI also well correlated with T1-W LV (r = 0.747, P = 0.003) and T2-W LV (r = 0.731, P = 0.005). Conclusion: Because patients with CADASIL have increased temporal cardiac repolarization variability as assessed by QTVI, this mechanism could underlie these patients’ risk of SD. Whether this easily assessed, non-invasive marker could be used to stratify the risk of malignant ventricular arrhythmias in patients with CADASIL and, possibly, to guide their therapeutic management warrants confirmation from larger prospective studies.

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

Postmortem histological studies have demonstrated that myelination in human brain white matter (WM) continues throughout adolescence and well into adulthood. We used in vivo diffusion-weighted magnetic resonance imaging to test for age-related WM changes in 42 adolescents and 20 young adults. Tract-Based Spatial Statistics (TBSS) analysis of the adolescent data identified widespread age-related increases in fractional anisotropy (FA) that were most significant in clusters including the body of the corpus callosum and right superior corona radiata. These changes were driven by changes in perpendicular, rather than parallel, diffusivity. These WM clusters were used as seeds for probabilistic tractography, allowing us to identify the regions as belonging to callosal, corticospinal, and prefrontal tracts. We also performed voxel-based morphometry-style analysis of conventional T1-weighted images to test for age-related changes in grey matter (GM). We identified a cluster including right middle frontal and precentral gyri that showed an age-related decrease in GM density through adolescence and connected with the tracts showing age-related WM FA increases. The GM density decrease was highly significantly correlated with the WM FA increase in the connected cluster. Age-related changes in FA were much less prominent in the young adult group, but we did find a significant age-related increase in FA in the right superior longitudinal fascicle, suggesting that structural development of this pathway continues into adulthood. Our results suggest that significant microstructural changes in WM continue throughout adolescence and are associated with corresponding age-related changes in cortical GM regions.

Background: Cerebral involvement is usually absent in pure adrenomyeloneuropathy (AMN). Recently, nonconventional MR studies have reported brain abnormalities in patients with pure AMN, providing evidence that occult cerebral involvement may occur in this disease. It remains unclear, however, whether these brain abnormalities reflect centripetal extension of spinal cord long-tract axonopathy or can be the expression of a pathologic process largely involving the brain. Methods: Conventional MRI and proton MR spectroscopic imaging ( 1 H-MRSI) data of four patients with pure AMN were compared to those of four men with spinal cord injury (SCI) and 10 age-matched healthy men (HM). Resonance intensity areas of N -acetylaspartate (NAA) and choline were calculated as ratios to creatine (Cr) in voxels located in white matter (WM) regions. Functional MRI (fMRI) data during simple motor task were obtained in a separate session in three patients with AMN and three age-matched HM. Results: Conventional MRI examinations were normal in all patients. On 1 H-MRSI, NAA/Cr values were lower in all WM regions of patients with AMN than in those of patients with SCI ( p p p = 0.04). At fMRI, patients with AMN showed a more pronounced activation than HM in all movement-associated cortical regions contralateral to the hand moved and an exclusive voxel activation of the primary motor, somatosensory, and posterior parietal cortices ipsilateral to the hand moved. Conclusions: CNS damage in pure adrenomyeloneuropathy is not confined exclusively to spinal cord and seems to primarily involve the brain. GLOSSARY: 1 H-MRSI = proton MR spectroscopic imaging; AC = anterior commissure; AMN = adrenomyeloneuropathy; BOLD = blood oxygenation level dependent; BR = brisk reflexes; Cho/Cr = choline to creatine ratio; Cr = creatine; DTI = diffusion tensor imaging; EA = endocrine abnormalities; FLAIR = fluid-attenuated inversion recovery; fMRI = functional MRI; FMRIB = Functional Magnetic Resonance Imaging of the Brain; FILM = FMRIB’s improved linear model; Fr-WM = frontal WM; HM = healthy men; Lac = lactate; MD = motor deficits; NAA = N -acetylaspartate; Naa/Cr = N -acetylaspartate to creatine ratio; PC = posterior commissure; PD = proton density; Post-WM = deep posterior WM; Pv-WM = periventricular WM; SA = sensory abnormalities; SCI = spinal cord injury; SP = spastic paraparesis; Sph Dis = sphincteric disturbances; VLCFA = very-long-chain fatty acids; VOI = volume of interest; WM = white matter.

SUMMARY: Morphometry and spectroscopy were performed in 3 patients with fragile X-associated tremor/ataxia syndrome (FXTAS). The brain stem and cerebellum were atrophic and satisfied criteria for olivopontocerebellar atrophy in 2 patients. However, the vermis was relatively spared and the basis pontis maintained its oval shape. The only spectroscopic abnormality was a decrease of the pontine N-acetylaspartate/creatine ratio in 1 patient. Atrophy and metabolic changes in FXTAS differ to some extent from those of olivopontocerebellar atrophy.

In the last few years, there has been an increased appreciation of the apparently primary role of neuronal and axonal injury in the pathogenesis of multiple sclerosis (MS) [1, 2]. This has been driven to a significant degree by the results of proton magnetic resonance (MR) spectroscopy (1H-MRS) studies, which have emphasized that substantial neuroaxonal damage occurs inside the demyelinating lesions as well as in the normal-appearing white matter (NAWM) and gray matter (GM) of the brain of patients with MS [2, 3]. All this has been confirmed pathologically [1, 4, 5] and has led to a reconsideration of the role of axonal damage in MS [6].

ObjectiveTo investigate if the effects of fingolimod 0.5mg on brain volume loss are mediated through effects on focal disease activity (FD) or independent-reduction of diffuse damage (DD).MethodsFREEDOMS and FREEDOMS-II data was pooled and analyzed post-hoc. Assessment of the percent brain volume change (PBVC) at M12 and 24, in patients with no evidence of FD, (absence of new Gd+ T1-lesions and/or new/enlarging T2-lesions) and clinical relapses. Regression analysis of the intent-to-treat (ITT) population to quantified whether the extent of the treatment effect was maintained for patients with new/active lesions and relapsesResultsOf the 1383 patients included, 808 patients (placebo=142; fingolimod=666) showed no FD at M12 and 573 patients (placebo=79; fingolimod=494) at M24 showed no FD. Fingolimod significantly reduced PBVC by 52% and 42% vs. placebo, over 12M and 24M respectively. In the pooled ITT population, fingolimod reduced 49% of PBVC (p

The authors describe an infant with vanishing white matter disease with demyelinating peripheral neuropathy. Sequence analysis of EIF2B5 gene showed that the patient was a double heterozygote, with novel missense mutation CGA--CAA in codon 269 of exon 6, resulting in the replacement of an arginine residue with glutamine.

Functional magnetic resonance imaging (fMRI) studies of the human brain have suggested that low-frequency fluctuations in resting fMRI data collected using blood oxygen level dependent (BOLD) contrast correspond to functionally relevant resting state networks (RSNs). Whether the fluctuations of resting fMRI signal in RSNs are a direct consequence of neocortical neuronal activity or are low-frequency artifacts due to other physiological processes (e.g., autonomically driven fluctuations in cerebral blood flow) is uncertain. In order to investigate further these fluctuations, we have characterized their spatial and temporal properties using probabilistic independent component analysis (PICA), a robust approach to RSN identification. Here, we provide evidence that: i. RSNs are not caused by signal artifacts due to low sampling rate (aliasing); ii. they are localized primarily to the cerebral cortex; iii. similar RSNs also can be identified in perfusion fMRI data; and iv. at least 5 distinct RSN patterns are reproducible across different subjects. The RSNs appear to reflect "default" interactions related to functional networks related to those recruited by specific types of cognitive processes. RSNs are a major source of non-modeled signal in BOLD fMRI data, so a full understanding of their dynamics will improve the interpretation of functional brain imaging studies more generally. Because RSNs reflect interactions in cognitively relevant functional networks, they offer a new approach to the characterization of state changes with pathology and the effects of drugs.

To assess neocortical changes and their relevance to cognitive impairment in early relapsing-remitting (RR) multiple sclerosis (MS).Conventional MR was acquired in 41 patients with RR MS and 16 demographically matched normal control subjects (NCs). An automated analysis tool was used with conventional T1-weighted MRI to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed using the Rao Brief Repeatable Battery. Relationship between volumetric MR measures and neuropsychological scores was assessed.Neuropsychological assessment allowed for the identification of 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. The whole MS sample showed lower values of normalized cortical volumes (NCVs) than did the NC group (p = 0.01). Upon grouping of MS patients according to cognitive performance, NCV values were lower (p = 0.02) in MS-ci patients than in both MS-cp patients and NCs. Moreover, there were positive correlations between NCV values and measures of verbal memory (r = 0.51, p = 0.02), verbal fluency (r = 0.51, p = 0.01), and attention/concentration (r = 0.65, p0.001) in MS-ci patients. Furthermore, NCV values were decreased in patients who scored lower on a greater number of tests (r = -0.58, p0.01) in the MS-ci group. None of the neuropsychological measures correlated to NCV values in the MS-cp patient group.Cortical atrophy was found only in cognitively impaired patients and was significantly correlated with a poorer performance on tests of verbal memory, attention/concentration, and verbal fluency. Gray matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Axonal and neuronal pathology have recently been increasingly regaining attention in multiple sclerosis (MS). There has been a shift in focus from considering functional impairment as primarily resulting from changes in the electrical conduction properties of axons after demyelination, towards an appreciation of the apparently primary role of neurodegeneration in the pathogenesis of this disease. Brain atrophy, which constantly occurs and progressively increases in MS patients, has greatly contributed to the development of this concept. As an expression of general tissue loss, brain atrophy is generally considered a global marker of adverse disease outcome. This seems to include, even in a primarily demyelinating disease such as MS, grey matter (GM) tissue abnormality. Accordingly, selective pathology in the cerebral GM has been shown in recent post-mortem [1–3] and in vivo [4–9] MS studies suggesting that neocortical pathology is more relevant in MS than previously thought.

In white matter diseases (WMD), conventional magnetic resonance imaging (MRI) has proved to be sensitive for detecting lesions and their changes over time. However, conventional MRI is not able to characterize and quantify the tissue damage within and outside these lesions. Other quantitative MR techniques have the potential to overcome such limitation. Among these techniques, MR spectroscopy (MRS), magnetization transfer imaging (MTI), and diffusion-weighted imaging (DWI) have been most extensively applied to the assessment of WMD. The present review will summarize the major contributions of these three MR techniques to the understanding of the evolution of WMD, with a special focus on multiple sclerosis (MS). The application of MR techniques to the study of MS has indeed dramatically changed our understanding of how MS causes irreversible deficits and can serve as a useful model to be applied to other WMD.

The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity, and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions that could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data. The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).

Objective: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family.Background: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation.Methods: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and 1H-MR spectroscopy.Results: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases.Conclusion: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.

Purpose Quantitative measurement of change in brain size and shape (e.g., to estimate atrophy) is an important current area of research. New methods of change analysis attempt to improve robustness, accuracy, and extent of automation. A fully automated method has been developed that achieves high estimation accuracy. Method A fully automated method of longitudinal change analysis is presented here, which automatically segments brain from nonbrain in each image, registers the two brain images while using estimated skull images to constrain scaling and skew, and finally estimates brain surface motion by tracking surface points to subvoxel accuracy. Results and conclusion The method described has been shown to be accurate ( approximately 0.2% brain volume change error) and to achieve high robustness (no failures in several hundred analyses over a range of different data sets).

The traditional, “text book” view of multiple sclerosis (MS) is that it is a selectively demyelinating disease that leaves axons intact. According to this view, functional deficits arise from chronic conduction block due to chronic demyelination over extended sections of axons because the depolarising sodium channels remain restricted to previously internodal regions. This is now known to be incorrect [1,2].

The authors describe the principal forms of genetic leucodystrophies with unknown metabolic pathogenesis, indicating their main clinical signs and the new findings concerning the molecular genetic that are useful for the laboratory confirmation of the clinical suspicion.

The advent of magnetic resonance (MR) imaging (MRI) has revolutionized the clinical approach to the evaluation of brain white matter (WM) disorders and has contributed significantly to the growth in our understanding of these diseases. The clinical importance of MRI in the management of patients with WM disorders lies in its great sensitivity for detecting brain lesions. However, in these disorders WM lesions can be due to a variety of pathological processes (autoimmune, metabolic, vascular, toxic, hereditary, etc.) and can be associated with many different types of myelin abnormalities (demyelination, hypomyelination, myelin rarefaction, etc.) [1].

La risonanza magnetica spettroscopica (MRS) è una tecnica non invasiva per la misura della concentrazione relativa di alcuni composti cerebrali. L'uso di questa tecnica nello studio delle malattie della materia bianca cerebrale ha apportato miglioramenti nella classificazione diagnostica e nelle misure relative all'andamento delle malattie. Un uso più estensivo delle tecniche di risonanza multimodale, comprendenti tomografia RM, spettroscopia ed altre modalità non convenzionali, dovrebbe quindi essere incoraggiato. Ciò permetterà una miglior comprensione della complessa dinamica dei cambiamenti patologici nelle malattie della sostanza bianca ed una più accurata valutazione della progressione e della risposta alla terapia della malattia stessa.

MELAS is a mitochondrial encephalomyopathy characterized clinically by recurrent stroke-like episodes, seizures, sensorineural deafness, dementia, hypertrophic cardiomyopathy, and short stature. The majority of patients are heteroplasmic for a mutation (A3243G) in the tRNAleu(UUR) gene in mitochondrial DNA (mtDNA). In cells cultured in vitro, the mutation produces a severe mitochondrial translation defect only when the proportion of mutant mtDNAs exceeds 95% of total mtDNAs. However, most patients are symptomatic well below this threshold, a paradox that remains unexplained. We studied the relationship between the level of heteroplasmy for the mutant mtDNA and the clinical and biochemical abnormalities in a large pedigree that included 8 individuals carrying the A3243G mutation, 4 of whom were asymptomatic. Unexpectedly, we found that brain lactate, a sensitive indicator of oxidative phosphorylation dysfunction, was linearly related to the proportion of mutant mtDNAs in all individuals carrying the mutation, whether they were symptomatic or not. There was no evidence for threshold expression of the metabolic defect. These results suggest that marked tissue-specific differences may exist in the pathogenic expression of the A3243G mutation and explain why a neurological phenotype can be observed at relatively low levels of heteroplasmy.

Axonal damage in multiple sclerosis has become an important issue. This has been emphasized by recent in vivo proton magnetic resonance (MR) spectroscopy and in vitro pathology studies that have found axonal damage in both lesions and the surrounding normal-appearing white matter. In particular, proton MR spectroscopy, by monitoring levels of N-acetylaspartate (a putative marker of axonal integrity), has been particularly illuminating, as the extent of axonal injury associated with white matter inflammation and demyelination had not been well appreciated from classical pathology studies. Recent MR data demonstrate that cerebral axonal damage begins and contributes to disability from the earliest stages of the disease. This implies that the apparently primary role of axonal damage and loss in the pathogenesis of the disease should be given due importance, and argues for the early treatment of multiple sclerosis with agents directed not only against inflammation, but also towards axonal protection.

Muscle biopsy tissue from a patient affected by the juvenile form of neuronal ceroid lipofuscinosis (NCL) was studied immunohistochemically using antibodies to beta-amyloid peptide and amyloid precursor protein. Positive reaction in muscle was specifically localized to autophagic vacuoles and blood vessel walls. Increased acid phosphatase reaction suggested enhanced lysosomal activity. We hypothesize that beta-amyloid is deposited in NCL muscle by a lysosomal mechanism similar to that proposed in other disorders involving beta-amyloid.

The advent of magnetic resonance imaging (MRI) has revolutionized the clinical approach to the evaluation of brain white matter disorders and has contributed significantly to expansion of the concept of these diseases. MRI is very sensitive at detecting white matter lesions, but conventional T1 and T2-weighted images do not provide specific pathological information about the lesions, and correlation between MRI lesion load and clinical disability is often weak. Proton magnetic resonance spectroscopy can provide chemical-pathological information of a given tissue in vivo. The use of this MR technique in brain white matter disorders has shown to improve diagnostic classification and to provide surrogate measures useful for monitoring disease evolution and response to therapeutic intervention.

Phosphorus magnetic resonance spectroscopy (MRS) was used to study muscle phosphates metabolism in several brain disorders. Those with primary mitochondrial encephalomyopathies showed the typical pattern of impaired oxidative metabolism at rest and during recovery after exercise. In migraine, Parkinson's disease and alternating hemiplegia muscle MRS observations lend support to a possible mitochondrial dysfunction. Similar observations in multiple sclerosis are probably the result of secondary deconditioning. In post polio syndrome and in some of the hereditary ataxias, elevated intracellular inorganic phosphates may be the result of another, yet unknown, metabolic impairment. Thus, muscle phosphate metabolism may be altered in various central nervous system (CNS) disorders by different metabolic impairments. All these possibilities should be taken into account when evaluating MRS results in brain diseases.

The term “impingement” means the presence, in the joint area, of a formation originating from one of the components in that same joint and limiting function by effecting the biomechanics of movement. The impingement syndrome in the shoulder is defined as friction between skeletal components due to articular disequilibrium caused by injury to the tendons and ligaments.

Muscle phosphorus magnetic resonance spectroscopy was used to study oxidative metabolism at rest and during recovery from exercise in 7 patients with sporadic inclusion body myositis (s-IBM), compared with normal controls (n=8) and mitochondrial myopathies (n=20). At rest, 6/7 patients had elevated inorganic phosphates. Recovery parameters were not different from controls, in contrast with mitochondrial myopathies, who showed abnormal rest and recovery. The normal recovery suggests that mitochondrial oxidative capacity is not impaired in s-IBM.

Recent magnetic resonance imaging (MRI) and magnetic resonance spectroscopic (MRS) techniques have focused the attention of the multiple sclerosis (MS) research community on reanalysis of classic pathological approaches that have suggested significant axonal injury in this demyelinating disease. There now is abundant evidence from animal work that substantial "innocent bystander" damage to axons can occur with central nervous system (CNS) inflammation. Given the close interactions between axons and glia, it is no surprise that glial damage leads to secondary axonal changes. MRI, MRS, and MRS imaging studies have emphasized that axonal loss or damage in MS can be both substantial and early. The dynamic observations that are allowed by these noninvasive measures of pathology have demonstrated direct correlations between these axonal changes and disability, making a compelling case for increased emphasis on finding treatments of MS that may limit damage to CNS axons or salvage injured axons.

It has been difficult to establish a strong correlation between total brain T2-weighted lesion volume on MRI and clinical disability in multiple sclerosis, in part because of the lack of pathological specificity of T2-weighted MRI signal changes. Proton magnetic resonance spectroscopy studies have shown that measurements of the resonance intensity of N-acetylaspartate (which is localized exclusively in neurons and neuronal processes in the mature brain) can provide a specific index of axonal damage or dysfunction. Here we report a 30-month longitudinal study of 29 patients with multiple sclerosis who had either a relapsing or a secondary progressive clinical course. Conventional brain MRI and single-voxel proton magnetic resonance spectroscopy examinations were obtained at intervals of 6-8 months with concurrent clinical evaluation. At the onset of the study, the brain N-acetylaspartate:creatine resonance intensity ratio was abnormally low for the whole group of patients (control mean = 2.93 +/- 0.2, patient mean = 2.56 +/- 0.4, P < 0.005). There were no significant differences between the relapsing and secondary progressive subgroups. Over the follow-up period, there was a trend towards a decrease (8%) in the brain N-acetylaspartate:creatine ratio for the 11 relapsing patients and a significant (P < 0.001) correlation between changes in the brain N-acetylaspartate:creatine ratio and expanded disability scale scores for the patients in this group. This correlation was even more evident for the patients who had clinically relevant relapses during the 30 months of follow-up (seven of 11 patients). Increases in T2-weighted lesion volumes (35% in 30 months for the group as a whole, P < 0.0001, without differences between the subgroups) did not correlate with disability either in the group of patients as a whole or in the different subgroups. We conclude that indices of axonal damage or loss such as brain N-acetylaspartate may provide a specific measure of pathological changes relevant to disability. Total T2-weighted lesion volumes, although more sensitive to changes with time than brain N-acetylaspartate, may be less relevant to understanding the progression of disability.

We studied the physiologic adaptation of patients with mitochondrial myopathies to aerobic training. Ten patients underwent individually supervised, moderate-intensity aerobic training on a treadmill for 8 weeks. Biochemical and functional measures improved with training. Estimated aerobic capacity increased by 30%. Blood lactate concentrations at rest and after exercise decreased by 30%. Muscle phosphorus magnetic resonance spectroscopy measurements of adenosine diphosphate recovery after exercise improved by more than 60%. Fatigue and tolerance to daily activities also improved. Although the improvement in exercise tolerance may be due in part to reversal of the effects of secondary deconditioning, this uncontrolled clinical trial suggests that aerobic training can benefit patients with mitochondrial myopathies.

We performed magnetic resonance imaging and magnetic resonance spectroscopic imaging on 28 patients with multiple sclerosis stratified for disability and clinical course (relapsing with at least partial remissions or secondary progressive disease). Lesions were segmented on the conventional proton density and T2-weighted magnetic resonance images, and lesion distribution images were generated for, each patient. The conventional magnetic resonance and spectroscopic images were transformed into a standard brain-based stereotaxic coordinate space, allowing comparison of images from different patients on a voxel-by-voxel basis. The spatial distribution of lesions in the transformed magnetic resonance images did not differ significantly between the relapsing and the progressive disease groups. We then generated from the individual data sets, group lesion probability distribution images for the relapsing and the progressive disease groups. The spatial distribution of metabolites was characterized with respect to lesion distribution using the magnetic resonance spectroscopic images transformed into stereotaxic space and averaged. The neuronal marker N-acetylaspartate was diffusely lower in the multiple sclerosis patients than in normal control subjects. Comparison of the averaged metabolite and T2-weighted lesion probability images confirmed loss of N-acetylaspartate in regions of both high and low lesion probability. This suggests that diffuse axonal volume loss or dysfunction extends beyond the inflammatory lesions of multiple sclerosis, perhaps due to microscopic disease or wallerian degeneration along projection pathways of axons traversing the lesions.

Magnetic resonance imaging (MRI) has revolutionized our understanding of disease activity in patients with multiple sclerosis. Advanced MR techniques, including magnetization transfer, diffusion, and spectroscopic imaging, now can be used to define specific pathological changes in lesions and offer promise for improved definition of the nature of individual lesions and the dynamics of their evolution. Combined, multimodal MR studies of the brains of patients with multiple sclerosis therefore soon may provide efficient, specific, and quantitative new approaches to assessment of outcome in therapeutic trials.

Twenty-four patients with exercise intolerance of undetermined origin were examined by muscle phosphorus magnetic resonance spectroscopy (31P-MRS) to test for a possible underlying defect in oxidative metabolism. Results were compared to those of 37 normal controls and 22 patients with well-defined mitochondrial disorders. In 17 (71%) patients with exercise intolerance, ADP recovery after exercise, an index of mitochondrial function, was abnormally slow. The energy state of phosphate-containing metabolites at rest was abnormal in 33% of patients. In 17/22 patients with well-defined mitochondrial disorders, ADP recovery was similarly slow. Abnormalities at rest were slightly more prevalent (50%) in this group of patients. Other 31P-MRS measurements did not add to the overall sensitivity in detecting abnormalities in either of these groups. We suggest that many patients with exercise intolerance of undetermined cause may have impaired muscle oxidative metabolism, that is an important causative factor in the pathophysiology of their symptoms.

In a 6-year longitudinal study of a patient with relapsing progressive multiple sclerosis (MS), we used proton magnetic resonance spectroscopy to asses N-acetylaspartate (NAA) from a large central brain volume to evaluate the relationship between this marker of neuronal integrity and clinical disability. During the follow-up period, there was one major relapse and its subsequent partial remission. Changes in the brain NAA to creatine ratio correlated strongly with clinical disability (Spearman rank coefficient= -0.73, p < 0.001). We interpret this as evidence that axonal dysfunction or loss contributes to functional impairment of patients with MS. Because the NAA signal in the large volume of interest originated predominantly from white matter than appeared normal on conventional MRI, these results also suggest that some degree of axonal dysfunction may be widespread in acute, severe relapses.