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Objective: To determine non-invasively the relation between the degree of axonal loss and the extent of demyelination in chronic lesions visible on MRI in patients with different subgroups of clinically definite multiple sclerosis using (1)H magnetic resonance spectroscopy ((1)H MRS) and magnetisation transfer imaging (MT). Conventional MRI is unable to differentiate between the various pathological processes occurring in the multiple sclerosis lesion. There are, however, newer MR techniques which show promise in this respect.Methods: (1)H MRS and MT were performed in 18 patients with clinically definite multiple sclerosis who had a wide range of disability and disease duration.Results: A significant correlation was found between a reduction in the concentration of N-acetyl aspartate (NAA; an in vivo marker of axonal loss or dysfunction) and a reduction in MT ratio (a probable marker of demyelination) in patients who had entered the secondary progressive stage of the disease. Patients with minimal disability after a disease duration of greater than 10 years-so called benign multiple sclerosis-showed a relative preservation of NAA and MT.Conclusions: Because a reduction in MT seems to be a relative marker for demyelination and a reduction of NAA from chronic lesions is indicative of axonal loss, this study supports the hypothesis that demyelination and axonal loss occur in the same chronic multiple sclerosis lesions. In addition, the degree of axonal loss and demyelination correlates with clinical heterogeneity. [ABSTRACT FROM AUTHOR]

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disorder caused by loss-of-function mutations in the thymidine phosphorylase gene (TYMP). We report here a patient compound heterozygous for two TYMP mutations: a novel g.4009G>A transition affecting the consensus splice donor site of intron 9, and a previously reported g.675G>C splice site mutation. The novel mutation causes exon 9 skipping but leaves the reading frame intact; however, TYMP protein was not detected by immunoblot analysis, suggesting that neither mutant allele is expressed as protein. The patient's fibroblasts showed gradual loss of the mitochondrial DNA-encoded subunit I of cytochrome-c oxidase, suggesting a progressive mitochondrial DNA defect in culture.

Pregnancy-related stroke is, fortunately, a rare event. However, when it occurs, there may be implications for management of the patient and delivery of the child. This article reviews the mechanisms and risk factors for stroke related to pregnancy, the presenting features, diagnosis and management of the different stroke types, and the implications for pregnancy and delivery.

Introduction: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Sources of data Literature search using Medline with keywords Parkinson's disease supplemented with previously published papers known to the author., Areas of Agreement: There have been significant recent advances in the understanding of the pathogenesis of the disease. There has also been a greater realization that the disorder may be associated with significant non-motor disturbances in addition to the more commonly recognized motor complications., Areas of Controversy: Although there is growing circumstantial evidence, it remains to be proven whether any of the current treatments for PD have a neuroprotective effect., Areas Timely for Developing Research: Although there is no cure, there are several management options for the early treatment of PD. As the disease progresses, further treatment options are available; however, the management of late-stage motor complications and non-motor symptoms remains particularly challenging and will benefit from further clinical research.

Magnetic resonance spectroscopy (MRS) has been used in a variety of conditions affecting the central nervous system. Until now, only the brain has been studied, and spectroscopy of the spinal cord has not been previously reported. During the past 12 months, we have been experimenting with MRS of the cervical spinal cord of healthy volunteers. We present this technique, its current limitations, and possible future technological improvements and potential applications.

Objectives: Multiple sclerosis lesions appear as areas of high signal on T2 weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI, appear hypointense compared with surrounding white matter. These hypointense T1 lesions are thought to represent areas of greater tissue damage compared with the more non-specific, total T2 lesion load. This study aimed to better characterise the properties of high signal T2 lesions with differing appearances on T1 weighted MRI using quantitative MR techniques., Methods: Eleven patients with secondary progressive multiple sclerosis were studied. Two high signal T2 lesions were selected from each patient-one of which appeared hypointense and one isointense on a T1 weighted image. A voxel was positioned around each lesion and for this volume of brain the metabolite concentrations were estimated using proton MR spectroscopy ((1)H-MRS) and the T1 relaxation time within each voxel calculated from a T1 map generated using a multislice technique., Results: Compared with isointense T1 lesions, hypointense T1 lesions exhibited a significantly lower absolute concentration of N-acetyl derived metabolites (tNAA) and a significantly higher absolute concentration of myo-inositol (Ins). T1 relaxation time correlated significantly with both tNAA (r=-0.8, p < 0.001) and Ins (r=0.5, p=0. 012). There was no correlation between T1 relaxation times and creatine/phosphocreatine or choline containing compounds., Conclusions: Prolonged T1 relaxation times seem to reflect the severity of axonal damage or dysfunction (inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in chronic multiple sclerosis lesions.

Proton magnetic resonance spectroscopy (MRS) was performed in a group of patients with multiple sclerosis (MS) and matched control subjects to examine the relationship between frontal lobe pathology and performance on tests of executive function. The N-acetyl aspartate/creatine ratio (NAA/Cr) was significantly reduced in frontal lesions and/or normal-appearing white matter in the patient group compared with the control group, but choline/creatine ratios did not differ. Although MRS abnormalities and executive deficits were not correlated for MS patients as a group, a few patients with more severe abnormalities of NAA/Cr ratio performed worse than other patients on the spatial working memory test, suggesting that subtle frontal neuropathological abnormalities detected by MRS may contribute to executive deficits. Further investigation is warranted to determine the value of MRS as an index of the pathophysiological processes leading to cognitive deficit.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

The concentration of the metabolite N-acetyl aspartate (NAA), thought to be a marker of axonal loss or damage, has been shown to be reduced in lesions, as demonstrated by high signal areas on T2-weighted MRI, and in normal-appearing white matter (NAWM) in established multiple sclerosis (MS). The stage of the disease when these changes first appear is not known. To try to determine this we studied 20 patients with clinically isolated syndromes, many of whom will be at the earliest clinical stages of MS, and 20 age- and sex-matched controls with single-voxel proton magnetic spectroscopy (MRS). MRS was performed using a General Electric 1.5T Signa EchoSpeed scanner (TR 3000 ms, TE 30 ms, PRESS). Absolute metabolite concentrations were determined using the LCModel fitting software. No significant reduction of NAA concentration was evident in the NAWM of the patients (patients: median 7.3 mM; controls: median 7.7 mM; P=0.19). There was, however, a significantly lower concentration of NAA in lesions (median 6.6 mM, P=0.015). Absolute values of choline-containing compounds, creatine and myo-inositol were significantly raised in the lesions (P=0.007, P=0.011 and P=0.002 respectively). The low NAA in lesions is consistent with axonal loss, damage or dysfunction occurring focally at the earliest clinical phase of the disease. The lack of any significant reduction in NAA in patient NAWM demonstrates that more widespread axonal changes are not yet detectable at this early clinical stage. A larger cohort and follow-up will be necessary to determine whether or not MRS findings have any prognostic significance for individual patients or sub-groups. This will also enable the clarification of the time course, pathogenesis and pathophysiological significance of the development of the low NAA, which is found in the NAWM of many patients with established MS.

Objectives: To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss., Methods: 1H magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31). Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group., Results: In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 mM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group. There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P>0.02)., Conclusion: These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease.

We investigated a patient with secondary progressive Multiple Sclerosis during an acute relapse and after 6 months using several Magnetic Resonance methods. Conventional Magnetic Resonance images demonstrated at the time of relapse a large gadolinium enhancing lesion. Using proton spectroscopy and Magnetisation Transfer images heterogeneous changes suggestive of oedematous swelling peripherally, and active myelin destruction centrally were demonstrated in the acute phase. After clinical recovery there was marked resolution of acute inflammatory Magnetic Resonance abnormalities and recovery of MR tissue parameters. In comparison with conventional Magnetic Resonance Imaging Magnetisation Transfer Imaging and Proton Spectroscopy provide improved characterisation of pathological changes in MS.

Proton magnetic resonance spectroscopy, localized to the lentiform nucleus, was carried out in nine patients with a clinical diagnosis of Steele-Richardson-Olszewski syndrome (SRO) and in eight healthy age-matched controls. Three of the nine SRO patients had a so-called "eye of the tiger sign" with high signal in the globus pallidus surrounded by a ring of low signal on T2 weighted magnetic resonance imaging previously only reported in Hallervorden-Spatz disease. One of these patients had pathologically proven SRO at postmortem. The SRO group showed a significant reduction in the median concentration from N-acetyl groups (median, 6.87 mM; range, 4.92-10.59 mM; p < 0.015) compared with the control group (median, 9.85 mM; range, 9.26-11.0 mM). The N-acetylaspartate concentration was significantly reduced in seven of the nine patients studied. The reduction of the N-acetylaspartate-creatine ratio from the lentiform nucleus in the SRO group may reflect neuronal loss, occurring predominantly in the globus pallidus. Proton magnetic resonance spectroscopy may be a useful, noninvasive technique to help differentiate the various parkinsonian syndromes.

The magnetisation transfer (MT) ratio of eight multiple sclerosis lesions has been studied serially. Initially, when the lesions showed gadolinium enhancement, there was a marked reduction in their MT ratio compared with normal white matter. Follow-up a mean of 11 months later (range 3-23 months), when the lesions no longer enhanced, revealed a consistent and usually marked recovery of the MT ratios towards normal. The MT ratio is thought to reflect the structural integrity of tissues with an important contribution from myelin and axons. MT imaging is a promising tool for elucidating pathophysiology and monitoring treatment in multiple sclerosis.

Deficits in executive function and the relationship to frontal lesion load as detected on MRI were investigated in 42 multiple sclerosis patients. A battery of neuropsychological test examining executive skills including computerized tests of planning and spatial working memory was administered to all subjects. Performance on these tests was impaired in the patient group when compared with a group of matched controls, but not all executive skills were affected to the same extent. Although a number of executive test scores correlated with the severity of frontal lesion load, it was difficult to disentangle the specific contribution of frontal lobe pathology to the impairment on executive tasks. This study highlights the difficulties in attempting to attribute specific cognitive abnormalities to focal brain pathology in the presence of widespread disease such as in multiple sclerosis.

Cognitive impairment is common in multiple sclerosis and although deterioration has been observed in individual patients at the time of relapse, improvement in cognitive function in parallel with remission of neurological impairment has proved more difficult to document. We describe a 21-year-old women with a one-year history of relapsing remitting multiple sclerosis, who was admitted to hospital following a severe relapse which rendered her quadriplegic. Detailed psychometric assessment was carried out during relapse and on recovery of neurological function, eight weeks later. There were improvements in arithmetic, naming, and comprehension tasks. The patient had T2 weighted and gadolinium-enhanced magnetic resonance imaging and magnetic resonance spectroscopy. These showed a reduction in lesion size, lesion enhancement, and changes in brain chemistry which parallel the improvement in cognitive performance.

We examined 13 patients with neurological manifestations of systemic lupus erythematosus (SLE) based on previous and/or current neurological or psychotic episodes by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) together with psychiatric and cognitive assessment. MRI was abnormal in 7 patients, showing high signal lesions in the white matter and/or cerebral atrophy. Proton MRS centred on white matter lesions in 5 patients showed a reduction in the N-acetyl aspartate creatine ratio compared with normal appearing white matter in the SLE group and in 10 healthy controls. This pattern of abnormality does not allow differentiation of SLE lesions from the chronic plaques occurring in multiple sclerosis. There was a very high incidence of current psychiatric morbidity in the SLE group, namely in 12 of the 13 patients. There was no correlation between the presence of current psychiatric involvement and/or cognitive dysfunction and abnormalities detected with MRI or MRS.

Proton magnetic resonance spectroscopy, localised to the lentiform nucleus, was carried out in three ex-professional boxers who developed a parkinsonian syndrome, six patients with idiopathic Parkinson's disease, and six age matched controls. The three ex-boxers all showed a pronounced reduction in the absolute concentration of N-acetylaspartate compared with the patients with idiopathic Parkinson's disease and the control group. This reduction is likely to reflect neuronal loss occurring in the putamen and globus pallidus and supports the hypothesis that the extrapyramidal syndrome that may occur in ex-boxers is a distinct entity from idiopathic Parkinson's disease.

Proton magnetic resonance spectroscopy, localized to the lentiform nucleus, was carried out in 7 patients with the pure or predominantly striatonigral variant (SND) of multiple system atrophy (MSA), 5 patients with the olivopontocerebellar variant of MSA, 9 patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD), and 9 healthy age-matched controls. The MSA group with predominantly striatonigral involvement showed a significant reduction in the N-acetylaspartate (NAA)/creatine ratio (median, 1.19; range, 0.96-2.0; p < 0.02) compared with the NAA/creatine ratio from the control group (median, 1.76; range, 1.61-2.0). In contrast, the IPD group had a normal NAA/creatine ratio (median, 1.82; range, 1.19-2.31; p > 0.05). The NAA/creatine ratio was markedly reduced in 6 of the SND patients and in only 1 IPD patient. The choline/creatine ratio was also significantly lower in the SND group (median, 1.02; range, 0.91-1.23; p < 0.04) compared with the control group (median, 1.22; range, 1.05-1.65). The IPD group showed a normal lentiform choline/creatine ratio (median, 1.13; range, 0.89-1.65; p = 0.25) compared with controls. The olivopontocerebellar group also showed a significant reduction in the NAA/creatine ratio from the lentiform nucleus (median, 1.47; range, 1.22-1.68; p < 0.01) compared with the controls as well as a nonsignificant reduction in the choline/creatine ratio (median, 0.93; range, 0.85-1.27; p < 0.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Serial proton magnetic resonance spectroscopy (MRS), was carried out at 1-2 monthly intervals on eight patients with multiple sclerosis who presented with evidence of a large acute cerebral white matter lesion. An MRS was obtained from acute lesions (volumes of interest 4-12 ml), which at presentation showed gadolinium-diethylenetriamine penta-acetic acid enhancement, and from similar volumes of normal appearing white matter lateral to the lesion and nearer the scalp. Follow-up ranged from 4 to 9 months (mean 6 months). Short echo spectra from acute enhancing lesions invariably showed the presence of large resonances at 0.9 and 1.3 p.p.m. compared with normal appearing white matter and healthy age matched controls, indicating that these peaks were not the result of voxel contamination from scalp fat. These resonances, which probably represent lipid products of myelin breakdown, were detected in lesions which had been enhancing for < 1 month and remained elevated for a mean of 5 months (range 4-8 months). The results provide evidence that short echo proton MRS can detect myelin breakdown products and that myelin breakdown occurs during the initial inflammatory stage of lesion development. The ratio of N-acetylaspartate (NAA) (a neuronal marker) relative to creatine was reduced in acute lesions and in normal appearing white matter. In six of the lesions studied there was, however, a subsequent rise in the NAA/creatine ratio indicating that axonal loss is not the only mechanism of reduction in the NAA/creatine ratio.