Treatment of Primary Autoimmune Cerebellar Ataxia with Mycophenolate.

Immune-mediated ataxias account for a substantial number of sporadic otherwise idiopathic ataxias. Despite some well-characterised entities such as paraneoplastic cerebellar degeneration where diagnostic markers exist, the majority of immune ataxias remained undiagnosed and untreated. We present here our experience in the treatment of suspected primary autoimmune cerebellar ataxia (PACA) using mycophenolate. All patients reported attend the Sheffield Ataxia Centre on a regular basis and had undergone extensive investigations, including genetic testing using next-generation sequencing, with other causes of ataxia excluded. The diagnosis of PACA was strongly suspected based on investigations, pattern of disease progression, and cerebellar involvement. Patients were treated with mycophenolate and monitored using MR spectroscopy of the cerebellar vermis. Thirty patients with PACA are reported here. Of these, 22 received mycophenolate (group 1). The remaining 8 were not on treatment (group 2-control group). Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr area ratio) in the treatment group was + 0.144 ± 0.09 (improved) and in the untreated group - 0.155 ± 0.06 (deteriorated). The difference was significant. We also demonstrated a strong correlation between the spectroscopy and the SARA score. We have demonstrated the effectiveness of mycophenolate in the treatment of PACA. The results suggest that immune-mediated ataxias are potentially treatable, and that there is a need for early diagnosis to prevent permanent neurological deficit. The recently published diagnostic criteria for PACA would hopefully aid the diagnosis and treatment of this entity.

Nonlinear interactions in the thalamocortical loop in essential tremor: A model-based frequency domain analysis.

There is increasing evidence to suggest that essential tremor has a central origin. Different structures appear to be part of the central tremorogenic network, including the motor cortex, the thalamus and the cerebellum. Some studies using electroencephalogram (EEG) and magnetoencephalography (MEG) show linear association in the tremor frequency between the motor cortex and the contralateral tremor electromyography (EMG). Additionally, high thalamomuscular coherence is found with the use of thalamic local field potential (LFP) recordings and tremulous EMG in patients undergoing surgery for deep brain stimulation (DBS). Despite a well-established reciprocal anatomical connection between the thalamus and cortex, the functional association between the two structures during "tremor-on" periods remains elusive. Thalamic (Vim) LFPs, ipsilateral scalp EEG from the sensorimotor cortex and contralateral tremor arm EMG recordings were obtained from two patients with essential tremor who had undergone successful surgery for DBS. Coherence analysis shows a strong linear association between thalamic LFPs and contralateral tremor EMG, but the relationship between the EEG and the thalamus is much less clear. These measurements were then analyzed by constructing a novel parametric nonlinear autoregressive with exogenous input (NARX) model. This new approach uncovered two distinct and not overlapping frequency "channels" of communication between Vim thalamus and the ipsilateral motor cortex, defining robustly "tremor-on" versus "tremor-off" states. The associated estimated nonlinear time lags also showed non-overlapping values between the two states, with longer corticothalamic lags (exceeding 50ms) in the tremor active state, suggesting involvement of an indirect multisynaptic loop. The results reveal the importance of the nonlinear interactions between cortical and subcortical areas in the central motor network of essential tremor. This work is important because it demonstrates for the first time that in essential tremor the functional interrelationships between the cortex and thalamus should not be sought exclusively within individual frequencies but more importantly between cross-frequency nonlinear interactions. Should our results be successfully reproduced on a bigger cohort of patients with essential tremor, our approach could be used to create an on-demand closed-loop DBS device, able to automatically activate when the tremor is on.

The role of MRI and CT of the brain in first episodes of psychosis.

AIM: To investigate whether imaging is associated with early detection of the organic causes of the first episode of psychosis (FEP). MATERIALS AND METHODS: Individuals with FEP but no neurological signs referred to a tertiary centre for cerebral magnetic resonance imaging (MRI) or computed tomography (CT) were reviewed retrospectively. Two groups were evaluated with either CT or MRI; the two groups were independent and no individual underwent both CT and MRI. RESULTS: One hundred and twelve consecutive cerebral MRI and 204 consecutive CT examinations were identified. Three (2.7%) individuals had brain lesions [brain tumour and human immunodeficiency virus (HIV) encephalopathy] potentially accountable for the psychosis at MRI. Seventy patients (62.5%) had incidental brain lesions, such as cerebral atrophy, small vessel ischaemic changes, unruptured Circle of Willis aneurysm, cavernoma, and arachnoid cysts at MRI. Three patients (1.5%) had focal brain lesions (primary or secondary tumours) potentially accountable for the psychosis at CT. One hundred and thirty-three patients (65.2%) had incidental brain lesions unrelated to the psychosis on CT scan. There was no significant difference between MRI and CT imaging in detecting organic disease potentially responsible for FEP (p < 0.001). CONCLUSION: Routine MRI or CT imaging of the brain is unlikely to reveal disease leading to a significant change in management. MRI was comparable with CT in terms of diagnosis of both pathological and incidental cerebral lesions. Therefore, routine brain structural imaging of FEP in patients without focal neurology may not be routinely required and if imaging is requested then CT may function equally as well as MRI as the first-line investigation.

Semi-automated and automated glioma grading using dynamic susceptibility-weighted contrast-enhanced perfusion MRI relative cerebral blood volume measurements.

OBJECTIVE: Despite the established role of MRI in the diagnosis of brain tumours, histopathological assessment remains the clinically used technique, especially for the glioma group. Relative cerebral blood volume (rCBV) is a dynamic susceptibility-weighted contrast-enhanced perfusion MRI parameter that has been shown to correlate to tumour grade, but assessment requires a specialist and is time consuming. We developed analysis software to determine glioma gradings from perfusion rCBV scans in a manner that is quick, easy and does not require a specialist operator. METHODS: MRI perfusion data from 47 patients with different histopathological grades of glioma were analysed with custom-designed software. Semi-automated analysis was performed with a specialist and non-specialist operator separately determining the maximum rCBV value corresponding to the tumour. Automated histogram analysis was performed by calculating the mean, standard deviation, median, mode, skewness and kurtosis of rCBV values. All values were compared with the histopathologically assessed tumour grade. RESULTS: A strong correlation between specialist and non-specialist observer measurements was found. Significantly different values were obtained between tumour grades using both semi-automated and automated techniques, consistent with previous results. The raw (unnormalised) data single-pixel maximum rCBV semi-automated analysis value had the strongest correlation with glioma grade. Standard deviation of the raw data had the strongest correlation of the automated analysis. CONCLUSION: Semi-automated calculation of raw maximum rCBV value was the best indicator of tumour grade and does not require a specialist operator. ADVANCES IN KNOWLEDGE: Both semi-automated and automated MRI perfusion techniques provide viable non-invasive alternatives to biopsy for glioma tumour grading.

3.0 T MRI of 2000 consecutive patients with localisation-related epilepsy.

OBJECTIVES: Clinical guidelines suggest that all patients diagnosed with localised seizures should be investigated with MRI to identify any epileptogenic structural lesions, as these patients may benefit from surgical resection. There is growing impetus to use higher field strength scanners to image such patients, as some evidence suggests that they improve detection rates. We set out to review the detection rate of radiological abnormalities found by imaging patients with localised seizures using a high-resolution 3.0 T epilepsy protocol. METHODS: Data were reviewed from 2000 consecutive adult patients with localisation-related epilepsy referred between January 2005 and February 2011, and imaged at 3.0 T using a standard epilepsy protocol. RESULTS: An abnormality likely to be related to seizure activity was identified in 403/2000 (20.2%) patients, with mesial temporal sclerosis diagnosed in 211 patients. 313/2000 (15.6%) had lesions potentially amenable to surgery. Abnormalities thought unrelated to seizure activity were found in 324/2000 (16.1%), with 8.9% having evidence of ischaemic disease. CONCLUSIONS: Since the introduction of the then National Institute for Clinical Excellence guidelines in 2004, the detection rate of significant pathology using a dedicated 3.0 T epilepsy protocol has not fallen, despite the increased numbers of patients being imaged. This is the largest study of epilepsy imaging at 3.0 T to date and highlights the detection rates of significant pathology in a clinical setting using a high-strength magnet. The prevalence of ischaemic disease in this population is significantly higher than first thought, and may not be incidental, as is often reported.

Contrasting natural histories of thoracic spine pneumatocysts: resolution versus rapid enlargement.

An intraosseous pneumatocyst is an unusual cause of gas in a vertebral body and is rarely reported in the thoracic spine. We report the evolution of thoracic spine pneumatocysts, one that enlarged rapidly with resorption of fluid and one that resolved. A 65-year-old female with lower back and left leg pain underwent MRI of the lumbar spine, which demonstrated a well-defined lesion in a T10 vertebral body of low-signal on T(1) and T(2) weighted imaging. CT confirmed this as a gas-containing cyst. Review of previous imaging showed that this lesion had initially contained fluid and had expanded rapidly over 14 months. It also showed smaller pneumatocysts, which had resolved. The variable natural history and imaging features of pneumatocysts make them an important differential diagnosis of an intravertebral lesion. Their aetiology is not known, but previous case reports suggest that they can occur spontaneously or in association with vacuum phenomenon in adjacent discs or facet joints. Previous reports have observed that they can fill with granulation tissue or fluid, and the case we report demonstrates that this fluid can be resorbed and that the pneumatocyst can undergo rapid enlargement. A pneumatocyst is a differential diagnosis for an expanding intravertebral lesion of indeterminate MRI characteristics. The diagnosis can be made with CT if the lesion is gas or gas and fluid filled.

Magnetic resonance imaging of epilepsy at 3 Tesla.

Patients with epilepsy often have a structural cause for their seizures and may benefit from surgical resection. As recommended in the National Institute of Health and Clinical Excellence (NICE) guidelines, magnetic resonance imaging (MRI) is used to screen for structural abnormalities in these patients and there is increasing evidence that 3T MRI has better sensitivity and specificity than 1.5T. This article reviews the imaging findings of many of the common diseases that can cause epilepsy.

Corpus callosum morphology and microstructure assessed using structural MR imaging and diffusion tensor imaging: initial findings in adults with neurofibromatosis type 1.

BACKGROUND AND PURPOSE: Imaging studies have shown that children with NF-1 have increased brain volumes compared with age-matched controls and the CCs are disproportionately large. The purpose of this study was to determine if the CC in adults with NF-1 differed from that in matched controls by using DTI and volumetric imaging. MATERIALS AND METHODS: MR imaging with DTI was performed in 10 adults with NF-1 and in 10 age-, sex-, and handedness-matched controls by using a 3T system. Total brain volumes and the areas and central lengths of the CC were calculated, along with the radial width of callosal subdivisions, in the 2 groups. RESULTS: Our results showed that the total brain volume was not significantly different between adults with NF-1 and matched controls. The length and total cross-sectional area of the CC were statistically larger in adults with NF-1 compared with controls (approximately 10% longer and 20% greater area). On DTI we found a preservation of the primary eigenvalue with increases in the minor eigenvalues at the genu. CONCLUSIONS: We have shown that the increased size of the CC found in children with NF-1 is also present in adults with the syndrome, whereas no difference in total brain volume was found.

Inhibin betaB expression in murine adipose tissue and its regulation by leptin, insulin and dexamethasone.

Inhibin betaB (INHBB; coding for the activin betaB subunit) has previously been identified in both human and rodent adipose tissue and using Taqman real-time PCR with specific primers we confirm the expression of INHBB mRNA in rodent adipose tissue. Expression of INHBB in murine epididymal adipose tissue was higher than in any of the other tissues studied and appears to be regulated by changes in energy balance and leptin. It was increased fourfold in the epididymal fat depot of ob/ob mice compared with the same fat depot in lean mice. The i.p. administration of leptin in obese ob/ob mice decreases the expression of INHBB. In human adipose tissue, INHBB is reduced by weight loss. In keeping with this, we demonstrate that INHBB expression in murine adipose tissue is decreased in fasting and increased upon refeeding. We show that INHBB is expressed in both the mature adipocyte and the stromal vascular fraction of adipose tissue. INHBB increases with the differentiation of pre-adipocytes into mature adipocytes in the 3T3-L1 cell line. In differentiated 3T3-L1 adipocytes, where receptors to activin have been previously reported, insulin increases the expression of INHBB, while dexamethasone decreases the expression of INHBB when compared with untreated control cells. Taken together, these results suggest that the regulation of INHBB expression in adipose tissue may play a physiological role in energy balance or the insulin insensitivity associated with obesity.

Chronic central administration of apelin-13 over 10 days increases food intake, body weight, locomotor activity and body temperature in C57BL/6 mice.

The peptide apelin has been located in a wide range of tissues, including the gastrointestinal tract, stomach and adipose tissue. Apelin and its receptor has also been detected in the arcuate and paraventricular nuclei of the hypothalamus, which are involved in the control of feeding behaviour and energy expenditure. This distribution suggests apelin may play a role in energy homeostasis, but previous attempts to discern the effects of apelin by acute injection into the brain have yielded conflicting results. We examined the effect of a chronic 10-day intracerebroventricular (i.c.v.) infusion of apelin-13 into the third ventricle on food intake, body temperature and locomotor activity in C57BL/6 mice. Apelin-13 (1 microg/day) increased food intake significantly on days 3-7 of infusion; thereafter, food intake of treated and control individuals converged. This convergence was potentially because of progressive conversion of apelin-13 to [Pyr(1)]apelin-13 which has a four-fold lower receptor binding affinity at the orphan G protein-coupled receptor, APJ. Locomotor activity was also higher in the apelin-treated mice, especially during the nocturnal peak, when most feeding occurs, and the first hours of the light phase. Body temperature was also elevated during this increased period of activity, but was otherwise unaffected. Apelin-13-infused animals gained more weight than the saline-infused controls, suggesting the elevated locomotor activity did not offset the increased food intake. Elevated locomotion and the consequent increases in body temperature were probably secondary effects to the increased food intake. These results suggest that apelin-13 may play a central role in the control of feeding behaviour and is one of only two peripheral ligands known to stimulate rather than inhibit intake. As apelin production is elevated during obesity, this may provide an important feed-forward mechanism exacerbating the problem. Antagonists of the apelin receptor may therefore be useful pharmaceuticals in the treatment of obesity.

Expression of neuromedin B in adipose tissue and its regulation by changes in energy balance.

Bombesin is one of the most powerful substances showing anorexic effects in the hypothalamus (Moody TW & Merali Z 2004 Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 25 511-520). In mammals, neuromedin B (NMB) is one member of a family of bombesin-like peptides, which have been shown to reduce food intake when administered systemically. Using Taqman real-time PCR with specific primers, we report the expression of NMB mRNA in both human and rodent adipose tissue. Expression of NMB in rodent epididymal adipose tissue was higher than in other tissues studied. Expression of NMB in adipose tissue appears to be regulated by changes in energy balance and leptin. It is decreased fourfold in the epididymal fat depot of ob/ob mice when compared with the same fat depot in lean mice. It is further decreased with the intra-peritoneally (i.p.) administration of leptin in both lean and obese ob/ob mice. This may relate to its function in food intake regulation or to changes in energy expenditure. We demonstrate that NMB expression in rodent adipose tissue is decreased in cold exposed animals. However, when we investigated the effects of NMB on resting metabolic rate by i.p. injection, there was no effect on oxygen consumption, RQ or physical activity when compared with saline-treated controls. In conclusion, NMB is expressed in both human and rodent adipose tissue and appears to be regulated by changes in energy balance. Given its anorexic effects centrally, it may form part of a new adipose tissue--hypothalamic axis regulating food intake.

Brain MR perfusion imaging in humans.

PURPOSE: To evaluate any possible advantages of high-concentration gadolinium chelates in the human brain thin-slice MR. MATERIAL AND METHODS: Thirty-six patients were allocated into six groups. Three groups had perfusion imaging performed using 7-mm-thick slices and the other three groups had 4-mm-thick slices. One group who had 7-mm slices and one group of 4-mm slices had 0.5 M gadolinium (20 ml) whilst other groups received the high-concentration gadolinium (1.0 M: 10 ml and 20 ml). The time-intensity curves were analysed for maximum signal reduction and signal-to-noise measurements. RESULTS: Twenty ml of the 1.0-M agent produced significantly increased maximum signal change and improvement in signal-to-noise when compared to 20 ml of 0.5 M. There was no significant difference between the maximum signal change when 20 ml of 0.5 M and 10 ml of 1.0 M agents were compared. There was no significant difference between the maximum signal changes when 7-mm and 4-mm slice thickness using the same dosing regimens. CONCLUSION: Four-mm slice thickness perfusion imaging can be performed with high-concentration gadolinium in the human brain and we discuss the advantages of this.

Multimodality MR imaging depiction of hemodynamic changes and cerebral ischemia in subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a common and serious neurologic emergent condition. We tested the hypothesis that multimodality MR imaging depicts changes in cerebral blood flow SAH, before any surgical or endovascular intervention, and that the frequency of these changes increases with time after ictus. METHODS: We prospectively examined 37 patients with suspected SAH and three with symptoms of acute stroke but who subsequently had SAH. Routine CT and multimodality MR imaging were performed within 18 h of presentation. Standard MR imaging, diffusion-weighted MR imaging, time-of-flight MR angiography, and dynamic first-pass gadolinium-enhanced MR perfusion imaging were performed. Images were reviewed for abnormalities in cerebral blood flow, ischemia, and infarction. Nine patients did not have SAH at CT and CSF investigations. Of 31 patients with proved SAH, 13 were examined during the acute stage (within 4 d of ictus) and 18, during the subacute stage (4-14 d after ictus). RESULTS: MR imaging showed alteration in cerebral blood flow parameters in 16 of 31 patients before surgery or endovascular treatment. The frequency of blood flow changes and associated complications increased with worsening clinical grade and increasing time after ictus. CONCLUSION: Multimodality MR imaging provides information not available from CT in patients with SAH. MR imaging shows oligemic and ischemic areas in SAH before surgery or endovascular treatment. MR imaging is a simple noninvasive method of assessing cerebral blood flow and its complications in SAH. It can be performed in a clinical environment.

Brain arteriovenous malformations: assessment with dynamic MR digital subtraction angiography.

BACKGROUND AND PURPOSE: Conventional catheter angiography (CCA) is the current reference standard for the diagnosis, assessment, and management of pial brain arteriovenous malformations (AVMs). The purpose of this study was to develop an MR angiographic technique that produces dynamic images comparable to those provided by CCA and to apply the technique to the investigation of pial brain AVMs. METHODS: Twenty patients with brain AVMs referred for stereotactic radiosurgery were recruited. All patients had CCA performed on a 1.5-T superconducting system. Sixty images were obtained at a rate of one image per second. Slices were orientated to produce Towne, lateral, and anteroposterior projections. A set of mask images was taken and then a series during the passage of a bolus of contrast material. MR examinations were assessed independently by neuroradiologists blinded to the conventional catheter angiographic findings. RESULTS: The nidus of the AVMs was depicted in 19 of the 20 patients, and correlation with CCA was excellent for measurements of maximum diameter. Venous drainage was correctly assessed in 18 of 19 cases. CONCLUSION: MR digital subtraction angiography shows promise as a noninvasive, dynamic angiographic tool for planning stereotactic radiosurgery of AVMs already delineated by catheter angiography. At present, it suffers from temporal and spatial resolution, which impede the assessment of some brain AVMs.

Brain iron deposition in Parkinson's disease imaged using the PRIME magnetic resonance sequence.

Iron content of the basal ganglia was investigated in 25 patients with idiopathic Parkinson's disease and 14 matched healthy control subjects using a partially refocused interleaved multiple echo sequence on a 1.5 Tesla MRI system. R(2)* (1/T(2)*) and R(2)' (1/T(2)') relaxation rates were higher in the substantia nigra of patients with Parkinson's disease, which indicates that iron content is elevated in this region. R(2)' was lower in the putamen, indicating reduced iron levels; reduction in this region was positively correlated with disease duration. Iron-related oxidative stress may contribute to the neurodegeneration of Parkinson's disease, which may lead to alterations in the iron levels of the striatum. We describe a simple, non-invasive technique for measuring iron content.

Interaction of free fatty acids with human leptin.

Relatively high concentrations of leptin are present in plasma and it is thought to play a major role in lipid homeostasis. Leptin is reported to lower tissue triglyceride content by increasing intracellular oxidation of free fatty acids (FFA). However very little is known regarding the interaction between leptin and plasma FFA. We studied the interaction of FFA with leptin using a direct radiolabelled fatty acid binding assay, a fluorescence assay, electrophoretic mobility and autoradiobinding. All these data indicate that binding of FFA with leptin is reversible and shows a positive co-operativity. The binding of FFA to leptin produces a change in the pI value of the leptin and also increased the electrophoretic mobility of the protein in native polyacrylamide gels. The change in leptin's electrophoretic mobility depends on the chain length and the number of double bonds of the fatty acid, as stearic acid, 18:0, had no effect whereas oleic acid, 18:1n-9, linoleic acid, 18:2n-6, arachidonic acid, 20:4n-6, and docosahexaneoic acid, 22:6n-3, affected leptin's mobility to different degrees. The physiological implication of leptin-FFA interaction is not known, however the interaction may depend on the plasma FFA composition and concentration which are known to vary in different pathological/physiological conditions.

Generation of a contig comprising YACs and BACs within chromosome region 1p13.1.

Chromosome region 1p13 is known to show loss of heterozygosity (LOH) in a number of human tumor types, including breast. We have generated a contig comprising YACs and BACs spanning part of 1p13.1 which includes the smallest region of overlapping loss identified in our earlier studies. The contig is anchored to the genetic map by a number of microsatellite markers, and by the use of CEPH YACs. We have excluded a number of candidate genes from this region, and we have oriented the contig with respect to the centromere and a number of other genes and markers on 1p13. This resource will be valuable in mapping the target for LOH in breast and other tumors, and may also be useful for the genetic analysis of other genes or diseases known to map to this region.

Identification and cloning in yeast artificial chromosomes of a region of elevated loss of heterozygosity on chromosome 1p31.1 in human breast cancer.

We have mapped a region of high loss of heterozygosity in breast cancer to a 2-cM interval between the loci D1S430 and D1S465 on chromosome 1p31.1. This region shows allelic imbalance in around 60% of breast tumors. As part of a strategy to clone the target gene(s) within this interval, we have generated a yeast artificial chromosome contig spanning over 7 Mb. YACs from the CEPH and Zeneca (formerly ICI) libraries have been obtained by screening with PCR-based STSs from the region for both previously identified loci and newly isolated STSs. The YACs have been assembled into a contig by a combination of approaches, including analysis of their STS content, generation of new STSs from the ends of key YACs, and long-range restriction mapping. These YAC clones provide the basis for complete characterization of the region of high loss in breast cancer and for the ultimate identification of the target gene(s).