Substrate reduction therapy in juvenile GM2 gangliosidosis

Substrate reduction therapy (SRT) is considered to be a potential therapeutic option for juvenile GM2 gangliosidosis (jGM2g). We evaluated the efficacy of SRT in jGM2g, assessing neurological, neuropsychological and brain magnetic resonance imaging (MRI) outcomes over a 24-month period of treatment. In an open-label and single-center study, five jGM2g patients (mean age 14.6 ± 4.5 years) received oral miglustat at doses of 100–200 mg t.i.d. adjusted to body surface area. Patients underwent general and neurological examinations, neuropsychological, electrophysiological, and brain MRI studies. All patients showed neurological deterioration over the period of the study, with particularly notable worsening of gait, speech and coordination. One patient experienced acute psychosis, and another showed worsening of pre-existing epilepsy. Some neuropsychological tests showed no evidence of deterioration in the three patients with high enough cognitive functioning for reliable assessment. Profound cognitive impairment in two children precluded neuropsychological evaluation. In four patients, evaluation of brain MRI showed no changes in white matter signal abnormalities and cerebellar atrophy noted at baseline, while one patient showed progression of cerebellar and supratentorial brain atrophy. Transmission electron microscopy analysis of peripheral mononuclear cells showed reduction of intracytoplasmatic inclusions with treatment. SRT with miglustat of patients with jGM2g failed to ameliorate progressive neurological deterioration, but apparently no worsening of some areas of cognitive function tested and brain MRI lesions was noted over 24 months of treatment. The results must be interpreted with care owing to the small sample of patients and the lack of a control-arm.     

The neural basis of motor sequencing: an fMRI study of healthy subjects

The present study used functional MRI to clarify the brain regions activated during a series of motor sequencing tasks in healthy volunteers. Ten subjects were scanned while performing three soft signs tasks ranging from simple (PT: palm tapping), moderate (PS: pronation/supination) to complex movements (FEP: fist-edge-palm). The FEP task induced significant activations within the cortical networks including bilateral sensorimotor, SMA, left parietal, and right cerebellum, but no activation in the prefrontal area. Moreover, the percentage signal changes within the left sensorimotor, left thalamus and right cerebellum showed an increase in activation with task complexity. The present findings challenge the traditional belief that FEP was a task for frontal lobe function but suggest that successful performance of more complex neurological soft sign tasks like FEP requires the participation of more brain areas than simple motor sequencing and coordination task like PS and PT. These also provide the empirical data on the neural basis of neurological soft signs for further study in other clinical group like schizophrenia in the near future.     

White matter alteration and cerebellar atrophy are hallmarks of brain MRI in alpha-mannosidosis

ObjectiveDespite profound neurological symptomatology there are only few MRI studies focused on the brain abnormalities in alpha-mannosidosis (AM). Our aim was to characterize brain MRI findings in a large cohort of AM patients along with clinical manifestations.MethodsTwenty-two brain MRIs acquired in 13 untreated AM patients (8 M/5F; median age 17 years) were independently assessed by three experienced readers and compared to 16 controls.ResultsFocal and/or diffuse hyperintense signals in the cerebral white matter were present in most (85%) patients. Cerebellar atrophy was common (62%), present from the age of 5 years. Progression was observed in two out of 6 patients with follow-up scans. Cortical atrophy (62%) and corpus callosum thinning (23%) were already present in a 13-month-old child. The presence of low T₂ signal intensity in basal ganglia and thalami was excluded by the normalized signal intensity profiling. The enlargement of perivascular spaces in white matter (38%), widening of perioptic CSF spaces (62%), and enlargement of cisterna magna (85%) were also observed. Diploic space thickening (100%), mucosal thickening (69%) and sinus hypoplasia (54%) were the most frequent non-CNS abnormalities.ConclusionWhite matter changes and cerebellar atrophy are proposed to be the characteristic brain MRI features of AM. The previously reported decreased T₂ signal intensity in basal ganglia and thalami was not detected in this quantitative study. Rather, this relative MR appearance seems to be related to the diffuse high T₂ signal in the adjacent white matter and not the gray matter iron deposition that has been hypothesized.     

慢性肾性高血压大鼠脑组织磁共振成像观察和超微结构的研究

目的研究慢性肾性高血压大鼠脑核磁共振成像(MRI)的变化和相应部位超微结构的改变。方法将SD大鼠分为对照组和模型组。用双肾双夹法建立肾性高血压动物模型，术后饲养12个月，用磁共振成像结合电镜观察大鼠脑组织的变化。结果1．正常组大鼠的血压、MRI表现及超微结构未发现异常。2．慢性肾性高血压模型大鼠血压升高；侧脑室旁尾壳核区域T22WI像上可见明显的条状高信号；髓鞘结构松散，可见轴突与髓鞘间及髓鞘板层间形成宽大的裂隙，部分神经纤维缺失，髓鞘脱落。结论慢性肾性高血压大鼠脑内出现明显的条状高信号，提示脑部神经纤维的病变可能己比较严重。     

Using arterial spin labeling perfusion MRI to explore how midazolam produces anterograde amnesia

While our previous work suggests that the midazolam-induced memory impairment results from the inhibition of new association formation, little is known about the neural correlates underlying these effects beyond the effects of GABA agonists on the brain. We used arterial spin-labeling perfusion MRI to measure cerebral blood flow changes associated with the effects of midazolam on ability to learn arbitrary word-pairs. Using a double-blind, within-subject cross-over design, subjects studied word-pairs for a later cued-recall test while they were scanned. Lists of different word-pairs were studied both before and after an injection of either saline or midazolam. As expected, recall was severely impaired under midazolam. The contrast of MRI signal before and after midazolam administration revealed a decrease in CBF in the left dorsolateral prefrontal cortex (DLPFC), left cingulate gyrus and left posterior cingulate gyrus/precuneus. These effects were observed even after controlling for any effect of injection. A strong correlation between the midazolam-induced changes in neural activity and memory performance was found in the left DLPFC. These findings provide converging evidence that this region plays a critical role in the formation of new associations and that low functioning of this region is associated with anterograde amnesia.     

Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis

Signal loss observed in the brain by MRI following the administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) has been correlated with immune cell activity in inflammatory areas during multiple sclerosis. Uptake of USPIO by circulating monocytes and their migration towards inflammatory areas have been considered as the most important mechanism for USPIO uptake by the brain parenchyma. However, the involvement of a damaged blood–brain barrier is also debated as a possible mechanism for cerebral USPIO uptake. Compared with these uptake‐associated issues, little is known about the clearance of USPIO from the brain. The acute uptake and chronic clearance of USPIO in the brain were therefore studied with MRI in an animal model of multiple sclerosis. Lewis Hannover rats with acute experimental autoimmune encephalomyelitis received a single intravenous injection of USPIO (300 µmol Fe/kg), and repetitive MRI of the brain and cervical lymph nodes, a possible drainage pathway, was performed. USPIO were detected in the brain within 1 h after injection independent of the severity of experimental autoimmune encephalomyelitis, and histological analysis revealed extracellular iron clusters colocalising with a leaky blood–brain barrier. Loss of signal was not present 72 h after USPIO injection, irrespective of the disease state. MR images of cervical lymph nodes showed USPIO accumulation at 24 h after administration, which stabilised at 72 h. Histological analyses revealed that USPIO accumulated in infiltrated macrophages in the medulla and subcapsular sinus. The current study demonstrates that USPIO enter the central nervous system directly after administration, pointing to the involvement of a damaged blood–brain barrier in the appearance of USPIO‐associated MR abnormalities. Furthermore, a possible role of the cervical lymph nodes as a drainage pathway of USPIO is suggested. These data shed new light on the use of USPIO in neuroinflammatory diseases, identifying USPIO as a marker for both cellular infiltration and blood–brain barrier damage. Copyright © 2010 John Wiley & Sons, Ltd.     

Simulated dive in rats lead to acute changes in cerebral blood flow on MRI, but no cerebral injuries to grey or white matter

In this study, the effect of a simulated dive on rat brain was investigated using several magnetic resonance imaging (MRI)-methods and immunohistochemistry. Rats were randomly assigned to a dive- or a control group. The dive group was exposed to a simulated air dive to 600 kPa for 45 min. Pulmonary artery was monitored for vascular gas bubbles by ultrasound. MRI was performed 1 h after decompression and at one and 2 weeks after the dive with a different combination of MRI sequences at each time point. Two weeks after decompression, rats were sacrificed and brains were prepared for histology. Dived rats had a different time-curve for the dynamic contrast-enhanced MRI signal than controls with higher relative signal intensity, a tendency towards longer time to peak and a larger area under the curve for the whole brain on the acute MRI scan. On MRI, 1 and 2 weeks after dive, T₂-maps showed no signal abnormalities or morphological changes. However, region of interest based measurements of T₂ showed higher T₂ in the brain stem among decompressed animals than controls after one and 2 weeks. Microscopical examination including immunohistochemistry did not reveal apparent structural or cellular injuries in any part of the rat brains. These observations indicate that severe decompression does not seem to cause any structural or cellular injury to the brain tissue of the rat, but may cause circulatory changes in the brain perfusion in the acute phase.     

Changes in blood lactate and muscle activation in elite rock climbers during a 15-m speed climb

Purpose

The purpose of this study was to investigate the changes in blood lactate concentration (BL) and muscle activity patterns during a 15-m speed climbing competition that consisted of ten consecutive climbing actions on a standardized artificial wall in trained rock climbers.

Methods

Twelve trained rock climbers participated in this study. Surface electromyography (sEMG) and video signals were synchronized and recorded during climbing. The blood lactate was also tested 3 min after completing the climb.

Results

The average climbing time was 8.1 ± 2.1 s for the 15-m speed climb across all subjects, accompanied by a BL of 7.6 ± 1.9 mmol/L. The climbing speed and power firstly increased and then slightly decreased relative to peak value during the 15-m speed climbing. The results showed there was a positive correlation between the BL and the climbing time, r = 0.59, P = 0.043. The sEMG showed the flexor digitorum superficialis (FDS) electric activity was the highest, followed by the biceps brachii (BB) and latissimus dorsi. The instantaneous median frequency of sEMG of FDS and BB significantly decreased during the 15-m speed climbing. All the participants showed the higher sEMG RMS (%) in the terminal phase than that in the initial phase, especially with a greater increase in the left upper limbs. However, the lower limbs muscles presented no significant changes in the sEMG amplitude during climbing.

Conclusions

The FDS and BB play an important role in completing the 15-m speed climbing. The median frequency of arm EMG decreased more than that of legs, suggesting more fatigue. The blood lactate concentration increases in the current study suggest that a certain amount of glycolysis supplies energy in completing 15-m speed rock climbing. Based on the current data, it is suggested that muscular endurance of FDS and BB muscles in upper limbs should be improved for our climbers in this study.

     

Factors influencing osteological changes in the hands and fingers of rock climbers

This study examines the osteological changes in the hands and fingers of rock climbers that result from intense, long-term mechanical stress placed on these bones. Specifically, it examines whether rock climbing leads to metacarpal and phalange modelling in the form of increased cortical thickness as well as joint changes associated with osteoarthritis. This study also attempts to identify specific climbing-related factors that may influence these changes, including climbing intensity and frequency of different styles of climbing. Radiographs of both hands were taken for each participant and were scored for radiographic signs of osteoarthritis using an atlas method. Total width and medullary width were measured directly on radiographs using digital calipers and used to calculate cross-sectional area and second moment of area based on a ring model. We compared 27 recreational rock climbers and 35 non-climbers for four measures of bone strength and dimensions (cross-sectional area, second moment of area, total width and medullary width) and osteoarthritis. A chi-squared test for independence was used to compare climber and non-climber osteoarthritis scores. For each measure of bone strength climbers and non-climbers were compared using a manova test. Significant manova tests were followed by principal components analysis (PCA) and individual anova tests performed on principal components with eigenvalues greater than one. A second PCA was performed on the climber subsample and the first principal component was then used as the dependent variable in linear regression variable selection procedures to determine which climbing-related variables affect bone thickness. The results suggest that climbers are not at an increased risk of developing osteoarthritis compared with non-climbers. Climbers, however, do have greater cross-sectional area as well as second moment of area. Greater total width, but not meduallary width, indicates that additional bone is deposited subperiosteally. The strength of the finger and hand bones are correlated with styles of climbing that emphasize athletic difficulty. Significant predictors include the highest levels achieved in bouldering and sport climbing.     

Distortion product otoacoustic emissions for assessment of intracranial hypertension at extreme altitude?

The levels of distortion product otoacoustic emissions (DPOAEs) change at frequencies between 0.75 and 1.5 kHz along with intracranial pressure (ICP) and DPOAEs are suggested for monitoring ICP changes. Elevated ICP plays a major role in high-altitude disease, but direct measurement is unlikely to be feasible at high altitudes. The aim of the presented study was to measure DPOAEs at extreme altitudes in order to determine whether information about elevated ICP can be obtained. Data are presented from DPOAE measurements at the frequencies 1, 1.5, 2, 3 and 4 kHz in 13 climbers during an ascent to Gasherbrum II (8,035 m) up to an altitude of 7,400 m. Valid DPOAE measurements could be obtained in all climbers. DPOAE levels exhibited great variability concerning both the affected frequency range and the change. As expected due to elevated ICP, DPOAE levels decreased in some of the climbers at 1 kHz. However, an even more pronounced decline of DPOAE levels was observed at 3 and 4 kHz, which cannot be explained by intracranial hypertension. Possible other reasons for DPOAE level changes at extreme altitude are hypoxia, increased serum osmolarity and unbalanced middle ear pressure. Only one climber developed severe acute mountain sickness with clinical signs of intracranial hypertension. The most pronounced decline of DPOAEs at 1 kHz was seen on that occasion, which suggests a possible use of DPOAEs for detection of intracranial hypertension and early detection of high-altitude cerebral edema.     

Climbing time to exhaustion is a determinant of climbing performance in high-level sport climbers

We studied which physiological and kinanthropometric characteristics determine climbing performance in 16 high-level sports climbers aged 29.9 ± 4.9 years. Body composition parameters were measured with dual energy X-ray absorptiometry scanner. We also measured kinanthropometric and physical fitness parameters. The sex-specific 75th percentile value of onsight climbing ability was used to divide the sample into expert (<75th) and elite (≥75th) climbers. All the analyses were adjusted by sex. The 75th percentile value of onsight climbing ability was 7b in women and 8b in men. There were no differences between expert and elite climbers in the studied variables, except in climbing time to exhaustion and bone mineral density. Elite climbers had a significantly higher time to exhaustion than the expert group (770.2 ± 385 vs. 407.7 ± 150 s, respectively, P = 0.001). These results suggest that, among climbers with a high level of performance, as those analysed in this study, climbing time to exhaustion is a major determinant of climbing performance.     

Cerebral blood flow velocity responses to hypoxia in subjects who are susceptible to high-altitude pulmonary oedema

Cerebral blood flow increases on exposure to high altitude, and perhaps more so in subjects who develop acute mountain sickness. We determined cerebral blood flow by transcranial Doppler ultrasound of the middle cerebral artery at sea level, in normoxia (fraction of inspired O₂, F _IO₂ 0.21), and during 15-min periods of either hypoxic (F _IO₂ 0.125) or hyperoxic (F _IO₂ 1.0) breathing, in 7 subjects with previous high-altitude pulmonary oedema, 6 climbers who had previously tolerated altitudes between 6000?m and 8150?m, and in 20 unselected controls. Hypoxia increased mean middle cerebral artery flow velocity from 69 (3) to 83 (4) cm?·?s^?1 (P??1 (P??1 (P??1 (P??1 (P??1 (P?相似文献   

Prospective study to evaluate the clinical and radiological outcome of patients with scleroderma of the face

Introduction

Scleroderma featuring rare connective tissue disease that manifests as skin sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement and localized scleroderma or morphea which classically presents benign evolution and self-limited, confined to the skin and/or underlying tissue. Recent studies show that the localized form may possibly course with involvement of internal organs and variable morbidity. This study aimed to determine the demographic characteristics, the prevalence of systemic manifestations and laboratory findings, as well as the association with autoimmune diseases, and the evolution of neurological findings, both clinical as brain MRI in patients with scleroderma of the face and its relation with the activity skin.

Methods

Patients with localized scleroderma with facial involvement were evaluated and underwent neurological examination, magnetic resonance imaging and ophthalmology evaluation. After 3 years, the patients were subjected again to MRI.

Results

We studied 12 patients with localized scleroderma of the face. Of this total, headache being the most frequent complaint found in 66.7% of patients, 33.3% had neurological changes possibly associated with scleroderma. As for ophthalmologic evaluation, 25% of patients showed abnormalities. The most frequent parenchymal finding was the presence of lesions with hyperintense or hypointense signal in 75% of patients, followed by ventricular asymmetry at 16.7%. Of the patients who had neurological deficits, 75% also had a change to MRI. In all patients, imaging findings after 3 years were unchanged. During this interval of 3 years, 25% of patients showed signs of activity of scleroderma.

Conclusion

Patients with localized scleroderma of the face have a high prevalence of neurological and ophthalmological changes. Based on these findings, we suggest that all cases of localized scleroderma of the face should be thoroughly examined for the presence of systemic changes.     

Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects

STUDY OBJECTIVES: To assess whether MRI detectable evidence of silent cerebrovascular disease is more prevalent in patients with obstructive sleep apnea (OSA) when compared to carefully matched control subjects. DESIGN AND SETTING: Case-control study of patients with OSA attending a specialist sleep clinic and matched control subjects drawn from the normal community. PARTICIPANTS: Forty-five sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness, matched to 45 control subjects without excessive sleepiness or evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension, and ischaemic heart disease. INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: All subjects underwent 24-hour ambulatory blood pressure recordings (before treatment in OSA patients) and sagittal T1, axial T2, and coronal dual echo cerebral MRI imaging to detect clinically silent abnormalities related to hypertensive cerebrovascular disease; areas of high signal foci in deep white matter (DWM), lacunae, and periventricular hyperintensity. Lacunae/high signal foci in DWM and/or periventricular hyperintensity were present in 15 (33%) OSA subjects and 16 (35%) controls, despite significant increases in mean daytime diastolic blood pressure (4.6mmHg, p<0.05), and both nighttime diastolic (7.2mmHg, p<0.001) and systolic blood pressures (9.2mmHg, p<0.05) in OSA subjects. These data exclude more than a 17% excess prevalence of MRI detected minor cerebrovascular disease in the OSA patients, with 95% confidence. CONCLUSIONS: Sub-clinical cerebrovascular disease is prevalent in both clinic patients with OSA and their matched control subjects. Despite the increased arterial blood pressures, there is, however, no apparent excess of MRI-evident subclinical cerebrovascular disease in patients with OSA compared to appropriately matched control subjects.     

The yield of subtelomeric FISH analysis in the evaluation of autistic spectrum disorders

To assess the frequency of cryptic subtelomeric rearrangements in children and adolescents with autism spectrum disorders, blood samples were studied using a complete set of subtelomeric FISH probes in 72 children with autism spectrum disorders. All children had normal high resolution karyotype, DNA fra-X analysis, brain MRI, metabolic work-up, and physical/neurological examination. Subtelomeric analysis did not detect abnormalities in any of the subjects, suggesting the uselessness of such investigations in individuals with primary autism spectrum disorders.     

October 2004: a 49-year-old man with progressive dementia

October 2004. A 49-year-old right-handed man developed progressive cognitive difficulties over a 4-month period. There was impairment in recent memory, calculations and language. He also developed fatigue, weight loss, gait imbalance and urinary incontinence. Past history included transfusion-associated Hepatitis C. Neurologic exam showed mild dysarthria, dysnomia, left sided neglect, bilateral Babinski signs, and a prominent grasp reflex. Laboratory testing provided no positive etiologic data. An EEG showed generalized intermittent slowing suggestive of a diffuse encephalopathy and decreased background in the right hemisphere, suggestive of a structural lesion. MRI showed multiple areas of high signal on FLAIR imaging and patchy enhancement. FDG-PET showed multi-focal areas of increased uptake, correlating with the abnormal areas on MRI, on a background of decreased uptake. A 4-vessel cerebral angiogram showed no abnormalities. A brain biopsy showed diffuse infiltrates of large malignant cells that were immunoreactive with antibodies to CD20, diagnostic of diffuse large B cell lymphoma. In summary, the clinical presentation suggested bilateral hemispheric involvement, which was supported by physical examination, EEG, MRI, and PET scans. The differential diagnosis for this presentation is limited to demyelinating disease such as multiple sclerosis, vascular dementia, and infiltrating neoplasm such as glioblastoma multiforme or lymphoma. Diagnosis was made by morphologic and immunohistochemical analysis of brain tissue.     

Dual-task interference between climbing and a simulated communication task

Climbers often need to maintain communication with other people. Previous research indicates that climbers remember less of the information communicated to them while climbing than when not climbing. In the present research, we investigated at what stage of memory the source of this impairment occurs. Participants were required to respond to words presented to them by saying out loud an associated word. This enforced encoding of the words, and was completed alone, as well as while climbing. Participants then recalled as many words as possible. A separate single-task condition had participants climb without making word associations. Word recall was reduced in the dual-task compared with the single word association task, but there was no difference in the number of word associations made. This indicates that the reduction in word recall was not a result of reduced encoding in the dual-task condition. Concurrent climbing may have reduced word recall by interfering with rehearsal and maintenance of words in memory.     

Costello syndrome and neurological abnormalities

Costello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies are brain atrophy, Chiari malformation and syringomyelia. Although there is insufficient data to propose strict guidelines, it seams reasonnable to have a low threshold for neuroimaging, in general, and particularly when neurologic signs or symptoms are present. Screening including cerebral MRI and EEG should be proposed after a diagnosis of Costello syndrome. The frequency of testing in such children should be guided by neurological follow-up.     

Psychiatric morbidity in patients with clinically isolated lesions of the type seen in multiple sclerosis: a clinical and MRI study

This study reports the psychiatric morbidity in 76 patients with clinically isolated lesions of the type seen in multiple sclerosis (optic neuritis, brain stem and cord lesions). The presence or absence of brain pathology was investigated using magnetic resonance imaging (MRI). A group of 33 patients suffering from rheumatic and neurological conditions not known to involve the brain was used for comparison. Normative MRI data were obtained from a group of 40 normal volunteers. Over half of the patients with the clinical presentation of single lesions had MRI abnormalities in the brain, but past and present psychiatric morbidity were similar in patients and controls and no significant associations were found between the presence of MRI abnormalities and psychiatric morbidity. The degree of social stress experienced by the patients with clinically isolated lesions appeared to be highly relevant in the causation of psychiatric symptoms.     

Multiparametric mapping of neurological soft signs in healthy adults

Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. Although previous studies have reported that NSS are associated with altered structure and function within fronto-parietal areas, it remains unclear whether the neuroanatomical basis of NSS may be confounded by underlying pathological processes, and by antipsychotic treatment. Morphological brain correlates of NSS in healthy subjects have seldom been investigated. This study evaluated the relationship between NSS levels and abnormalities of subcortical and cortical structures in healthy individuals. High-resolution MRI data at 3 Tesla were obtained from 68 healthy individuals. Automated segmentation of caudate nucleus, putamen, globus pallidus, thalamus, and brainstem was performed using both FSL-FIRST and Freesurfer. The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index). NSS were examined on the Heidelberg Scale and related to both subcortical and cortical measurements. Using two fully automated brain segmentations methods, we found no significant association between NSS levels and morphological changes in subcortical structures. Higher NSS scores were associated with morphological changes of cortical thickness, area and folding in multiple areas comprising superior frontal, middle temporal, insular and postcentral regions. Our findings demonstrate the benefit of surface-based approaches when investigating brain correlates of NSS. The data lend further support to the hypothesis that NSS in healthy individuals involve multiple cortical rather than subcortical brain regions.