bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia
Authors: Hart Ian K. , Waters Caroline , Vincent Angela , Newland Claire , Beeson David , Pongs Olaf , Morris Christine , Newsom‐Davis John
Published: January 2005

Antibody‐mediated autoimmunity underlies a diverse range of disorders, particularly in the nervous system where the extracellular domains of ion channels and receptors are especially vulnerable targets. We present here a novel means of detecting autoantibodies where the genes of the suspected target proteins are known, and use it to detect specific autoantibodies in acquired neuromyotonia (Isaacs' syndrome), a disorder characterized by hyperexcitable motor nerves and sometimes by central abnormalities. We expressed different human brain voltage‐gated potassium channels in Xenopus oocytes by injecting the relevant α‐subunit complementary RNA, and detected antibody binding by immunohistochemistry on frozen sections. Antibodies were detected to one or more human brain voltage‐gated potassium channel in 12 of 12 neuromyotonia patients and none of 18 control subjects. The results establish neuromyotonia as a new antibody‐mediated channelopathy and indicate the investigative potential of this molecular immunohistochemical assay.
Appropriate number of plasma exchanges in Guillain‐Barré syndrome
Authors:   The French Cooperative Group on Plasma Exchange in Guillain‐Barré Syndrome
Published: January 2005

Plasma exchange (PE) is the standard treatment in Guillain‐Barré syndrome (GBS) patients who have lost the ability to walk. The effect of exchanges before this stage and the optimal number of exchanges for the other patients are still unknown. We randomized 556 GBS patients according to severity and number of exchanges as follows: Zero versus 2 PEs for patients who could walk—with or without aid—but not run, or who could stand up unaided (mild group); 2 versus 4 PEs for patients who could not stand up unaided (moderate group); and 4 versus 6 PEs for mechanically ventilated patients (severe group). In the mild group, 2 PEs were more effective than none for time to onset of motor recovery (median, 4 vs 8 days, respectively). In the moderate group, 4 PEs were more beneficial than 2 for time to walk with assistance (median, 20 vs 24 days) and for 1‐year full muscle‐strength recovery rate (64% vs 46%). Six PEs were no more beneficial than 4 in the severe cases. Patients with mild GBS on admission should receive 2 PEs. Patients with moderate and severe forms should benefit from 2 further exchanges.
Soluble adhesion molecules (sVCAM‐1 and sICAM‐1) in cerebrospinal fluid and serum correlate with MRI activity in multiple sclerosis
Authors: Rieckmann Peter , Altenhofen Bernd , Riegel Antje , Baudewig Jürgen , Felgenhauer Klaus
Published: January 2005

We performed a prospective study to correlate quantitative brain magnetic resonance imaging activity (gadolinium‐diethylenetriaminepentaacetic acid enhancement) to cerebrospinal fluid and serum levels of soluble adhesion molecules in 46 patients with newly diagnosed multiple sclerosis (MS) and 30 control subjects with other diseases of the central nervous system. In all patients, magnetic resonance imaging of the brain and lumbar puncture were performed on the same day. In 32 (70%) of 46 MS patients, 8 (80%) of 10 patients with acute viral encephalitis, but none of the control subjects with noninflammatory diseases, gadolinium‐enhancing lesions were detected. There was a significant correlation between the cerebrospinal fluid/serum ratios for soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 as well as serum levels for both molecules and the area of gadolinium‐enhancing lesions. No obvious correlation was observed between magnetic resonance imaging findings and cerebrospinal fluid cell count, protein concentration, or intrathecal immunoglobulin production. In patients with a single periventricular gadolinium‐enhancing lesion (n = 16), we observed a strong negative correlation between the distance from the lateral ventricles and the cerebrospinal fluid/serum ratios for soluble intercellular adhesion molecule‐1/albumin and soluble vascular cell adhesion molecule‐1/albumin. These results suggest that intrathecal production of the two soluble adhesion molecules, as well as serum levels for soluble vascular cell adhesion molecule‐1, in patients with MS reflect magnetic resonance imaging activity of typical periventricular lesions.
Mononeuropathy multiplex in rhesus monkeys with chronic lyme disease
Authors: England John D. , Bohm Rudolf P. , Roberts E. Donald , Philipp Mario T.
Published: January 2005

Peripheral neuropathy is a recognized but poorly understood manifestation of Lyme disease. We performed serial electrophysiological studies on 8 rhesus monkeys chronically infected with the JD1 strain of Borrelia burgdorferi and compared the results with those of similar studies on 10 uninfected control monkeys. Four infected and 2 uninfected animals underwent sural nerve biopsy. Five of the infected and 1 of the uninfected animals also had postmortem neuropathological examinations. Altogether, 5 of the infected monkeys demonstrated primarily axonal‐loss‐variety multifocal neuropathies. Only one nerve lesion exhibited findings compatible with demyelination. Pathologically, peripheral nerve specimens showed multifocal axonal degeneration and regeneration and occasional perivascular inflammatory cellular infiltrates without vessel wall necrosis. Free spirochetal structures were not seen, but several macrophages exhibited positive immunostaining with a highly specific anti‐B. burgdorferi, 7.5‐kd lipoprotein monoclonal antibody. In the infected animals, serial analysis of serum antibodies to B. burgdorferi showed increasing numbers of IgG specificities and new IgM specificities, suggesting persistent infection. Thus, peripheral neuropathy in the form of a mononeuropathy multiplex develops frequently in rhesus monkeys chronically infected with B. burgdorferi. The pathogenesis of these nerve lesions is not yet known, but our studies suggest an immune‐mediated process perhaps driven by persistent infection with B. burgdorferi.
Correlation of clinical, magnetic resonance imaging, and cerebrospinal fluid findings in optic neuritis
Authors: Jacobs Lawrence D. , Kaba Samer E. , Miller Colleen M. , Priore Roger L. , Brownscheidle Carol M.
Published: January 2005

We found 42 of 74 patients (57%) with isolated monosymptomatic optic neuritis to have 1 to 20 brain lesions, by magnetic resonance imaging (MRI). All of the brain lesions were clinically silent and had characteristics consistent with multiple sclerosis (MS). None of the patients had ever experienced neurologic symptoms prior to the episode of optic neuritis. During 5.6 years of follow‐up, 21 patients (28%) developed definite MS on clinical grounds. Sixteen of the 21 converting patients (76%) had abnormal MRIs; the other 5 (24%) had MRIs that were normal initially (when they had optic neuritis only) and when repeated after they had developed clinical MS in 4 of the 5. Of the 53 patients who have not developed clinically definite MS, 26 (49%) have abnormal MRIs and 27 (51%) have normal MRIs. The finding of an abnormal MRI at the time of optic neuritis was significantly related to the subsequent development of MS on clinical grounds, but interpretation of the strength of that relationship must be tempered by the fact that some of the converting patients had normal MRIs and approximately half of the patients who did not develop clinical MS had abnormal MRIs. We found that abnormal IgG levels in the cerebrospinal fluid correlated more strongly than abnormal MRIs with the subsequent development of clinically definite MS.
Peripheral neuropathy in human immunodeficiency virus—infected patients with the diffuse infiltrative lymphocytosis syndrome
Authors: Moulignier Antoine , Authier François‐Jérôme , Baudrimont Marielle , Pialoux Gilles , Belec Laurent , Polivka Marc , Clair Bernard , Gray Françoise , Mikol Jacqueline , Gherardi Romain K.
Published: January 2005

A subset of human immunodeficiency virus (HIV)‐infected patients develop persistent CD8 hyperlymphocytosis and a Sjögren's syndrome‐like syndrome associated with multivisceral CD8 T‐cell infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV‐infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV‐infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA‐DR5 and 1 was HLA‐DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T‐cell lymphoma was observed during follow‐up, but 2 patients developed a primary B‐cell lymphoma. We conclude that DILS neuropathy represents HIV‐associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host‐determined and antigendriven response to HIV.
Machado‐Joseph disease gene product is a cytoplasmic protein widely expressed in brain
Authors: Paulson Henry L. , Das Sonal S. , Crino Peter B. , Perez Matthew K. , Patel Sonal C. , Gotsdiner Denise , Fischbeck Kenneth H. , Pittman Randall N.
Published: January 2005

Machado‐Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin‐3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin‐3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin‐3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin‐3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell‐specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin‐3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.
Various types of herediary inclusion body myopathies map to chromosome 9p1‐q1
Authors: Argov Zohar , Tirman Efrat , Eisenberg Iris , Sadeh Menahem , Siedman Christine E. , Siedman J. G. , Karpati George , Mitrani‐Rosenbaum Stella
Published: January 2005

Hereditary inclusion body myopathies are a clinically heterogeneous group of disorders characterized by adult‐onset, slowly progressive muscle weakness and typical histopathology: rimmed vacuoles and filamentous inclusions. The disorders are usually inherited as an autosomal recessive trait. The gene responsible for the disease found in Iranian Jews, who present wih quadriceps‐sparing myopathy, maps to chromosome 9p1‐q1. We address the question of whether hereditary inclusion myopathies are genetically as well as clinically heterogeneous disorders. We mapped the disease gene segregating in two families of Afghani‐Jewish and one family of Iraqi‐Jewish descent to the chromosome 9 locus. Similarly, the disease gene segregating in a non‐Jewish family from India mapped to the same locus. By contrast, the disease gene segregating in a French‐Canadian family in which affected individuals had central nervous system involvement as well as hereditary inclusion body myopathy, did not map to this locus. We conclude that many but not all forms of autosomal recessive hereditary inclusion body myopaty are caused by a gene defect that maps to chromosome 9p1‐q1.
Complex I function in familial and sporadic dystonia
Authors: Schapira A. H. V. , Warner T. , Gash M. T. , Cleeter M. W. J. , Marinho C. F. M. , Cooper J. M.
Published: January 2005

A significant proportion of patients with inborn errors of teh mitochondrial respiratory chain exhibit movement disordrs, particularly dystonia. Point mutations of mitochondrial DNA (mtDNA) are usually expressed systemically, adn defects of platelet respiratory chain function have been described in patients with mtDNA mutations and Leber's hereditary optic neuropathy (LHON). Recent resports have documented families with dystonia in association with LHON and mtDNA complex I gene mutations. We have examined mitochondrial function in platelet mitochondria from patients with familial generalized dystonia (linked or not linked to 9q34) and sporadic focal dystonia. We confirm a previous report of a specific complex I defect in patients with sporadic focal dystonia but could not find any abnormality in patients with familial generalized dystonia, linked or not to 9q34. These results support the existence of a mitochondrial deficiency in sporadic focal dystonia and provide a biochemical dimension to the clinical and genetic distinction between focal and generalized familial dystonia.
Cortical reorganization in patients with facial palsy
Authors: Rijntjes Michel , Tegenthoff Martin , Liepert Joachim , Leonhardt Georg , Kotterba Sylvia , Müller Stephan , Kiebel Stephan , Malin Jean‐Pierre , Diener Hans‐Christoph , Weiller Cornelius
Published: January 2005

Possible changes in the organization of the cortex in patients with facial palsy, serving as a model of peripheral motor deefferentation, were investigated by using transcranial magnetic stimulation (TMS) and positron emission tomography (PET). With TMS, the size of the area producing muscle‐evoked potentials (MEPs) of the abductor pollicis brevis muscle, the sum of MEP amplitudes within this area, and the volume over the mapping area were compared between both hemispheres in 8 patients. With PET, increases in regional cerebral blood flow, measured with the standard H215O2bolus injection technique, were compared between 6 patients and 6 healthy volunteers during sequential finger opposition. Patients moved the hand ipsilateral to the facial palsy, the control subjects the right hand. Of 9 patients in total, 5 participated in both experiments. With both methods, an enlargement of the hand field contralateral to the facial palsy was found, extending in a lateral direction, into the site of the presumed face area. The PET data showed that the enlargemement of the hand field in the somatosensory cortex (SMC) is part of a widespread cortical reorganization, including the ipsilateral SMC and bilateral secondary motor and sensory areas. We report for the first time, using two different noninvasive methods, that peripheral, mere motor deefferentation is a sufficient stimulus for reorganizational changes in the healthy adult human cortex.
Cerebral generators involved in the pathogenesis of the restless legs syndrome
Authors: Bucher Stefan F. , Seelos Klaus C. , Oertel Wolfgang H. , Reiser Maximilian , Trenkwalder Claudia
Published: January 2005

The pathophysiology of periodic limb movements and sensory leg discomfort in the restless legs syndrome is unknown. With high‐resolution functional magnetic resonance imaging, we localized for the first time cerebral generators associated with sensory leg discomfort and periodic limb movements in 19 patients with restless legs syndrome. During sensory leg discomfort there was mainly bilateral activation of the cerebellum and contralateral activation of the thalamus. During the combined periodic limb movement and sensory leg discomfort conditions, patients also showed activity in the cerebellum and thalamus. In contrast to the sensory leg discomfort condition alone, the combined condition was associated with additional activation in the red nuclei and brainstem close to the reticular formation. Voluntary imitation of periodic limb movements by patients and control subjects was not associated with brainstem activity, but with additional activation in the globus pallidus and motor cortex. These findings indicate that cerebellar and thalamic activation may occur because of sensory leg discomfort and that the red nucleus and brainstem are involved in the generation of periodic limb movements in patients with restless legs syndrome.
Increases in soluble VCAM‐1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon β‐1b
Authors: Calabresi Peter A. , Tranquill Laura R. , Dambrosia James M. , Stone Lael A. , Maloni Heidi , Bash Craig N. , Frank Joseph A. , McFarland Henry F.
Published: January 2005

Interferon β‐1b reduces clinical exacerbations and disease activity in multiple sclerosis as shown by magnetic resonance imaging, but the mechanism of action is unknown. We investigated the correlation between the levels of soluble adhesion molecules and a reduction in contrast‐enhancing lesions on gadopentetate dimeglumine magnetic resonance images after treatment with interferon β‐1b. We determined levels of soluble vascular cell adhesion molecule‐1, intercellular adhesion molecule‐1, E‐selectin, L‐selectin, and tumor necrosis factor receptor (60 kd) in monthly serum samples from patients with definite multiple sclerosis before and during treatment with interferon β‐1b. The level of soluble adhesion molecules was correlated with the number of newly enhancing lesions on monthly contrast‐enhanced images. Levels of soluble vascular cell adhesion molecule during treatment were significantly increased compared to control or pretreatment values. The median levels (ng/ml) of this adhesion molecule were 580.3 (range; 373.0–640.7) for the healthy subjects, and 551.4 (489.7–875.5) for patients prior to treatment and 847.9 (591.5–1,232.9) during treatment. Levels of the other soluble adhesion molecules and soluble tumor necrosis factor receptor were not significantly changed during treatment. The increase in soluble vascular cell adhesion molecule correlated with a decrease in the number of contrast‐enhancing lesions on magnetic resonance images. These data suggest a novel mechanism of action for interferon β‐1b by direct interference with the adhesion cascade, which may prevent activated T cells from trafficking into the central nervous system.
Dutch hereditary cerebral amyloid angiopathy: Structural lesions and apolipoprotein E genotype
Authors: Bornebroek M. , Haan J. , Van Duinen S. G. , Maat‐Schieman M. L. C. , Van Buchem M. A. , Bakker E. , Van Broeckhoven C. , Roos R. A. C.
Published: January 2005

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type is caused by a mutation at codon 693 of the β amyloid precursor protein gene. The disease is clinically characterized by strokes and dementia. In addition to cerebral plaques, cerebral amyloid angiopathy is the pathological hallmark. We investigated the correlation between radiological (white matter hyperintensities and focal lesions on magnetic resonance images) and pathological lesions (cerebrovascular amyloid angiopathy and plaques) and the apolipoprotein E genotype in patients with the disease. Twenty‐five patients were studied using magnetic resonance imaging, and brain tissue from 8 patients was studied histopathologically. Neither the white matter hyperintensity scores nor the number of focal lesions on magnetic resonance images were associated with the presence of an ϵ4 allele. Nor was a correlation found between the number and type of plaques and the apolipoprotein E genotype. All patients had severe amyloid angiopathy in all cortical areas investigated. This study showed that the apolipoprotein E genotype does not modulate amyloidrelated structural lesions in hereditary cerebral hemorrhage with amyloidosis of the Dutch type.
Painful proximal diabetic neuropathy: Inflammatory nerve lesions and spontaneous favorable outcome
Authors: Said Gérard , Elgrably Fabienne , Lacroix Catherine , Planté Violaine , Talamon Céline , Adams David , Tager Michel , Slama Gérard
Published: January 2005

Proximal diabetic neuropathy is a disabling neuropathy that occurs predominantly in non‐insulin‐dependent diabetic patients over the age of 50. Inflammatory lesions have been found in nerve biopsy specimens of diabetic patients with severe proximal neuropathy or with other patterns of multifocal neuropathy. Some of these patients respond dramatically to treatment with corticosteroids or with other immunomodulators. In this article we report on our findings in 4 additional patients with painful proximal diabetic neuropathy and different patterns of inflammatory nerve lesions whose condition improved spontaneously shortly after performance of a nerve biopsy, without additional treatment.
A mismatch between kinesthetic and visual perception in Parkinson's disease
Authors: Demirci Mehmet , Grill Stephen , McShane Lisa , Hallett Mark
Published: January 2005

Kinesthesia may be defective in patients with Parkinson's disease (PD), and this defect conceivably has a role in parkinsonian hypokinetic symptoms. In the present study, PD patients used kinesthetic perception to estimate the amplitude of passive angular displacements of the index finger about the metacarpophalangeal joint and to scale them as a percentage of a reference stimulus. The reference stimulus was either a standard kinesthetic stimulus preceding each test stimulus (task K) or a visual representation of the standard kinesthetic stimulus (task V). In task V, the PD patients' underestimation of the amplitudes of finger perturbations was significantly greater than that of normal subjects, but not for task K. PD patients' underestimation was also greater in task V than in task K; the difference between the underestimations was significantly greater than for normal subjects. These results suggest that, when kinesthesia is used to match a visual target, distances are perceived to be shorter by the PD patients. Assuming that visual perception is normal, kinesthesia is “reduced” in PD patients. This reduced kinesthesia, when combined with the well‐known reduced motor output and probably reduced corollary discharges, implies that the sensorimotor apparatus is “set” smaller in PD patients than in normal subjects.
The clinical syndrome of early‐life bilateral hippocampal sclerosis
Authors: Delong G. Robert , Heinz E. Ralph
Published: January 2005

Four infants had bilateral hippocampal sclerosis by magnetic resonance scans, including oblique coronal fast spin echo images of the temporal lobes; [18F]fluorodeoxyglucose–positron emission tomographic scans, done in 2 infants, showed isolated bilateral anterior temporal lobe hypometabolism. All had epilepsy with episodes of status epilepticus. Despite adequate motor and sensory functions, all failed to develop language (or lost attained language), social skills, and complex purposive or adaptive activity, even after epilepsy was controlled. Bilateral hippocampal dysfunction in early life appears to be associated with a profound failure of cognitive capacities, including language learning and learning of complex social and adaptive skills in general. The deficits correspond to the cognitive deficits of severe infantile autism. Hippocampal function, or more generally medial temporal lobe function, appears necessary for language learning in the infant, as well as for complex social and adaptive learning.
Cytokine profile of myelin basic protein—reactive T cells in multiple sclerosis and healthy individuals
Authors: Hermans Guy , Stinissen Piet , Hauben Lysiane , van den Berg‐Loonen Ella , Raus Jef , Zhang Jingwu
Published: January 2005

Myelin basic protein (MBP)‐reactive T cells have been implicated in the autoimmune pathogenesis of multiple sclerosis (MS). In this study, we examined the cytokine profile of 531 primary MBP‐reactive T‐cell lines and 72 independently established clones from 32 patients with MS and 18 healthy controls (NS) by using highly sensitive enzyme‐linked immunosorbent assays. An increased number of primary T‐cell lines producing interferon‐γ (IFNγ) and/or interleukin‐4 (IL‐4) in response to MBP were found in patients with MS compared with controls. No distinct Th1 or Th2 subtypes could be demonstrated among the MBP‐reactive clones. IL‐4 was more frequently observed among MS‐derived clones. Clones derived from MS patients produced increased levels of IL2, IL4, tumor necrosis factor‐α (TNFα), IFNγ, and IL‐10, but not IL‐6. It is interesting that MBP‐reactive T cells from MS patients expressing the disease‐associated HLA‐DRBI 15 allele produced increased quantities of TNFα, a cytokine suggested to play an important role in inflammation and demyelination. When challenged with either MBP or a bacterial superantigen, the clones expressed similar levels of the proinflammatory cytokine IFNγ. Our study suggests a functional difference in T‐cell responses to MBP in patients with MS compared with healthy individuals, and provides further insights into the role of MBP‐reactive T cells and their cytokine profile in the inflammatory processes of MS.
Polymerase chain reaction—based detection of Tropheryma whippelii in central nervous system Whipple's disease
Authors: Lynch T. , Odel J. , Fredericks D. N. , Louis E. D. , Forman S. , Rotterdam H. , Fahn S. , Relman D. A.
Published: January 2005

Whipple's disease of the central nervous system (CNS) may be associated with normal intestinal histology as a result of minimal or patchy involvement. The diagnosis is difficult and is frequently made post mortem. We studied 6 patients with clinically suspected CNS Whipple's disease; 2 had oculomasticatory myorhythmia (OMM) fitting criteria for a diagnosis of definite CNS Whipple's disease. One of the 2 had duodenal histology highly suggestive of Whipple's disease; the other 5 patients had normal duodenal histology. DNA was extracted from paraffin‐embedded duodenal tissues in all patients and frozen pontine tissue in 1. Two primer pairs (WF‐WR, W3F‐W2R) were used in separate polymerase chain reactions (PCRs) to amplify fragments of Tropheryma whippelii 16S rDNA from these tissue samples. PCR amplicons were detected only in the duodenal tissues from the 2 patients with OMM. The sequences of these amplicons were identical to the corresponding region of the previously published Tropheryma whippelii 16S rDNA sequence. PCR‐based assays of intestinal or brain tissue may be of value for confirming, and possibly refuting, a clinical diagnosis of CNS Whipple's disease in a patient with any combination of dementia, supranuclear gaze palsy, hypothalamic manifestations, myoclonus, seizures, ataxia, or OMM, especially when tissue histology is unrevealing.
Effect of Lambert‐Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse
Authors: Waterman Sally A. , Lang Bethan , Newsom‐Davis John
Published: January 2005

Somatic muscle weakness and autonomic symptoms characterize the autoimmune Lambert‐Eaton myasthenic syndrome (LEMS). The former results from IgG autoantibody–mediated down‐regulation of P/Q‐type voltage‐gated calcium channels at motor nerve terminals and consequent reduction in acetylcholine release; the basis for the autonomic symptoms is unknown. Using ω‐conotoxins GVIA and MVIIC and ω‐agatoxin IVA that block N‐, Q‐, and P‐type channels, we investigated ex vivo the calcium channels subserving transmitter release from postganglionic parasympathetic neurons in the bladder and from postganglionic sympathetic neurons in the vas deferens of mice injected with IgG from LEMS patients or from controls. Calcium influx through N‐, P‐, and Q‐type channels subserved transmitter release from parasympathetic and sympathetic neurons in control mice. In test mice, the component of transmitter release subserved by P‐type channels was abolished by four of four LEMS IgG preparations, that subserved by Q‐type channels was significantly reduced by three, and that subserved by N‐type channels by one. Thus, LEMS IgG impairs transmitter release from parasympathetic and sympathetic neurons through down‐regulation of one or more subtypes of voltage‐gated calcium channels. The results suggest that antibody‐mediated interference with specific ion channel function may also underlie autonomic dysfunction occurring in other autoimmune diseases.
Hippocampal N‐acetylaspartate in neocortical epilepsy and mesial temporal lobe epilepsy
Authors: Vermathen Peter , Ende Gabriele , Laxer Kenneth D. , Knowlton Robert C. , Matson Gerald B. , Weiner Michael W.
Published: January 2005

Previous magnetic resonance spectroscopy (MRS) studies have shown that N−acetylaspartate (NAA) is reduced not only in the ipsilateral but also in the contralateral hippocampus of many patients with mesial temporal lobe epilepsy (mTLE). The reason for the contralateral damage is not clear. To test whether the hippocampus is also damaged if the focus is outside the hippocampus, we have measured patients with neocortical epilepsy (NE). Therefore, the goals of this study were to determine if hippocampal NAA is reduced in NE and if hippocampal NAA discriminates NE from mTLE. MRS imaging (MRSI) studies were performed on 10 NE patients and compared with MRSI results in 23 unilateral mTLE patients and 16 controls. The results show that, in contrast to mTLE, NAA was not reduced in the hippocampus of NE patients, neither ipsilateral nor contralateral to the seizure focus. These results suggest that repeated seizures do not cause secondary damage to the hippocampus. The absence of spectroscopic differences in NE may help to distinguish NE from mTLE.
Glial cell line–derived neurotrophic factor–levodopa interactions and reduction of side effects in parkinsonian monkeys
Authors: Miyoshi Yasuyuki , Zhang Zhiming , Ovadia Aliza , Lapchak Paul A. , Collins Frank , Hilt Dana , Lebel Carl , Kryscio Richard , Gash Don M.
Published: January 2005

Glial cell line–derived neurotrophic factor (GDNF) stimulates the nigrostriatal dopaminergic pathway and improves motor functions in animal models of parkinsonism. Sinemet is currently the most widely used drug for treating Parkinson's disease. The present study has evaluated GDNF–Sinement interactions in parkinsonian rhesus monkeys. Both GDNF and Sinemet, when given alone, significantly improved total parkinsonian scores. The response to Sinement did not change after intracerebroventricular vehicle injections. In contrast, there was a functional interaction between GDNF and levodopa. When comparing the levodopa dose response before and after GDNF treatment, significant behavioral improvements were seen after trophic factor administration at every levodopa dose level except 500 mg. Adverse responses to Sinemet treatment alone in parkinsonian animals included vomiting, dykinesias, dystonias, and stereotypic movements. Combined GDNF–Sinemet treatment significantly reduced the occurrence of these levodopa‐induced side effects, with a >90% decrease in adverse responses seen at the mid‐Sinemet (250 mg levodopa–25 mg carbidopa) dose level. The only side effect from GDNF treatment was a transitory weight loss. Thus, combined GDNF–Sinemet treatment could be of therapeutic value in treating parkinsonism, by producing a greater functional response and by mitigating adverse responses to Sinemet treatment.
Central levodopa metabolism in Parkinson's disease after administration of stable isotope—labeled levodopa
Authors: Durso Raymon , Evans James E. , Josephs Ephraim , Szabo George K. , Evans Barbara A. , Handler Joseph S. , Jennings Dana , Browne Thomas R.
Published: January 2005

We report the use of a new stable isotope–labeled form of levodopa (LD) to examine in vivo central LD metabolism in Parkinson's disease (PD). Eight patients representing a wide spectrum of disease severity were administered 50 mg of carbidopa orally followed in 1 hour by an intravenous bolus of 150 mg of stable isotope–labeled LD (ring‐1′,2′,3′,4′,5′,6′‐13C6). Serial blood samples were taken every 30 to 60 minutes and a lumbar puncture was performed 6 hours after the infusion. The average percentage of labeled homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) was 54% (SD, 9%; range, 34–67%). The mean CSF labeled HVA concentration was 34.7 ng/ml (SD, 20.2 ng/ml; range, 11.3–67.9 ng/ml). Area under the curve for labeled serum LD closely predicted CSF labeled HVA concentrations (r = 0.747, p = 0.033). Labeled CSF HVA levels did not significantly correlate with either quality or duration of response to the labeled LD dose. In a similar manner, labeled CSF HVA concentrations were not influenced by duration of disease or previous daily LD dosage. These findings support the hypothesis that levodopa‐induced benefit in PD is not severely limited by a defect in central levodopa metabolism.
Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region
Authors: Korinthenberg R. , Sauer M. , Ketelsen U.‐P. , Hanemann C. O. , Stoll G. , Graf M. , Baborie A. , Volk B. , Wirth B. , Rudnik‐Schöneborn S. , Zerres K.
Published: January 2005

Three newborn siblings presented with generalized weakness, asphyxia, facial diplegia, and external ophthalmoplegia. Electrophysiological testing showed inexcitability of motor and sensory nerves and myographic signs of denervation. Nerve biopsies and postmortem examination showed loss of myelinated fibers and axonal damage in sensory and mixed nerves. Many spinal motor neurons were chromatolytic although their number was normal. Molecular genetic investigations revealed a homozygous deletion of the survival motor neuron (SMN) gene and a loss of markers Ag1‐CA and C212 in the paternal haplotype. These findings are consistent with the diagnosis of an unusually severe type of spinal muscular atrophy. Given the large extent of the deletion, it must be considered that the unusual severe phenotype with involvement of brainstem nuclei and afferent nerves might also be due to changes of yet unknown genes neighboring the SMN gene.
Factor V Leiden mutation: An unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis
Authors: Thorarensen Olafur , Ryan Stephen , Hunter Jill , Younkin Donald P.
Published: January 2005

Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.
Recommendations from the national multiple sclerosis society clinical outcomes assessment task force
Authors: Rudick Richard , Antel Jack , Confavreux Christian , Cutter Gary , Ellison George , Fischer Jill , Lublin Fred , Miller Aaron , Petkau John , Rao Stephen , Reingold Stephen , Syndulko Karl , Thompson Alan , Wallenberg Joy , Weinshenker Brian , Willoughby Ernest
Published: January 2005

This article provides recommendations from the National Multiple Sclerosis Society's Clinical Outcomes Assessment Task Force. The Task Force was appointed in 1994 and charged with recommendending improved approaches for clinical outcomes assessment in future controlled clinical trials. The recommendations herein follow extensive deliberation and data analysis during 2.5 years. General principles and desirable measurement attributes were used to assess alternative measurement techniques and clinical scales. On the basis of the analysis of existing multiple sclerosis (MS) data sets, a new measurement approach is proposed. The approach is based on quantitative functional composites that consist of simple quantitative measures from the major clinical dimensions of MS combined into a single score. Quantitative functional composites are likely to provide improved precision and sensitivity in future MS clinical trials. Studies necessary to further refine quantitative functional composites as useful MS clinical trial outcomes are delineated.
Dietary fat intake and the risk of incident dementia in the Rotterdam study
Authors: Kalmijn Sandra , Launer Lenore J. , Ott Alewijn , Witteman Jacqueline C. M. , Hofman Albert , Breteler Monique M. B.
Published: January 2005

A high intake of saturated fat and cholesterol and a low intake of polyunsaturated fatty acids have been related to an increased risk of cardiovascular disease. Cardiovascular disease has been associated with dementia. We investigated the association between fat intake and incident dementia among participants, age 55 years or older, from the population‐based prospective Rotterdam Study. Food intake of 5,386 nondemented participants was assessed at baseline with a semiquantitative food‐frequency questionnaire. At baseline and after an average of 2.1 years of follow‐up, we screened for dementia with a three‐step protocol that included a clinical examination. The risk of dementia at follow‐up (RR [95% CI]) was assessed with logistic regression. After adjustment for age, sex, education, and energy intake, high intakes of the following nutrients were associated with an increased risk of dementia: total fat (RR = 2.4 [1.1–5.2]), saturated fat (RR = 1.9 [0.9–4.0]), and cholesterol (RR = 1.7 [0.9–3.2]). Dementia with a vascular component was most strongly related to total fat and saturated fat. Fish consumption, an important source of n‐3 polyunsaturated fatty acids, was inversely related to incident dementia (RR = 0.4 [0.2–0.9]), and in particular to Alzheimer's disease (RR = 0.3 [0.1–0.9]). This study suggests that a high saturated fat and cholesterol intake increases the risk of dementia, whereas fish consumption may decrease this risk.
Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21–22
Authors: Baker Matt , Kwok John B. J. , Kucera Steve , Crook Richard , Farrer Matthew , Houlden Henry , Isaacs Adrian , Lincoln Sarah , Onstead Luisa , Hardy John , Wittenberg Leonie , Dodd Peter , Webb Sonja , Hayward Nick , Tannenberg Tony , Andreadis Athena , Hallupp Marianne , Schofield Peter , Dark Frances , Hutton Michael
Published: January 2005

An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty‐eigth affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 · 8.9 years). We mapped the disease locus to an approximately 26‐cM region of chromosome 17q21–22 with a maximum two‐point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP‐17 candidate region, were also sequenced. This analysis included the microtubule‐associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
Aging and the brain: A new frontier
Authors: Drachman David A.
Published: January 2005

With aging, both “normal” senescent age‐related changes (ARCs) and late‐onset diseases affect the brain, producing declines in performance. The brain as a postmitotic structure is particularly vulnerable to ARCs, and senescence is by far the most powerful risk factor for neurological diseases of the elderly such as sporadic Alzheimer's disease. The concept of senescence as an immutable result of the passage of time is yielding to understanding of the biology of ARCs. Both individual and species differences in longevity illustrate the variable effects of time. Whereas human life expectancy has been extended by prevention and treatment of specific diseases, life span can be altered by modifying the processes producing ARCs. Models of prolonged life span (eg, modifications of Caenorhabditis elegans longevity genes, restricted caloric intake)demonstrate the feasibility of extending longevity throughout the phylogenetic spctrum. Both programmed and variable factors produce ARCs. Cell survival depends on a balance of opposing factors–oncogene and anti‐oncogene products, cyclins, growth factors, and so on; apoptotic death results when the balance shifts. Variable factors, including accumulation of oxygen free radicals, protein conformational changes, decline in chaperone functions, and secondary loss of mitochondrial energy production, can also result in neuronal degeneration. To prevent the increased neuronal vulnerability of senescence, ARCs must be modified. The “new frontier” in neurology is the challenge of understanding the changes of aging, both to determine their impact on disease and to prevent their consequences.
Spinocerebellar ataxia type 6: CAG repeat expansion in α1a voltage‐dependent calcium channel gene and clinical variations in japanese population
Authors: Ikeuchi Takeshi , Takano Hiroki , Koide Reiji , Igarashi Shuichi , Tanaka Hajime , Tsuji Shoji , Takahashi Hitoshi , Horikawa Yoh , Honma Yoshiaki , Onishi Yoji , Nakao Naoki , Sahashi Ko , Tsukagoshi Hiroshi , Inoue Kiyoharu
Published: January 2005

Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat expansion in the α1A voltage‐dependent calcium channel gene has been found to be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98 Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of the SCA1, SCA2, Machado‐Joseph disease/SCA3, and dentatorubral‐pallidoluysian atrophy genes were excluded, and 5 apparently sporadic cases of cortical cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%) comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG repeats ranged from 21 to 26 repeat units and was found to be correlated inversely with age at onset. We identified 2 SCA6 patients homozygous for expanded CAG repeats, whose ages at onset were earlier than the 95% lower confidence level, suggesting the presence of a gene dosage effect of expanded CAG repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients. Patients with a prolonged disease course showed other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes.
Increased serum levels of soluble CD95 (APO‐1/Fas) in relapsing‐remitting multiple sclerosis
Authors: Zipp Frauke , Weller Michael , Calabresi Peter A. , Frank Joseph A. , Bash Craig N. , Dichgans Johannes , McFarland Henry F. , Martin Roland
Published: January 2005

CD95/CD95 ligand interactions are critically involved in the negative regulation of peripheral T‐cell responses. Here, we report that serum levels of soluble CD95 are significantly elevated in patients with relapsing remitting multiple sclerosis. In a transectional study, CD95 levels did not correlate with clinical disability or lesion formation on magnetic resonance imaging. Longitudinally, Expanded Disability Status Scale changes were associated with high CD95 levels. Interferon‐β (IFNβ) treatment led to an initial increase and subsequent decline of serum CD95 levels. Interestingly, patients generating neutralizing antibodies to the drug had significantly higher baseline CD95 levels before IFNβ treatment than those without neutralizing antibodies.
Upregulation of Fas/Fas ligand in inclusion body myositis
Authors: Fyhr Ing‐Marie , Oldfors Anders
Published: January 2005

In inclusion body myositis, T cells invade and destroy nonnecrotic muscle fibers. The mechanism by which T cells damage muscle fibers in inflammatory myopathies is not known. In this study we have investigated the expression of Fas and Fas ligand in muscle in five patients with inclusion body myositis. Reverse transcription polymerase chain reaction showed upregulation of both Fas and Fas ligand in all inclusion body myositis patients. Immunohistochemical investigation showed expression of Fas ligand in many of the muscle infiltrating mononuclear cells. Fas was expressed both in mononuclear cells and on the surface of muscle fibers in inclusion body myositis patients and in patients with polymyositis but not in patients with Duchenne muscular dystrophy or denervation. The results indicate that the Fas/Fas ligand system may be of importance for the inflammatory reaction and T‐cell–mediated muscle cell injury.
Gene transfer to schwann cells after peripheral nerve injury: A delivery system for therapeutic agents
Authors: Sørensen Jesper , Haase Georg , Krarup Christian , Gilgenkrantz Helene , Kahn Axel , Schmalbruch Henning
Published: January 2005

We transferred a reporter gene to Schwann cells to test whether they might serve as an endoneurial delivery system for therapeutic proteins. A replication‐defective adenoviral vector carrying the gene for β‐galactosidase (lacZ) was injected into the distal segment of intact or crushed sciatic nerves of adult rats, and the expression of lacZ was histochemically assessed. Less than 1% of the Schwann cells became reactive in intact nerves, but up to 18% of the proliferating Schwann cells of injured nerves expressed lacZ. Gene expression decayed with time but might persist for up to 2 months. It was enhanced by immunosuppression: daily cyclosporin A injections reduced both proliferation of Schwann cells and lymphocytic infiltration of the nerve, whereas tolerance induced by a single intrathymic injection of the vector 4 days after birth abolished the inflammatory response but not the proliferation of Schwann cells. The vector itself did not impede axonal regeneration. The results indicate that adenoviral gene transfer to Schwann cells in injured nerves is possible and suggest that induced production of neurotrophic factor may represent a therapeutic supplement to surgical nerve repair.