bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical management of superficial siderosis following cervical nerve root avulsion
Authors: Tapscott Stephen J. , Eskridge Joseph , Kliot Michel
Published: January 2005

Neurosensory hearing loss, ataxia, spastic paraparesis, sphincter dysfunction, somatosensory disturbances, and cognitive effects are associated with superficial siderosis of the central nervous system caused by chronic intrathecal bleeding. We describe superficial siderosis that developed more than a decade following traumatic brachial nerve root avulsion. While cerebrospinal fluid analysis indicated chronic intrathecal bleeding, angiography did not localize a specific source. Surgical intervention that included repair of a meningeal diverticulum and venous cauterization resulted in overall reduction, but not complete elimination, of central nervous system bleeding.
Amyloid (Aβ) deposition in chromosome 1–linked Alzheimer's disease: The volga german families
Authors: Mann D. M. A. , Iwatsubo T. , Nochlin D. , Sumi S. M. , Levy‐Lahad E. , Bird T. D.
Published: January 2005

Amyloid β protein (Aβ) deposition was investigated in the frontal cortex of 6 cases of (genetically confirmed) chromosome 1–linked Alzheimer's disease (AD) (PS‐2 gene mutation) among the Volga German families using the end‐specific monoclonal antibodies BA27 and BC05 to detect the presence of Aβ40 and Aβ42(43), respectively. In all patients, Aβ42(43) was the predominant peptide species present, although the total amount of Aβ40 and Aβ42(43) deposited in plaques did not differ from that seen in sporadic AD and was significantly lower than that occurring in AD due to PS‐1 gene mutations. Therefore, mutations in the PS‐2 gene, like those in the presenilin‐1 (PS‐1) and amyloid precursor protein (APP) genes, are associated with an initial and preferential deposition of Aβ42(43) within the brain. Although the mechanisms(s) whereby the PS‐1 and PS‐2 gene mutations operate remains unclear, it seems from the present study that the effect of the PS‐2 gene mutation on the brain is muuch less severe, at least as far as Aβ deposition is concerned, than that of the PS‐1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.
Proton magnetic resonance spectroscopic imaging for discrimination of absence and complex partial seizures
Authors: Cendes Fernando , Stanley Jeff A. , Dubeau FrançOis , Andermann Frederick , Arnold Douglas L.
Published: January 2005

We performed proton magnetic resonance spectroscopic imaging of the temporal lobes between, during, and soon after nonconvulsive seizures in 20 patients with documented temporal lobe epilepsy, 5 patients with primary generalized epilepsy, and 2 patients with secondary generalized epilepsy. Our objective was to determine whether there were metabolic changes observable by magnetic resonance spectroscopic imaging during seizures and whether these changes were specific for focal or generalized nonconvulsive seizures. We found a significant increase in lactate to creatine plus phosphocreatine (lactate/creatine) values, reflecting an imbalance in energy supply and demand or an adaptation in response to ictal neuronal discharges, during and soon after complex partial seizures, but not during or soon after absence seizures associated with generalized epilepsy. In patients with temporal lobe epilepsy, the N‐acetylaspartate resonance relative to creatine plus phosphocreatine was low in one or both temporal lobes, indicating neuronal loss or damage. This was not observed in patients with primary generalized epilepsy. The regions with abnormal lactate/creatine and N‐acetylaspartate/creatine values corresponded to the epileptogenic focus as defined by clinical‐electroencephalographic investigation. There was no change in the N‐acetylaspartate/creatine values in the temporal lobes between the interictal, ictal, or postictal states. We conclude that (1) partial seizures are associated with abnormally high lactate levels, but absence seizures are not, and (2) no short‐term changes of N‐acetylaspartate occur during or soon after complex partial seizures or absence seizures. These findings may be related to the lack of postictal confusion in patients with absence seizures, as well as with the more benign course of primary generalized epilepsy with nonconvulsive attacks.
Stereotactic thalamotomy in tremor‐dominant Parkinson's disease: An H215O PET motor activation study
Authors: Boecker Henning , Wills Adrian J. , Ceballos‐Baumann Andres , Samuel Michael , Thomas David G. T. , Marsden C. David , Brooks David J.
Published: January 2005

Stereotactic thalamotomy is an effective treatment for severe drug‐resistant tremor. The thalamus, however, facilitates motor activiry, and thalamotomy would be predicted to inhibit movement‐associated cortical activation. Two tremulous parkinsonian patients were studied with H2 15O position emission tomography before and after left ventalis intermedius thalamotomy. Subjects were scanned at rest and during performance of externally paced joystick movements in freely selected direstions with the right hand. Thalamotomy relieved tremor but, as perdicted, led to dercreased activation of the left sensorimotor cortex, lateral premotor cortex, and parietal area 7 on hand movement.
1H‐magnetic resonance spectroscopy—determined cerebral lactate and poor neurological outcomes in children with central nervous system disease
Authors: Ashwal Stephen , Holshouser Barbara A. , Tomasi Lawrence G. , Shu Stanford , Perkin Ronald M. , Nystrom Gerald A. , Hinshaw David B.
Published: January 2005

By using proton magnetic resonance spectroscopy (1H‐MRS), cerebral lactate has been shown to be elevated in a wide variety of pediatric and adult neurological diseases. In this study we compared 36 newborns, infants, and children with elevated lactate peaks on 1H‐MRS with 61 patients witout an identifiable lactate signal. 1H‐MRS was acquired from the occipital gray and parietal white matter (8 cm3 volume, STEAM sequence with echo time = 20 msec, repetition time = 3.0 seconds) and data were expressed as ratios of different metabolite peak areas (N‐acetylaspartate [NA]/creatine [Cr], NA/choline [Ch], and Ch/Cr) and the presence of a characteristic lactate doublet peak at 1.3 ppm. Outcomes (Pediatric Cerebral Performance Category Scale score; PCPCS) were assigned 6 to 12 months after injury. Patients with lactate peaks were more likely to have suffered a cardiac arrest, were more often hyperglycemic, and had lower Glasgow Coma Scale scores on admission. They were also more likely to have abnormal metabolite ratios when compared with agematched controls or with patients without detectable lactate. Of prognostic importance, patients with increased lactate were more likely to be severely disabled (39% vs 10%), survive in a persistent vegetative state (13% vs 2%), or have died (39% vs 7%). In contrast, patients with similar conditions without increased lactate were more likely to have had a good outcome (23% vs 3%) or recovered to a mild (38% vs 6%) or moderate disability (20% vs 0%). Our data suggest that 1H‐MRS is useful in the prediction of long‐term outcomes in children with neurological disorders. Patients with elevated cerebral lactate are more likely to die acutely or are at greater risk for serious long‐term disability.
Atrophy of the corpus callosum, cognitive impairment, and cortical hypometabolism in progressive supranuclear palsy
Authors: Yamauchi Hiroshi , Fukuyama Hidenao , Nagahama Yasuhiro , Katsumi Yukinori , Dong Yun , Konishi Junji , Kimura Jun
Published: January 2005

Recent studies disclosed neurofibrillary degeneration in layer 3 of the association cortex in patients with progressive supranuclear palsy. This lesion may be associated with corpus callosum atrophy and may impair the function of cortical regions indispensable for complex cognitive activity. To investigate whether corpus callosum atrophy is associated with cognitive impairment and cerebral cortical hypometabolism, we studied 10 patients with progressive supranuclear palsy using magnetic resonance imaging and positron emission tomography with fluorodeoxyglucose as a tracer. Compared with 23 age‐matched control subjects, the patients had significantly decreased callosal area‐skull area ratios, with anterior predominance of the degree of atrophy. The corpus callosum atrophy was accompanied by a decreased mean cortical glucose metabolic rate, predominantly in the frontal region of the cortex, and poor performance on the picture arrangement subtest of the Wechsler Adult Intelligence Scale and the verbal fluency task. We conclude that corpus callosum atrophy with anterior predominance is present in progressive supranuclear palsy, and that this atrophy is associated with cognitive impairment and cerebral cortical hypometabolism, especially in the frontal cortical region. Corpus callosum atrophy may reflect the pathological changes in the cerebral cortex, accentuated in the frontal region, that contribute to the development of frontal lobe dysfunction in this disease.
Leukodystrophy in patients with ovarian dysgenesis
Authors: Schiffmann Raphael , Tedeschi Gioacchino , Kinkel R. Philip , Trapp Bruce D. , Frank Joseph A. , Kaneski Christine R. , Brady Roscoe O. , Barton Norman W. , Nelson Lawrence , Yanovski Jack A.
Published: January 2005

We describe clinical, biochemical, pathological, and spectroscopic findings in 4 women, aged 15 to 29 years, from three unrelated families who had a unique combination of a central neurvous system white matter disease and primary ovarian failure. All had normal initial development but 3 had borderline low IQ and academic difficulties in primary school. Puberty did not develop in 2 patients and was arrested in a third patient. The fourth patient had premature ovarian failure at the age of 13 years. Head magnetic resonance imaging showed diffuse white matter disease, with frontal cortical atrophy in the most clinically advanced patient. All patients had normal karyotype and normal findings on extensive evaluations for known leukodystrophies, for other metabolic diseases, and for causes of ovarian failure. Proton magnetic resonance spectroscopic imaging showed reduction of choline‐containing compounds in the affected white matter in all patients and reduction of N‐acetylaspartate in the unaffected frontal white matter of 2 patients. All patients had evidence of primary gonadal insufficiency with a normal hypothalamic‐hypophyseal axis. Pathological analysis showed streak ovaries in 1 patient and signs of hypomyelination, and gliosis on brain biopsy in another patient. In conclusion, we present a novel group of patients who have in common leukodystrophy, primary ovarian dysfunction, and magnetic resonance spectroscopic abnormalities.
Periventricular nodular heterotopia and intractable temporal lobe epilepsy: Poor outcome after temporal lobe resection
Authors: Li L. M. , Dubeau F. , Andermann F. , Fish D. R. , Watson C. , Cascino G. D. , Berkovic S. F. , Moran N. , Duncan J. S. , Olivier A. , Leblanc R. , Harkness W.
Published: January 2005

We describe 5 women and 5 men with periventricular nodular heterotopia and electroclinical features suggestive of temporal lobe epilepsy, who were surgically treated for control of medically refractory seizures. Magnetic resonance imaging revealed bilateral periventricular nodular heterotopia in 7 of the 10 patients. Because of the lack of clear localization, 6 patients were studied with intracranial depth electrode recordings. Seizures were of hippocampal onset (3 patients), regional temporal lobe onset (2 patients), or occipital‐temporal onset (1 patient). Anterior temporal lobectomy was performed in 6 patients; selective amygdalohippocampectomy, in 1; and anterior temporal lobectomy plus resection of the heterotopic tissue, in 3. None of the 9 patients followed for more than 12 months postoperatively were seizure free. Two patients were initially seizure free for approximately 18 months, but then seizures recurred. One patient had a major reduction in seizure frequency at a 39‐month follow‐up after most of the unilateral heterotopic tissue was included in the temporal resection. Temporal resection did not lead to a long‐term favorable outcome in this group of patients with periventricular nodular heterotopia and epileptogenic discharges involving the temporal lobe. This sugests a more widespread disorder with epileptogenic activity possibly originating in or near the heterotopic tissue. The clinical and electrographic features of periventricular nodular heterotopia pointing to temporal lobe origin are misleading and temporal resection does not result in long‐term cessation of seizures.
Short‐ and long‐term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease
Authors: Wenning Gregor K. , Odin Per , Morrish Paul , Rehncrona Stig , Widner Håkan , Brundin Patrik , Rothwell John C. , Brown Richard , Gustavii Björn , Hagell Peter , Jahanshahi Marjan , Sawle Guy , Björklund Anders , Brooks David J. , Marsden C. David , Quinn Niall P. , Lindvall Olle
Published: January 2005

Six patients with Parkinson's disease were followed for 10 to 72 months after human embryonic mesencephalic tissue from four to seven donors was grafted unilaterally into the putamen (4 patients) or putamen plus caudate (2 patients). After 8 to 12 months, positron emission tomography showed a 68% increase of 6‐L−[18F]‐fluorodopa uptake in the grafted putamen, no change in the grafted caudate, and minor decreases in nongrafted striatal regions. There was therapeutically valuable improvement in 4 patients, but only modest changes in the other 2, both of whom developed atypical features. Patient 4 was without L−dopa from 32 months and had normal fluorodopa uptake in the grafted putamen at 72 months. Overall, the L−dopa dose was reduced by a mean of 10 and 20%, “off” time was reduced by 34 and 44%, and the “off” phase Unified Parkinson's Disease Rating Scale motor score by 18 and 26%, and the duration of the response to a single L−dopa dose increased by 45 and 58% during the first and second years after surgery, respectively. Rigidity and hypokinesia improved bilaterally, but mainly contralateral to the implant. No consistent changes in dyskinesias were observed. We conclude that transplantation of embryonic mesencephalic tissue leads to highly reproducible survival of dopaminergic neurons, inducing clinically valuable improvements in most recipients.
Sporadic focal dystonia in Northwest Germany: Molecular basis on chromosome 18p
Authors: Leube B. , Hendgen T. , Kessler K. R. , Knapp M. , Benecke R. , Auburger G.
Published: January 2005

Idiopathic focal dystonia (IFD) is the most common form of idiopathic torsion dystonia in the Euroamerican population, with a prevalence of about 30 per 100,000. Although most patients claim a negative family history, we recently mapped this syndrome to chromosome 18p as an autosomal dominant trait in Family K from Northwest Germany. We now have investigated sporadic patients with IFD from the same geographic area both clinically and molecularly with chromosome 18p markers. The data indicate that most of these apparently sporadic patients have inherited the same mutation as Family K from a common ancestor and, in fact, owe their disease to autosomal dominant inheritance at low penetrance. The data also indicate that this dystonia mutation (DYT7) is the predominant cause of IFD, at least in this area of Northwest Germany, and that its location can be narrowed from a 30‐ to a 6‐centimorgan region close to marker D18S1098.
Nicotinic receptor stimulation protects neurons against β‐amyloid toxicity
Authors: Kihara T. , Shimohama S. , Sawada H. , Kimura J. , Kume T. , Kochiyama H. , Maeda T. , Akaike A.
Published: January 2005

β‐Amyloid (Aβ), a major constituent of senile plaques in Alzheimer's disease (AD), is thought to contribute to the neurodegeneration. We examined the effects of nicotinic receptor agonists on Aβ cytotoxicity in cultured rat cortical neurons. The number of viable neurons decreased significantly when cultures were exposed to synthetic Aβ peptides (25–35). Concomitant administration of nicotine with Aβ markedly reduced the number of dead cells. This nicotine‐induced neuroprotection was dependent on the concentration. When hexamethonium or mecamylamine, nicotinic antagonist, was added, neuroprotective effect of nicotine was blocked, which indicates that effect of nicotine was mediated by nicotinic receptors. In addition, a selective α7‐receptor antagonist, α‐bungarotoxin (α‐BTX), blocked the neuroprotective effect of nicotine. Furthermore, incubation with 3–(2,4)‐dimethoxybenzylidene anabaseine (DMXB), a selective α7–receptor agonist, protected against Aβ‐induced neuronal death. These results suggest that α7–receptor activation plays an important role in neuroprotection against Aβ cytotoxicity. This study suggests that nicotinic receptor stimulation, especially α‐receptor activation, may be able to protect neurons from degeneration induced by Aβ and may have effects that counter the progress of AD.
Calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors: A molecular determinant of selective vulnerability in amyotrophic lateral sclerosis
Authors: Williams T. L. , Day N. C. , Ince P. G. , Kamboj R. K. , Shaw P. J.
Published: January 2005

The cause of the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) remains unexplained. One potential pathogenetic mechanism is chronic toxicity due to disturbances of the glutamatergic neurotransmitter system, mediated via α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA)‐sensitive glutamate receptors. Functional AMPA receptors consist of various combinations of four subunits (designated GluR1–4). The GluR2 subunit is functionally dominant and renders AMPA receptors impermeable to calcium. Most native AMPA receptors in the mammalian central nervous system (CNS) contain the GluR2 subunit and are calcium impermeable. We have investigated the composition of AMPA receptors expressed on normal human spinal motor neurons by in situ hybridization to determine their likely subunit stoichiometry. Highly significant levels of mRNA were detected for the GluR1, GluR3, and GluR4 subunits. However, GluR2 subunit mRNA was not detectable in this cell group. The absence of detectable GluR2 mRNA in normal human spinal motor neurons prdicts that they express calcium‐permeable AMPA receptors unlike most neuronal groups in the human CNS. Expression of atypical calcium‐permeable AMPA receptors by human motor neurons provides a possible mechanism whereby disturbances of glutamate neurotransmission in ALS may selectively injure this cell group.
Autosomal dominant dementia with widespread neurofibrillary tangles
Authors: Reed Lee A. , Schelper Robert L. , Solodkin Ana , Van Hoesen Gary W. , Van Hoesen Gary W. , Solodkin Ana , Morris John C. , Trojanowski John Q. , Grabowski Thomas J. , Talbot Chris J. , Schmidt Marie Luise , Goate Alison , Wragg Michelle A.
Published: January 2005

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early‐onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with α‐rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years'l disease duration, the proband's neuropathologic examination demonstrated abudant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaque were absent. The tangles were recognized by antibodies specific for phosphorylation‐independent (Tau−2, T46, 133, and Alz‐50) and phosphorylation‐dependent epitopes (AT8, T3P, PHF‐1, 12E8, AT6, AT18, AT30) in proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.
In vivo skeletal muscle mitochondrial function in Leber's hereditary optic neuropathy assessed by 31P magnetic resonance spectroscopy
Authors: Lodi R. , Taylor D. J. , Tabrizi S. J. , Kumar S. , Sweeney M. , Wood N. W. , Styles P. , Radda G. K. , Schapira A. H. V.
Published: January 2005

We used 31P magnetic resonance spectroscopy (31P‐MRS) to asses in vivo skeletal muscle mitochondrial function in 10 Leber's hereditary optic neuropathy patients/carriers with a mitochondrial DNA (mtDNA) mutation at one of three nucleotide positions, 11,778, 14,484, and 3,460. We studied one affected patient for each mutation and two unaffected carriers with the 11,778 or 3,460 mutation and three carriers with 14,484. All subjects were homoplasmic except the two 3,460 carriers, who showed 80% and 15% of mutated mtDNA. 31P‐MRS at rest disclosed some abnormalities in all subjects. In particular, the phosphorylation potential was below the normal range in all cases. During recovery from exercise, the maximum rate of mitochondrial ATP production (Vmax) was reduced to 27% of normal in the 11,778 mutation and to 53% in the 14,484 mutation patient/carrier groups. Mitochondrial Vmax was within the normal range in all subjects with the 3,460 mutation but correlated inversely with the percentage of mutated mtDNA. This in vivo study shows that the 11,778 mutation causes a mitochondrial impairment more severe than the 14,484 and that the 3,460 mutation results in only a mild depression of muscle mitochondrial function.
Ontogeny of ipsilateral corticospinal projections: A developmental study with transcranial magnetic stimulation
Authors: Müller K. , Kass‐Iliyya F. , Reitz M.
Published: January 2005

Transcranial magnetic stimulation (TMS) has been used to describe the maturation of the corticospinal tract in children. Ipsilateral corticospinal connections have been demonstrated with TMS in patients with congenital mirror movements, in patients after hemispherectomy, and in children with hemiplegic cerebral palsy. The goal of the study was to find out whether corticospinal ipsilateral projections in children can be demonstrated during the first decade of life as part of normal ontogeny. For this purpose, we examined 50 normal children (age range, 3–11 years) with focal TMS over the left and right hemispheres to target muscles in proximal and distal parts of the upper extremity (first dorsal interosseus, biceps brachii, and brachioradialis). To lower the stimulation threshold, we stimulated under voluntary preinnervation. In two‐thirds of the children we elicited ipsilateral motor evoked potentials (MEPs). This occurred more often in proximal than in distal muscles. The latency of the ipsilateral MEPs was about 12 to 14 msec longer than the usual contralateral response. From the age of 10, and in adults, ipsilateral MEPs could not be detected. Also considering lesion data from adult patients, the most likely explanation for the disappearance of ipsilateral corticospinal connections after the age of 10 years is an increasing transcallosal inhibitory influence during development. The presence of ipsilateral corticospinal connections appears to be a normal state in ontogeny.
Alterations in opioid receptor binding in Parkinson's disease patients with levodopa‐induced dyskinesias
Authors: Piccini P. , Weeks R. A. , Brooks D. J.
Published: January 2005

Levodopa‐induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa‐induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [11C]diprenorphine to assess changes in cerebral receptor binding on a voxel‐by‐voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa‐induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.
Quantitative neuropathology and quantitative magnetic resonance imaging of the hippocampus in temporal lobe epilepsy
Authors: Van Paesschen W. , Revesz T. , Duncan J. S. , King M. D. , Connelly A.
Published: January 2005

The aims of this study were to examine the relationships of hippocampal T2 (HCT2) relaxation time and magnetic resonace (MR)‐based hippocampal volume (HCV) to neuronal (ND) and glial cell densities (GD) of hippocampal neuronal cell layers, and to obtain a better clinicopathological definition of hippocampal sclerosis (HS) and end folium sclerosis (EFS). Fifty‐three hippocampi with HS, 6 with EFS, and 6 control hippocampi were studied. Pathologically, the HS group had a significantly higher logarithm (log) GD/ND than the controls in all hippocampal subregions, and than the EFS group in all subregions except the granule cell layer of the dentate gyrus (GCDG). The EFS group had a significantly higher log GD/ND than the control group only in the GCDG. Clinical correlations suggested that EFS may be the consequence of temporal lobe seizures and not an epileptogenic entity. Hippocampal atrophy in HS was associated with neuronal cell depletion and concomitant gliosis in the cornu Ammonis (CA) 1, CA2, CA3, and hilus. An increased HCT2 was associated with damage in the CA1 and also the hilus and has a different neuropathological basis than HCV loss. MR‐based HCV measurement and HCT2 mapping, therfore, give complementary information in the presurgical evaluation of temporal lobe epilepsy and longitudinal studies.
Isolation and characterization of an oligodendrocyte precursor–derived B‐cell epitope in multiple sclerosis
Authors: Archelos Juan J. , Trotter Jacqueline , Previtali Stefano , Weißbrich Benedikt , Toyka Klaus V. , Hartung Hans‐Peter
Published: January 2005

In a search for possible central nervous system–specific autoantigens in multiple sclerosis (MS), a λ‐phage protein expression library was constructed from an oligodendrocyte‐precursor cell line. The library was screened with pooled cerebrospinal fluid (CSF) from 54 patients with definite MS according to the criteria of Poser. Pooled CSF samples from 44 patients with other neurological disease including bacterial meningitis and viral encephalitis were used as control. A total of 1,000,000 colonies were screened and 6 positive clones were detected. At the DNA level none of the sequences showed significant homology to a known coding sequence. All 6 clones contained an open reading frame for small peptides ranging from 14 to 38 amino acids. It was noteworthy that 5 clones contained a common sequence of 7 amino acids, which was highly homologous to a translated consensusAlurepeat epitope. Screening of sera and CSF from patients with MS showed that approximately 44% reacted with these so‐calledAlupeptides, end‐point antibody titers in their sera ranging from 1:1,000 to 1:25,000. In addition, some samples selected by their reactivity withAlupeptides stained intensively the cytoplasm of oligodendrocyte precursors but not of astrocytes ex vivo. We postulate that autoantibodies to a hitherto unknown oligodendrocyte precursor‐derived B‐cell epitope could contribute to the pathogenesis in a subgroup of MS patients.
Magnetic resonance studies of intramuscular interferon β–1a for relapsing multiple sclerosis
Authors: Simon Jack H. , Jacobs Lawrence D. , Campion Marilyn , Wende Karl , Simonian Nancy , Cookfair Diane L. , Rudick Richard A. , Herndon Robert M. , Richert John R. , Salazar Andres M. , Alam John J. , Fischer Jill S. , Goodkin Donald E. , Granger Carl V. , Lajaunie Michelle , Martens‐Davidson Anna L. , Meyer Maryjoel , Sheeder Jeanelle , Choi Kim , Scherzinger Ann L. , Bartoszak David M. , Bourdette Dennis N. , Braiman Jonathan , Brownscheidle Carol M. , Coats Michael E. , Cohan Stanley L. , Dougherty David S. , Kinkel Revere P. , Mass Michele K. , Munschauer Fredrick E. , Priore Scd Roger L. , Pullicino Patrick M. , Scherokman Barbara J. , Weinstock‐Guttman Bianca , Whitham Ruth H. ,   and The Multiple Sclerosis Collaborative Research Group
Published: January 2005

The Multiple Sclerosis Collaborative Research Group trial was a double‐blind, randomized, multicenter, phase III, placebocontrolled study of interferon α‐1a (IFNβ‐1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNβ‐1a, 30 μg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNβ‐1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNβ‐1a patients was 1,578 and −12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium‐enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNβ‐1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long‐term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.
Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy
Authors: Fry  ,   US Modafinil in Narcolepsy Multicenter Study Group
Published: January 2005

Narcolepsy is a central nervous system disorder characterized by excessive daytime sleepiness and cataplexy. This placebocontrolled, double‐blind, randomized, parallel‐group, 18‐center study assessed the efficacy and safety of modafinil, a new wake‐promoting drug for treating sleepiness in narcolepsy. Subjects with narcolepsy (n = 283) received daily modafinil, 200 or 400 mg, or placebo, for 9 weeks, followed by an open‐label treatment period. Subjective sleepiness was measured with the Epworth Sleepiness Scale. Objective sleepiness was assessed with the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Level of illness was measured with the Clinical Global Impression of Change. Modafinil significantly reduced all measures of sleepiness and was associated with significant improvements in level of illness. Medication‐related adverse expriences were few, dose‐dependent, and mostly rated mild to moderate. Modafinil taken once daily was a very well tolerated and effective wake‐promoting agent in the treatment of excessive daytime somnolence associated with narcolepsy. Modafinil demonstrated an excellent safety profile for up to 40 weeks of open‐label treatment and efficacy was maintained, suggesting that tolerance will not develop with long‐term use. Modafinil is a pharmacologically and clinically promising compound for the treatment of pathological daytime somnolence.
Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis
Authors: Wisniewski K. E. , Zhong N. , Kaczmarski W. , Kaczmarski A. , Kida E. , Brown W. T. , Schwarz K. O. , Lazzarini A. M. , Rubin A. J. , Stenroos E. S. , Johnson W. G. , Wisniewski T. M.
Published: January 2005

We present a clinicopathological study and the first molecular genetic analysis of a family with 2 siblings affected by a rare, protracted form of juvenile neuronal ceroid lipofuscinosis (JNCL). Molecular genetic studies showed that both siblings, in addition to being heterozygous for the 1.02‐kb CLN3 deletion, a common mutation in JNCL, also had a G‐to‐A missense mutation at nucleotide 1,020 of the CLN3 cDNA sequence on the non‐1.02‐kb deletion chromosomes. This point mutation resulted in a substitution of glutamic acid by lysine at position 295 of the CLN3 protien. Thus, a single point mutation at residue 295 of the CLN3 protien in protracted JNCL may underlie the phenotype in this form, which differs from that in classic JNCL.
Restricted use of VH4 Germline segments in an acute multiple sclerosis brain
Authors: Owens Gregory P. , Kannus Hanna , Burgoon Mark P. , Smith‐Jensen Tracey , Devlin Mary E. , Gilden Donald H.
Published: January 2005

Multiple sclerosis (MS) cerebrospinal fluid and brain contain increased IgG and oligoclonal bands. Whether this oligoclonal and polyclonal IgG is directed against a disease‐relevant antigen remains unknown. To distinguish between random activation versus a targeted B‐cell response, we analyzed the IgG heavy chain variable region (VH) repertoire expressed in different lesions of an acute MS brain. To obtain a representative sample of the VH repertoire, we constructed directional complementary DNA libraries from plaque‐periplaque messenger RNA and amplified VH regions from the library by nested polymerase chain reaction. When MS VH sequences were aligned to germline segments, about 60% of different VH sequences in the acute MS brain were VH4 germline segments, significantly greater than the known approximately 20% VH4 germline prevalence. Specific VH sequences were overrepresented and expressed at multiple plaque sites. Within some overexpressed populations, there were distinct sequence differences (clonal variants) indicative of clonal expansion. Alignment of VH sequences to their closest germline counterparts revealed extensive somatic mutation and the preferential accumulation of amino acid replacement mutations in complementarity determining regions. These observations suggest the limited B‐cell response found in this acute MS brain was antigen driven.
Proton magnetic resonance spectroscopy in an italian family with spinocerebellar ataxia type 1
Authors: Mascalchi Mario , Tosetti Michela , Plasmati Rosaria , Bianchi Maria Cristina , Tessa Carlo , Salvi Fabrizio , Frontali Marina , Valzania Franco , Bartolozzi Carlo , Tassinari Carlo Alberto
Published: January 2005

Linkage and DNA analysis, magnetic resonance (MR) imaging, and single‐voxel proton MR spectroscopy were obtained in 10 members of an Italian kindred with spinocerebellar ataxia type 1 (SCA1). The size of the basis pontis, cerebellar hemispheres, middle cerebellar peduncles, and medulla oblongata were decreased in 4 members carrying the SCA1 gene, compared with 6 unaffected subjects. Diffuse signal changes in the pons and cerebellum were observed only in the carrier with the longest disease duration and greatest disability. The N‐acetylaspartate/creatine ratio and the choline/creatine ratio in the basis points were markedly decreased in 2 symptomatic SCA1 carriers and moderately decreased in 2 asymptomatic SCA1 carriers, compared with the unaffected family members and a control group of 10 healthy volunteers. Minor decreases in the N‐acetylaspartate/creatine ratio and the normal choline/creatine ratio, demonstrated by MR spectroscopy in the pons, is likely to reflect a loss of neuronal viability and might represent a biochemical marker of SCA1 more sensitive than brainstem and cerebellum atrophy and signal changes shown by MR imaging.
Unmyelinated nerve fibers in sural nerve in pure autonomic failure
Authors: Kanda Takashi , Tomimitsu Hiroyuki , Yokota Takanori , Ohkoshi Norio , Hayashi Michiyuki , Mizusawa Hidehiro
Published: January 2005

We examined sural nerve biopsy specimens from 7 patients with pure autonomic failure (PAF). The mean unmyelinated nerve fiber diensity in these patients was 40% less than in age‐matched controls. Increased numbers of clusters of collagen pockets not containing unmyelinated axons were the most prominent finding in PAF. This appears to reflect recent dropout of a group of sympathetic efferents and suggests grouping of unmyelinated fibers by modality at the level of the sural nerve trunk.
Mutation analysis in myophosphorylase deficiency (McArdle's disease)
Authors: Vorgerd Matthias , Kubisch Christian , Burwinkel Barbara , Reichmann Heinz , Mortier Wilhelm , Tettenborn Barbara , Pongratz Dieter , Lindemuth Rainer , Tegenthoff Martin , Malin Jean‐Pierre , Kilimann Manfred W.
Published: January 2005

Inherited deficiency of myophosphorylase leads to glycogen storage disease type V (McArdle's disease). We performed mutation analysis in 9 patients of eight unrelated families from Germany with typical cliniclal presentation of myophos‐phorylase deficiency. Beside previously described mutations we identified four novel mutations in the myophorsphorylase gene. Four patients were homozygous for a nonsense mutation Arg49Stop that has been reported to be the most common mutation in white patients. Two affected siblings were compound heterozygotes for a novel missense mutation Gly685Arg and the nonsense mutation Arg49Stop. One patient carried a novel nonsense mutation Arg575Stop and a previously identified missense mutation Gly204Ser. In another patient, we identified a novel missense mutation Gln665Glu and a single‐base deletion delA in Lys753. One patient of Turkish ancestry carried a newly identified homozygous A‐to‐G transition (ATG to GTG) abolishing the translation initiation codon of the myophosphorylase gene. These results suggest that Arg49Stop also is the most common genetic error associated with myophosphorylase deficiency in the German population. Our findings further demonstrate molecular heterogeneity of myophosphorylase deficiency among the clinically homogenous patients we studied.
Correlations between monthly enhanced MRI Lesion rate and changes in T2 Lesion volume in multiple sclerosis
Authors: Molyneux P. D. , Filippi M. , Barkhof F. , Gasperini C. , Yousry T. , Lruyen L. , Lai H. M. , Rocca M. A. , Moseley I. F. , Miller D. H.
Published: January 2005

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium‐enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1‐weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.
Near and far visual space in unilateral neglect
Authors: Vuilleumier P. , Valenza N. , Mayer E. , Reverdin A. , Landis T.
Published: January 2005

A 24‐year‐old right‐handed woman with a right temporal hematoma showed marked left visual neglect for far but not near space in a variety of tasks systematically given in near and far distance conditions. This case thus provides the dissociation opposite to Halligan and Marshall's patient, who had neglect for near but not far space after a right parietal stroke. Furthermore, although she made rightward errors in bisecting far‐distant lines, our patient made smaller opposite leftward errors for near‐distant lines. The evidence that unilateral neglect of far and near visual space may exist independently supports a division in the neural systems subserving attention to different compartments of the extrapersonal space in humans.
Multiple sclerosis: In situ evidence for antibody‐ and complement‐mediated demyelination
Authors: Storch Maria K. , Piddlesden Sara , Haltia Matti , Iivanainen Matti , Morgan Paul , Lassmann Hans
Published: January 2005

We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center.
Cerebrospinal fluid homovanillic acid levels in rapid‐onset dystonia‐parkinsonism
Authors: Brashear Allison , Butler Ian J. , Hyland Keith , Farlow Martin R. , Dobyns William B.
Published: January 2005

Rapid‐onset dystonia‐parkinsonism (RDP) is characterized by sudden onset over hours to days of dystonia, dysphagia, dysarthria, and parkinsonism. RDP has been reported by our group in two apparently unrelated families. We now report analysis of cerebrospinal fluid metabolites of dopamine, norepinephrine, and serotonin for mild and severely affected individuals, known asymptomatic gene carriers, and at‐risk individuals from both families with RDP. Levels of the dopamine metabolite homovanillic acid (HVA) were decreased in severely affected patients and in some asymptomatic gene carriers. HVA levels increased with treatment in some affected individuals, but this increase did not predict clinical response to carbidopa/levodopa. We suggest that a low HVA level is a biological marker with modest association to the diagnosis of RDP.
Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene
Authors: Cudkowicz M. E. , McKenna‐Yasek D. , Chen C. , Hedley‐Whyte E. T. , Brown R. H.
Published: January 2005

We examined 11 subjects with inherited amyotrophic lateral sclerosis (familial amyotrophic lateral sclerosis, FALS) associated with the most common copper/zinc superoxide dismutase 1 (SOD1) mutation, an alanine for valine substitution in codon 4 (A4V). Autopsies were performed on 5 subjects. The clinical and pathological findings are described and compared with those of 9 sporadic ALS (SALS) subjects. There was no clinical evidence of upper motor neuron (UMN) involvement in 10 FALS A4V subjects. All subjects had lower motor neuron (LMN) signs and electrophysiological evidence of denervation in at least three limbs. All SALS subjects had signs of both UMN and LMN involvement. Pathological studies found severe abnormalities of LMNs in all FALS and SALS subjects. UMN involvement was either absent or mild in the A4V SOD1 FALS subjects and severe in the SALS subjects. Pathological abnormalities in systems other than the motor neurons were more frequent in the FALS A4V subjects. This information suggests that current diagnostic criteria for ALS, requiring clinical evidence for both upper and lower motor neuron involvement, should be modified; ie, the diagnosis should be deemed established when there is evidence of denervation in three or more limbs and a mutation in the gene for SOD1, even without clinical signs of UMN involvement.
Fast eye movement initiation of ocular torsion in mesodiencephalic lesions
Authors: Bentley C. R. , Bronstein A. M. , Faldon M. , Farmer S. , Gresty M. A. , Matthews T. D. , Paine M. , Plant G. T. , Riordan‐Eva P.
Published: January 2005

Three patients with episodic ocular torsion and skew deviation due to mesodiencephalic lesions were studied by using binocular three‐dimensional scleral search coils. The conjugate ocular torsion (upper pole of each eye rotating toward the side of the brainstem lesion) was initiated by a torsional fast eye movement. During prolonged episodes, torsional nystagmus was also present. Cessation of the ocular torsion and skew deviation occurred by slow eye movements with exponentially decreasing velocities in 2 patients, and by multiple fast torsional movements in 1 patient. In 1 patient, the abnormal eye movements were temporally linked to dystonic movements in the limbs on the side opposite the brainstem lesion. The occurrence of skew deviation with conjugate ocular torsion in brainstem lesions has been attributed to functional asymmetry in vestibular pathways responsible for the slow‐phase compensatory eye movement response to roll. In comparison, the findings in our patients show that in mesodiencephalic lesions conjugate ocular torsion with skew deviation may be generated by torsional fast eye movements, indicating activation of the burst cells of the rostral interstitial nucleus of the medial longitudinal fasciculus.
Tau is a candidate gene for chromosome 17 frontotemporal dementia
Authors: Poorkaj Parvoneh , Bird Thomas D. , Wijsman Ellen , Nemens Ellen , Garruto Ralph M. , Anderson Leojean , Andreadis Athena , Wiederholt Wigbert C. , Raskind Murray , Schellenberg Gerard D.
Published: January 2005

Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP‐17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21‐22 in a 2‐ to 4‐centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800‐D17S791 FTDP‐17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP‐17 families revealed nine DNA sequence variants, eight of which were also identified controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP‐17 family but not in the second FTDP‐17 family. Three lines of evidence indicate that the Val279Met change is an FTDP‐17 causative mutation. First, the mutation site is highly conserved, and normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co‐segregates with the disease in family A. Third, the mutation is not found in normal controls.