bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunochemical analysis of dopamine transporter protein in Parkinson's disease
Authors: Miller Gary W. , Staley Julie K. , Heilman Craig J. , Perez Jeffrey T. , Mash Deborah C. , Rye David B. , Levey Allan I.
Published: January 2005

The plasma membrane dopamine transporter (DAT) is considered to be a reliable marker of presynaptic dopaminergic terminal loss. Previous in vivo imaging and postmortem binding studies have detected a loss in striatal DAT binding in Parkinson's diseased (PD) brain; however, these techniques have poor spatial resolution and may suffer from nonspecific binding of some ligands. In this study, we use novel highly specific monoclonal antibodies to distinct epitopes of human DAT to quantify and localize the protein. Western blot analysis revealed marked reductions in DAT immunoreactivity in putamen, caudate, and nucleus accumbens of PD brain compared with control cases, and the reductions were significantly correlated to disease duration. Immunohistochemistry revealed DAT‐immunoreactive fibers and puncta that were dense throughout the striatum of control brains but that were drastically reduced in putamen of PD brains. Caudate from PD brains showed a significant degree of sparing along the border of the ventricle, and the nucleus accumbens was relatively preserved. An unexpected finding was that discrete islands of DAT immunoreactivity were preserved within the matrix of PD putamen. Thus, immunological analysis of DAT protein provides novel and sensitive means for localizing and quantifying DAT protein in PD and other neurological disorders involving dopaminergic systems.
Regional and cellular expression of the dentatorubral‐pallidoluysian atrophy gene in brains of normal and affected individuals
Authors: Nishiyama K. , Nakamura K. , Murayama S. , Yamada M. , Kanazawa I.
Published: January 2005

Dentatorubral‐pallidoluysian atrophy is an autosomal dominant neurodegenerative disorder characterized by dementia and spinocerebellar degeneration. Recently, part of the gene responsible for this disorder was cloned containing a CAG repeat, and predominant neuronal expression of the gene was proved only through Northern blot analysis in rats. In this study, we investigated the regional and cellular expression of the dentatorubral‐pallidoluysian atrophy gene in the central nervous system of normal and affected humans, as well as in rat brains. In normal control human subjects, the gene messenger RNA was present in all brain regions examined, with the highest levels seen in the cerebellum, hippocampus, substantia nigra, and pontine nuclei. Its expression in the striaum, globus pallidus, and cerebral cortex was intermediate. The gene was expressed predominantly in neurons; a low but significant level of expression was also seen in glial cells. Neurons susceptible to degeneration in dentatorubral‐pallidoluysian atrophy did not selectively express high or low levels of its gene messenger RNA. In brains affected by the disorder, the distribution and levels of gene messenger RNA were comparable to those of the normal controls in all the areas. In the rat brains, gene messenger RNA expression was very similar to that in human brain. It was also expressed predominantly in neurons, while low‐level expression was observed in glial cells. It is apparent from these results that the presence of expanded trinucleotide repeats in dentatorubral‐pallidoluysian atrophy does not result in the absence of its gene messenger RNA expression or in altered patterns or levels of expression.
High frequency of apolipoprotein E ϵ2 Allele in hemorrhage due to cerebral amyloid angiopathy
Authors: Nicoll James A. R. , Burnett Claire , Love Seth , Graham David I. , Dewar Debbie , Ironside James W. , Stewart Janice , Vinters Harry V.
Published: January 2005

From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA‐related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE ϵ2 was 0.25 and the frequency of apoE ϵ4 was 0.18. Patients with CAA‐related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE ϵ4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA‐related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE ϵ4 frequency somewhat lower than non‐AD controls without hemorrhage. However, in CAA‐related hemorrhage, the apoE ϵ2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE ϵ2 may be a risk factor for cerebral hemorrhage due to CAA, apoE ϵ4 is a risk factor for concomitant AD but not an independent risk factor for CAA‐related hemorrhage.
Motor neuron syndromes in cancer patients
Authors: Forsyth P. A. , Dalmau J. , Graus F. , Cwik V. , Rosenblum M. K. , Posner J. B.
Published: January 2005

Previous reports indicate that motor neuron disease (MND) may rarely be associated with systemic cancer. We have encountered 14 patients with MND and cancer who formed three distinct groups. Group 1: Three patients developed a rapidly progressive MND, less prominent symptoms of involvement of other areas of the nervous system, and anti‐Hu antibodies. Group 2: Five women developed signs of upper motor neuron (UMN) disease, initially resembling primary lateral sclerosis (PLS), and breast cancer. In 4, symptoms of UMN occurred within 3 months of cancer diagnosis or tumor recurrence. They had no metastases or spinal cord compression. Serum anti‐neuronal antibodies were negative. Three patients are alive (follow‐up of 156, 15, and 12 months), and 2 remain without lower motor neuron signs. Group 3: Six patients developed MND resembling amyotrophic lateral sclerosis between 47 months before and 48 months after their cancer diagnosis. In group 1, the MND associated with the anti‐Hu antibody is unequivocally paraneoplastic. In group 2, the proximate onset of MND with the diagnosis of cancer or its recurrence, its pure or long‐lasting UMN signs, and its association with breast cancer, suggest that the disorder may be paraneoplastic. Although for most cancer patients who develop MND the occurrence of both disorders is probably coincidental, in some patients with MND a careful search for an underlying cancer is warranted (ie, patients in groups 1 and 2).
A double‐blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus
Authors: Averbuch‐Heller L. , Tusa R. J. , Fuhry L. , Rottach K. G. , Ganser G. L. , Heide W. , Büttner U. , Leigh R. J.
Published: January 2005

We conducted a double‐blind crossover trial comparing gabapentin (up to 900 mg/day) to baclofen (up to 30 mg/day) as therapy for acquired nystagmus in 21 patients. We measured visual acuity and the nystagmus before, and at the end of, 2 weeks on each medication. For a group of 15 patients with acquired pendular nystagmus (APN), visual acuity improved significantly with gabapentin, but not with baclofen. Gabapentin significantly reduced APN median eye speed in all three planes, but baclofen did so only in the vertical plane. In 10 patients with APN, the reduction of nystagmus with gabapentin was substantial and 8 of these elected to continue taking the drug. In 6 patients with downbeat or torsional downbeat nystagmus, changes in median slow‐phase eye speed were less consistent with both drugs, either increasing or decreasing, and being dependent on viewing conditions. Only 1 patient showed consistent reduction of median eye speed, and this was achieved by either drug. Our findings suggest that gabapentin may be an effective treatment for many patients with APN and that occasional patients with downbeat nystagmus will respond to gabapentin or baclofen.
Association of Campylobacter jejuni serotype with antiganglioside antibody in Guillain‐Barré syndrome and Fisher's syndrome
Authors: Yuki Nobuhiro , Takahashi Masaki , Tagawa Yumi , Kashiwase Kouichi , Tadokoro Kenji , Sairo Kahiko
Published: January 2005

Using Penner's method and Lior's scheme, we serotyped 31 isolates from patients with Guillain‐Barré syndrome, 7 isolates from those with Fisher's syndrome, and isolates from patients with sporadic enteritis. PEN 19 of Campylobacter jejuni was isolated more frequently from the Guillain‐Barré syndrome patients (16/31 isolates, 52%) than from the sporadic enteritis patients (5%). LIO 7 of C. jejuni also was isolated more frequently from the Gillain‐Barré syndrome patients (14/31 isolates, 45%) than from the enteritis patients (3%). One reason why Guillain‐Barré syndrome is rare, despite the high incidence of C. jejuni enteritis, may be the low frequencies of PEN 19 and LIO 7. The frequency of positive anti‐GM 1 antibody titers in the Guillain‐Barré syndrome patients with PEN 19 isolates was higher than that in the Guillain‐Barré syndrome and Fisher's syndrome patients without PEN 19 isolates. We speculate that the serotypic determinant of PEN 19 aids in the production of anti‐GM 1 antibody by a GM 1−like lipopolysaccharide. In contrast, 5 of the 7 isolates from the Fisher's syndrome patients belonged to PEN 2:LIO 4. The IgG anti‐GQ 1b antibody was associated with PEN 2 and LIO 4. These serotypic determinants may aid in the production of IgG anti‐GQ 1b antibody by a GQ 1b−like lipopolysaccharide.
Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy
Authors: Kuzniecky Ruben , Guthrie Barthon , Mountz James , Bebin Martina , Faught Edward , Gilliam Frank , Liu Hong‐Gang
Published: January 2005

Hypothalamic hamartomas and gelastic seizures are often associated with cognitive deterioration, behavioral problems, and poor response to anticonvulsant treatment or cortical resections. The origin and pathophysiology of the epileptic attacks are obscure. We investigated 3 patients with this syndrome and frequent gelastic seizures. Ictal single‐photon emission computed tomography performed during typical gelastic seizures demonstrated hyperperfusion in the hamartomas, hypothalamic region, and thalamus without cortical or cerebellar hyperperfusion. Electroencephalographic recordings with depth electrodes implanted in the hamartoma demonstrated focal seizure origin from the hamartoma in 1 patient. Electrical stimulation studies reproduced the typical gelastic events. Stereotactic radiofrequency lesioning of the hamartoma resulted in seizure resulted in seizure remission without complications 20 months after surgery. The functional imaging findings, electrophysiological data, and results of radiofrequency surgery indicate that epileptic seizures in this syndrome originate and propagate from the hypothalamic hamartoma and adjacent structures.
Selective vestibular damage in neurosarcoidosis
Authors: von Brevern M. , Lempert T. , Bronstein A. M. , Kocen R.
Published: January 2005

We report a patient with neurosarcoidosis who developed bilateral benign paroxysmal positional vertigo (BPPV) of the posterior canals, deafness, and absent responses to conventional caloric and rotational vestibular testing. Additional rotation in the planes of the vertical semicircular canals revealed relative sparing of vertical canal function. This vertical–horizontal canal dissociation explains the presence of BPPV and suggests that the vestibular damage in this patient is secondary to a vasculitic neuropathy.
Ischemic lesion volumes in acute stroke by diffusion‐weighted magnetic resonance imaging correlate with clinical outcome
Authors: Löuvbld Karl‐Olof , Baird Alison E. , Schlaug Gottfried , Benfield Andrew , Siewert Bettina , Voetsch Barbara , Connor Ann , Burzynski Cara , Edelman Robert R. , Warach Steven
Published: January 2005

Diffusion‐weighted magnetic resonance imaging detects ischemic injury within minutes after onset, and has been used to demonstrate drug efficacy in animal models of stroke. In 50 patients diagnosed with acute ischemic stroke ( < 24‐hour duration) within the middle cerebral artery territory, lesion volume was measured by diffusion‐weighted imaging. Thirty‐four patients also had volumes measured by T2‐weighted imaging chronically (median time, 7.5 weeks; mean, 15.9 weeks). Clinical severity was measured by the National Institutes of Health Stroke Scale Score and the Barthel index. Acute lesion volumes correlated with the acute stroke scale score (r = 0.56), the chronic stroke scale score (r = 0.63), and chronic lesion volumes (r = 0.84). Chronic volumes correlated with the chronic stroke scale score (r = 0.86) and the Barthel index (r = −0.60). When only cortically based lesions were considered, the correlations relating acute lesion volume measured by diffusion‐weighted imaging (r = 0.61) and chronic lesion volume measured by T2‐weighted imaging (r = 0.90) to the chronic stroke scale score were higher. These results provide evidence that lesion volumes determined by diffusion‐weighted imaging acutely may be predictive of clinical severity and outcome, and may support a role for diffusion‐weighted imaging in the assessment of acute stroke therapies in clinical trials.
Quantitative assessment of cardiovascular autonomic function in Guillain‐Barré syndrome
Authors: Flachenecker P. , Wermuth P. , Hartung H.‐P. , Reiners K.
Published: January 2005

To study the temporal course and the relationship between autonomic failure and motor weakness in Guillain‐Barré syndrome (GBS), a total of 164 autonomic function tests were serially applied for up to 1 year in 13 consecutive patients. Results were compared with those obtained in 25 healthy volunteers and 13 patients with other neurological diseases. Parasympathetic function tests comprised heart rate responses to Valsalva maneuver, deep breathing, and active change of posture, whereas sympathetic vasomotor function was assessed by blood pressure responses to handgrip and standing. At the height of the disease, subclinical autonomic involvement of both parasympathetic and sympathetic arms was revealed in the vast majority of patients. Abnormalities of autonomic function tests improved gradually over time, paralleling the recovery of motor function, but were only partially related to clinically significant autonomic dysfunction. Correlation analysis suggested that tachycardia in the context of GBS might be caused by a reduction of sympathetically mediated peripheral vascular tone rather than by vagal failure.
Association of myopathy with large‐scale mitochondrial dna duplications and deletions: Which is pathogenic?
Authors: Manfredi Giovanni , Vu Tuan , Bonilla Eduardo , Schon Eric A. , DiMauro Salvatore , Arnaudo Enrica , Zhang Lee , Rowland Lewis P. , Hirano Michio
Published: January 2005

We identified large‐scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50–year‐old woman with an adult‐onset progressive myopathy. The predominant mtDNA abnormality was a 21.2–kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6–kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA‐encoded COX subunits. By single‐fiber polymerase chain reaction analysis, COX‐negative fibers contained a low number of wild‐type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.
Otolith—Ocular responses in familial episodic ataxia linked to chromosome 19p
Authors: Furman Joseph M.
Published: January 2005

We evaluated several members of a family with episodic ataxia type 2 linked to chromosome 19p by using a battery of vestibulo‐ocular reflex (VOR) tests. Testing focused on the otolith–ocular reflex and semicircular canal–otolith interaction. Our aims were to improve understanding of the structures important for the VOR and to define further the range of vestibulo‐ocular, in particular otolith–ocular, manifestations within a family with episodic ataxia. Ocular motor, semicircular canal–ocular, and semicircular canal–otolith interaction assessments suggested impairment of the vestibulocerebellum (ie, the flocculonodular lobe); the brainstem appeared to be relatively spared. Eye movements during constant velocity off‐vertical axis rotation (OVAR), a pure otolith stimulus, indicated that the modulation component of the response was normal whereas the bias component was reduced or nearly absent. Based on these data, it appears that the cerebellum is not responsible for the generation of the modulation component of the response to OVAR. However, the bias component appears to depend on the caudal midline cerebellum.
A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism
Authors: Green Donnella S. , Hayward Lawrence J. , George Alfred L. , Cannon Stephen C.
Published: January 2005

Twenty different point mutations have been identified in the gene coding for the α subunit of the adult skeletal muscle sodium channel in families with hyperkalemic periodic paralysis, paramyotonia congenita, and the potassium‐aggravated myotonias. One novel mutation (Val781Ile) was reported in an adopted boy with potassium‐sensitive weakness and cardiac dysrhythmia. The confidence in establishing this rare amino acid substitution as a causative mutation was limited by the absence of family members for segregation analysis. Functional expression studies herein show that Val781Ile is most likely a benign polymorphism and not a disese‐associated mutation.
Maternally inherited encephalopathy associated with a single‐base insertion in the mitochondrial tRNATrp gene
Authors: Santorelli F. M. , Tanji K. , Sano M. , Shanske S. , El‐Shahawi M. , Kranz‐Eble P. , Dimauro S. , De Vivo D. C.
Published: January 2005

We identified a single thymidine inserton at nucleotide postion 5537 (T5537i) in the mitochondrial DNA transfer RNA gene for tryptophan in a family in which the proband had a progressive neurological disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and ecreased activities of oxidative metabolism enzymes, in particular complex IV. Complex IV was also severely reduced in autopsy tissues, including heart and brain tissues, from the Leigh syndrome infant. The novel T5537i mutaion was very abundant in tissues from the proband and the infant (>92%) and less abundant (range, 42–89%) in blood, hair follicles, and skin fibroblasts from 4 maternal relatives, 3 of whom showed a neuropsychiatric disturbance. The mutation was not found in more than 100 control subjects. The degree of heteroplasmy in blood correlated well with the severity of the clinical presentation, suggesting specific segregation with the disease.
Increased 3‐nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation
Authors: Ferrante Robert J. , Shinobu Leslie A. , Schulz Jörg B. , Matthews Russell T. , Thomas Craig E. , Kowall Neil W. , Gurney Mark E. , Beal M. Flint
Published: January 2005

Mutations in copper/zinc superoxide dismutase (SOD1) cause a subset of cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express these point mutations develop progressive paralysis and motor neuron loss thought to be caused by a gain‐of‐function of the enzyme. The gain‐of‐function may be an enhanced ability of the mutant SOD1 to generate ·OH radicals or to facilitate peroxynitrite‐mediated nitration of proteins. We found significant increases in concentrations of 3‐nitrotyrosine, a marker of peroxynitrite‐mediated nitration, in upper and lower spinal cord and in cerebral cortex of transgenic mice with the FALS‐associated G93A mutation. Malondialdehyde, a marker of lipid peroxidation, was increased in cerebral cortex. 3‐Nitrotyrosine‐, heme oxygenase‐1–, and malondialdehyde‐modified protein immunoreactivities were increased throughout SOD1 transgenic mice spinal cord but particularly within motor neurons. These results suggest that the gain‐of‐function of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative damage, which may play a role in neuronal degeneration.
Monoclonal antibodies to purified cortical lewy bodies recognize the mid‐size neurofilament subunit
Authors: Galvin James E. , Lee Virginia M.‐Y. , Baba Minami , Mann David M. A. , Dickson Dennis W. , Yamaguchi Hisako , Schmidt M. Luise , Iwatsubo Takeshi , Trojanowski John Q.
Published: January 2005

Lewy bodies (LBs) are filamentous intraneuronal inclusions that are hallmark lesions of Parkinson's disease, and LBs have been shown, by immunohistochemistry, to contain cytoskeletal as well as other cellular proteins. Similar LBs also occur in the cortical neurons of a subset of patients with Alzheimer's disease (AD), and cortical LBs are the predominant or sole lesions in the brains of patients with an AD‐like dementia known as diffuse Lewy‐body disease (DLBD). To gain insight into the biochemical composition of LBs, we generated monoclonal antibodies (mAbs) to LBs purified from the brains of patients with DLBD. Here, we describe three of these new mAbs (LB48, LB202, and LB204) that stained LBs by immunohistochemistry and recognized the medium molecular mass neurofilament (NF) protein in western blots. These results support the hypothesis that NF subunits are integral components of LBs. Continued efforts to clarify the composition of LBs are likely to lead to novel strategies for the antemortem diagnosis of LB disorders as well as to insight into the role LBs play in the degeneration of affected neurons in these disorders.
Magnetoencephalography in partial epilepsy: Clinical yield and localization accuracy
Authors: Knowlton R. C. , Laxer K. D. , Aminoff M. J. , Roberts T. P. L. , Wong S. T. C. , Rowley H. A.
Published: January 2005

The goals of this study were to determine (1) the yield of magnetoencephalography (MEG) according to epilepsy type, (2) if MEG spike sources colocalize with focal epileptogenic pathology, and (3) if MEG can identify the epileptogenic zone when scalp ictal electroencephalogram (EEG) or magnetic resonance imaging (MRI) fail to localize it. Twenty‐two patients with mesial temporal (10 patients), neocortical temporal (3 patients), and extratemporal lobe epilepsy (9 patients) were studied. A 37‐channel biomagnetometer was used for simultaneously recording MEG with EEG. During the typical 2–3–hour MEG recording session, interictal epileptiform activity was observed in 16 of 22 patients. MEG localization yield was greater in patients with neocortical epilepsy (92%) than in those with mesial temporal lobe epilepsy (50%). In 5 of 6 patients with focal epileptogenic pathology, MEG spike sources were colocalized with the lesions. In 11 of 12 patients with nonlocalizing (ambiguous abnormalities or normal) MRI, MEG spike sources were localized in the region of the epileptogenic zone as ultimately defined by all clinical and EEG information (including intracranial EEG). In conclusion, MEG can reliably localize sources of spike discharges in patients with temporal and extratemporal lobe epilepsy. MEG sometimes provides noninvasive localization data that are not otherwise available with MRI or conventional scalp ictal EEG.
Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys
Authors: Chugani Diane C. , Muzik Otto , Rothermel Robert , Behen Michael , Chakraborty Pulak , Mangner Thomas , Da Silva Edné A. , Chugani Harry T.
Published: January 2005

Based on reports of increased platelet serotonin in 30 to 50% of autistic subjects, abnormal serotonergic neurotransmission may be important in the pathogenesis of autism. However, serotonin metabolite measurements in cerebrospinal fluid of autistic subjects have failed to demonstrate consistent abnormalities. Using α‐[11C]methyl‐L−tryptophan as a tracer for serotonin synthesis with positron emission tomography, we now report unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Asymmetries of serotonin synthesis were found in frontal cortex, thalamus, and dentate nucleus of the cerebellum in all 7 boys, but not in the 1 autistic girl studied. Decreased serotonin synthesis was found in the left frontal cortex and thalamus in 5 of the 7 boys and in the right frontal cortex and thalamus in the 2 remaining autistic boys. In all 7 cases, elevated serotonin synthesis in the contralateral dentate nucleus was observed. Statistically significant differences between autistic boys and their nonautistic siblings (n = 5) were obtained when comparing asymmetry indices for frontal cortex, thalamus, and dentate nucleus combined as well as individually for frontal cortex and thalamus. These serotonergic abnormalities in a brain pathway, important for language production and sensory integration, may represent one mechanism underlying the pathophysiology of autism.
Idiopathic torsion dystonia linked to chromosome 8 in two mennonite families
Authors: Almasy L. , Bressman S. B. , Raymond D. , Kramer P. L. , Greene P. E. , Heiman G. A. , Ford B. , Yount J. , De Leon D. , Chouinard S. , Saunders‐Pullman R. , Brin M. F. , Kapoor R. P. , Jones A. C. , Shen H. , Fahn S. , Risch N. J. , Nygaard T. G.
Published: January 2005

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb‐onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult‐onset, and predominantly cranial–cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial–cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40−cM segregates with ITD in these families, suggesting a shared mutation from the recent past.
Long‐term stroke risk in children with sickle cell disease screened with transcranial doppler
Authors: Adams R. J. , McKie V. C. , Carl E. M. , Nichols F. T. , Perry R. , Brock K. , McKie K. , Figueroa R. , Litaker M. , Weiner S. , Brambilla D.
Published: January 2005

Stroke is an important complication of sickle cell disease. Stroke prediction is clinically important because it offers the possibility of primary prevention. In 1992, transcranial Doppler (TCD) evidence of elevated intracranial internal carotid or middle cerebral artery velocity was demonstrated to be associated strongly with an increased risk of ischemic stroke. This study extends the original study and includes 125 more children, longer follow‐up, and intracranial hemorrhage in the stroke‐risk model. Elevated time averaged mean maximum blood flow velocity, especially when velocity is 200 cm/sec or greater by TCD, was associated strongly with stroke risk. The cases not predicted by TCD point to the need for more information on the optimal timing of TCD surveillance for stroke risk.
Clinical and magnetic resonance imaging findings in batten disease: Analysis of the major mutation (1.02‐kb deletion)
Authors: Järvelä Irma , Autti Taina , Lamminranta Sirkka , Åberg Laura , Raininko Raili , Santavuori Pirkko
Published: January 2005

A total of 36 patients with Batten disease (juvenile‐onset neuronal ceroid lipofuscinosis), homozygous or heterozygous for the major mutation, a 1.02‐kb deletion, in the CLN3 gene, were studied to relate their genotype to their clinical phenotype. The onset of visual failure and epilepsy was highly concordant in both groups. Great inter and intrafamilial heterogeneity was demonstrated in the development of mental and physical handicap and in magnetic resonance imaging findings among both homozygous and heterozygous patients. The 1.02‐kb deletion in homozygous form was always associated with mental and physical handicap, whereas the heterozygous phenotype could be extremely benign without affecting the intellectual level of the patient. Our data suggest that genetic background, modifying genes, and environmental factors all influence the final phenotype of Batten disease.
Presurgical multimodality neuroimaging in electroencephalographic lateralized temporal lobe epilepsy
Authors: Knowlton Robert C. , Laxer Kenneth D. , Ende Gabriele , Hawkins Randall A. , Wong Stephen T. C. , Matson Gerald B. , Rowley Howard A. , Fein George , Weiner Michael W.
Published: January 2005

The purpose of this study was to compare 2hyphen;[18F]fluoro‐2‐deoxy−D−glucose positron emission tomography (FDG‐PET), hippocampal volumetry (HV), T2 relaxometry, and proton magnetic resonance spectroscopic imaging (1H‐MRSI) in the presurgical neuroimaging lateralization of patients with nonlesional, electroencephalogram (EEG)‐defined unilateral temporal lobe epilepsy (TLE). Twenty‐five patients were prospectively studied, along with age‐matched controls. T2 relaxometry examinations were performed in 13 patients. Comparison of FDG‐PET, HV, and 1H‐MRSI was possible in 23 patients. FDG‐PET lateralized 87% of patients, HV 65%, N‐acetyl aspartate (NAA)/(choline [Cho] + creatine [Cr]) 61% and [NAA] 57%. Combined HV and NAA/(Cho + Cr) results lateralized 83% of the patients, a value similar to PET. Of 10 patients with normal magnetic resonance imaging (MRI) scans, 2 were lateralized with HV, 6 with FDG‐PET, 4 with NAA/(Cho + Cr), and 3 with [NAA]. T2 relaxometry lateralized no patients without hippocampal atrophy. Bilateral abnormality was present in 29 to 33% of patients with 1H‐MRSI measures and 17% with HV. Only hippocampal atrophy correlated with postoperative seizure‐free outcome. FDG‐PET remains the most sensitive imaging method to correlate with EEG‐lateralized TLE. Both FDG‐PET and 1H‐MRSI can lateralize patients with normal MRI, but only the presence of relative unilateral hippocampal atrophy is predictive of seizure‐free outcome. Bilaterally abnorma; MRI and 1H‐MRSI measures do not preclude good surgical outcome.
Human immunodeficiency virus type 1 and its coat protein gp 120 induce apoptosis and activate JNK and ERK mitogen‐activated protein kinases in human neurons
Authors: Lannuzel Annie , Tardieu Marc , Hery Christiane , Barnier Jean Vianney , Vincent Jean Didier , Guibert Bernard , Van Tan Huynh , Gray Francoise
Published: January 2005

Detection of apoptotic neurons and microglial cells in the brains of human immunodeficiency virus type 1 (HIV‐1)‐infected patients has suggested that programmed cell death may be implicated in the physiolpathology of HIV‐1 encephalopathy. To analyze in vitro the intracellular signals induced by HIV‐1 in human neurons and the associated neuronal death, we tested cultured human central nervous system (CNS) cells for apoptosis induced by HIV‐1 and gp120 and for signaling pathways activated by gp120. HIV‐1 and gp120 induced apoptosis of neurons and microglial cells but not of astrocytes or transformed microglial cells. Gp120 activated c‐Jun N‐terminal kinase (JNK) and p42 extracellular regulated kinase (ERK) in primary CNS cells, with an early peak of activation at 2 to 5 minutes that was not present when pure microglial or astrocyte cultures were tested, followed by a late and sustained activation (10 and 60 minutes) in primary and enriched glial cell cultures as well as in transformed microglial cells. This demonstrates that gp120 could be an effector of HIV‐1‐induced apoptosis in the CNS and act directly on neuronal and glial cells.
Amyloid β‐protein deposition in the leptomeninges and cerebral cortex
Authors: Shinkai Yasuhisa , Morishima‐Kawashima Maho , Ihara Yasuo , Yoshimura Masahiro , Shimada Hiroyuki , Ito Yuji , Yanagisawa Katsuhiko
Published: January 2005

To further investigate the process of amyloid β‐protein (Aß) deposition, we determined, using sensitive enzyme immunoassays, the levels of Aβ40 and Aβ42 (Aβs) in the soluble and insoluble fractions of the leptomeninges (containing arachnoid mater and leptomeningeal vessels) and cerebral cortices from elderly control subjects showing various stages of Aβ deposition and from patients affected by Alzheimer's disease (AD). In both locations, insoluble Aβ levels were higher by ordersof magnitude than soluble Aβ levels. Soluble Aβ levels. Soluble Aβ levels in cortices were much lower than those in leptomeninges. In insoluble Aβ in the cortex, Aβ42 was by far the predominant species, and Aβ42 in AD cortices was characterized by the highest degree of modifications in the amino terminus. In contrast, this Aβ42 predominance was not observed in insoluble Aβ in the leptomenings, which were found to be able to accumulate Aβs to an extent similar to that in the cortex, on a weight basis. The levels of insoluble Aβ in the leptomeninges or cortex generally correlated with the degree of cerebral amyloid angiopathy or the abundance of senile plaque, respectively. However, the presence of plaque‐free cortical samples showing significant levels of insoluble Aβ42 suggests that biochemically detectable Aβ accumulation precedes immunocytochemically detectable Aβ deposition in the cortex.
A triethnic comparison of intracerebral hemorrhage mortality in Texas
Authors: Morgenstern Lewis B. , Spears William D.
Published: January 2005

Intracerebral hemorrhage (ICH) is a significant cause of stroke death. Little is known about the relative risk of Hispanic Americans (HAs), African Americans (AAs), and non‐Hispanic whites (NHWs) for ICH mortality. Based on the high prevalence of hypertension in AAs and the low prevalence of hypertension in HAs, we expected AAs to have the highest ICH mortality rates and HAs the lowest. Race/ethnic age‐specific ICH mortality rates were calculated from Texas vital statistics for the years 1980 through 1995. Rate ratios (RRs) are reported with NHWs as the referent group. There were 15,042 deaths due to ICH in Texas during this time. In the 45‐ to 59‐year age group, AAs had an RR of 4. The RR for HAs was 1.9. In the 60hyphen; to 74‐year age range, AAs had an RR of 1.7 and HAs had an RR of 1.3. In the 75+ age group, the rates were similar among all three race/ethnic groups. We conclude that there is a significant interaction of age and race/ethnicity for ICH. At younger ages, AAs and HAs have the highest ICH mortality rates. Access to care and socioeconomic status may play a role in the unexpectedly high ICH mortality rates in HAs.
Detection of 14‐3‐3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt‐Jakob disease
Authors: Zerr Inga , Bodemer Monika , Gefeller Olaf , Otto Markus , Poser Sigrid , Wiltfang Jens , Windl Otto , Kretzschmar Hans A. , Weber Thomas
Published: January 2005

The analysis of 14‐3‐3 protein in cerebrospinal fluid (CSF) was shown to be highly sensitive and specific for the diagnosis of Creutzfeldt‐Jakob disease (CJD). However, the predictive value of this test in the clinical diagnosis of, and its relation to, sporadic, genetic, and iatrogenic CJD cases have yet to be established. CSF samples of suspect CJD cases seen in the prospective German surveillance study were tested for the presence of 14‐3‐3 protein by using a modified western blot (WB) technique. WB detected 14‐3‐3 protein in 95.4% of definite and 92.8% of probable cases. In two patients classified initially as not having CJD the test was positive, and both were later proved to have definite CJD. The positive predictive value is 94.7% and the negative predictive value is 92.4%. False‐positive results in a single CSF analysis were seen in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and progressive dementia of unknown cause. WB analysis for 14‐3‐3 protein was positive in only 5 of 10 cases of familial forms of spongiform encephalopathies. CSF analysis for 14‐3‐3 protein should thus be performed in any case suspect for CJD.
Physiological characterization of taxol‐induced large‐fiber sensory neuropathy in the rat
Authors: Cliffer Kenneth D. , Siuciak Judith A. , Carson Susan R. , Radley Heather E. , Park John S. , Lewis Dacie R. , Zlotchenko Elizabeth , Nguyen Trang , Garcia Karen , Tonra James R. , Stambler Nancy , Cedarbaum Jesse M. , Bodine Sue C. , Lindsay Ronald M. , Distefano Peter S.
Published: January 2005

The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose‐related peripheral neuropathy in humans. We produced a dose‐dependent large‐fiber sensory neuropathy, without detrimental effects on general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H‐wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail‐flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol‐induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.
Cytochrome c Oxidase subunit I microdeletion in a patient with motor neuron disease
Authors: Comi Giacomo P. , Bordoni Andreina , Salani Sabrina , Franceschina Liliana , Sciacco Monica , Prelle Alessandro , Fortunato Francesco , Zeviani Massimo , Napoli Laura , Bresolin Nereo , Moggio Maurizio , Ausenda Carlo D. , Taanman Jan‐Willem , Scarlato Guglielmo
Published: January 2005

An out‐of‐frame mutation of the mitochondrial DNA‐encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron‐like degeneration. The mutation is a heteroplasmic 5‐bp microdeletion located in the 5′ end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single‐fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease(MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by‐product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.
Association between the gene encoding the E2 subunit of the α‐ketoglutarate dehydrogenase complex and Parkinson's disease
Authors: Kobayashi Tomonori , Matsumine Hiroto , Matuda Sadayuki , Mizuno Yoshikuni
Published: January 2005

Dihydrolipoamide succinyltransferase (E2, EC 2.3.1.61, chromosome 14q24.2–3) is a specific subunit of human α‐ketoglutarate dehydrogenase complex (KGDHC). A biallelic intragenic polymorphism was identified in E2 gene of KGDHC. It was a single nucleotide substitution between G (in allele 1) and A (in allele 2) at the position that does not change amino acid code. Using this intragenic polymorphism as a marker, we investigated the association between this gene and Parkinson's disease. Frequencies of the genotypes that carry allele 2 were significantly higher in the Parkinson's disease group than in the control group. The results indicated that a genetic variant of the E2 gene itself or in close proximity to the gene constitutes one of the genetic risk factors for Parkinson's disease.
Amyloid angiopathy in a volga german family with Alzheimer's disease and a presenilin‐2 mutation (N141I)
Authors: Nochlin David , Bird Thomas D. , Nemens Ellen J. , Ball Melvyn J. , Sumi S. Mark
Published: January 2005

We report the neuropathological features in 6 members of a Volga German family with autosomal dominant Alzheimer's disease linked to chromosome 1 who had a presenilin‐2 mutation (N141I). The most significant feature in this family was the presence of severe or moderately severe amyloid angiopathy in five family members with clinical dementia. The index case with the presenilin‐2 mutation had late‐onset dementia at age 73 years, died of an acute intracerebral hemorrhage, and pathologically showed severe amyloid angiopathy but only rare neuritic senile plaques and neurofibrillary tangles. That she was apolipoprotein E ϵ2/3 heterozygous suggests that the ϵ2 allele may have exerted a selective protective effect resulting in late onset relatively mild Alzheimer's disease despite severe amyloid angiopathy. This family emphasizes the need for more investigation into the role of presenilin mutation in amyloid deposition, especially in the cerebral vasculature, and the role of these changes in clinical dementia.
Localization of the giant axonal neuropathy gene to chromosome 16q24
Authors: Flanigan Kevin M. , Crawford Thomas O. , Griffin John W. , Goebel Hans H. , Kohlschütter Alfried , Ranells Judith , Camfield Peter R. , Ptáček Louis J.
Published: January 2005

Giant axonal neuropathy (GAN) is a degenerative disorder of the peripheral nerves that is inherited as an autosomal recessive trait, presenting in early childhood and progressing to death, usually by late adolescence. Diagnosis is made by peripheral nerve biopsy, in which a striking pathological finding is seen—fibers distorted by giant axonal swellings filled with densely packed bundles of neurofilaments (the primary intermediate filament in neurons), with segregation of other axoplasmic organelles. In addition to disorganized neurofilaments in nerve, disorganization of other members of the intermediate filament family of proteins is seen in other tissues; this implies that the underlying defect is one of generalized intermediate filament organization, with neurofilaments predominantly affected. We have pursued a genomewide search for regions of homozygosity of descent in 5 consanguineous families. A 5.3‐cM region of homozygosity, shared in all 5 families, was found on chromosome 16q24, and linkage was established to this locus with a LOD score of 4.18 at Θ = 0.00 at the most tightly linked marker, D16S3098. Determination of this locus is the first step toward characterizing the gene responsible for a fundamental property of intermediate filament organization and may shed light on other disorders (such as amyotrophic lateral sclerosis) in which neurofilament pathology is prominent.
Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure
Authors: Benarroch Eduardo E. , Smithson Inge L. , Low Phillip A. , Parisi Joseph E.
Published: January 2005

The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including the C1/A1 groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular outflow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [TH]‐positive) neurons of the VLM are depleted in these patients. Medullas were obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was immersion fixed in 2% paraformaldehyde at 4°C for 24 hours and cut into 1‐cm blocks in the coronal plane from throughout the medulla. Serial 50‐μm sections were collected and one section every 300 μm was stained for TH. There was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may provide a substrate for some of the autonomic and endocrine manifestations of MSA.
[11C]Raclopride‐PET studies of the Huntington's disease rate of progression: Relevance of the trinucleotide repeat length
Authors: Antonini Angelo , Leenders Klaus L. , Eidelberg David
Published: January 2005

We used [11C]raclopride and positron emission tomography (PET) to assess the relationship between striatal dopamine D2 receptor binding, trinucleotide repeat number (CAG), and subject age in 10 asymptomatic and 8 symptomatic carriers of the Huntington's disease (HD) mutation. In both preclinical and symptomatic gene carriers, we found significant correlations between CAG repeat length and the ratio of percent loss in striatal D2 receptor binding divided by age. In accord with neuropathological studies, we obtained an intercept at 35.5 CAG repeats in the symptomatic HD patients. Nontheless, we noted that the slopes of the correlation lines differed significantly for the presymptomatic and symptomatic cohorts. These PET results support the notion that the HD disease process is a function of trinucleotide length and age, and that the development of clinical signs and symptoms is associated with CAG repeat lengths greater than 35.5. However, our analysis also suggests that striatal degeneration may proceed in a nonlinear fashion. These findings have implications for the design of neuroprotective strategies for the treatment of HD.
Facioscapulohumeral dystrophy: A distinct regional myopathy with a novel molecular pathogenesis
Authors: Tawil Rabi , Figlewicz Denise A. , Griggs Robert C. , Weiffenbach Barbara ,   The FSH Consortium
Published: January 2005

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of muscle. Until recently, FSHD had received little attention because of its relatively benign course and the perception that it represented a syndrome rather than a distinct myopathy. Research interest into this disease was reignited with the demonstration of linkage of FSHD to chromosome 4q35 in 1990. Clinical and molecular genetic research in FSHD has since helped define it as a distinct clinical entity, outlined its natural history, and defined the primary molecular defect associated with the condition. FSHD is now known to be associated with large deletions of variable size on chromosome 4q35. These deletions, however, do not appear to disrupt a transcribed gene but are thought to interfere with the expression of a gene or genes located proximal to the deletions. These observations complicate the search for the FSHD gene but also imply the presence of a potentially novel molecular pathognesis.