bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of terguride, a partial D2 agonist, on MPTP‐lesioned parkinsonian cynomolgus monkeys
Authors: Akai Tetsuo , Yamaguchi Motonori , Mizuta Eiji , Kuno Sadako
Published: January 2005

Behavioral effects of terguride, a partial dopamine D2 agonist, on 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–lesioned parkinsonian cynomolgus monkeys were compared with those of the dopamine agonist apomorphine and the dopamine antagonist haloperidol. Terguride alone ameliorated the parkinsonism without inducing any sign of excitability, irritability, or aggressiveness (hyperactivity). Apomorphine alone also ameliorated the parkinsonism but induced marked hyperactivity. Haloperidol alone caused worsening of the parkinsonism, inducing transient eyelid closure. In combination with apomorphine, terguride suppressed the hyperactivity induced by apomorphine without reducing its antiparkinsonian effets. Pretreatment with haloperidol suppressed both the antiparkinsonian effects and the hyperactivity induced by apomorphine. Terguride thus exhibits both antiparkinsonian and antihyperactivity effects in a monkey model of Parkinson's disease, suggesting that terguride might be beneficial for treating motor dysfunction and dopaminergic psychosis in advanced Parkinson's disease.
Skew deviation with ocular torsion: A vestibular brainstem sign of topographic diagnostic value
Authors: Brandt Thomas , Dieterich Marianne
Published: January 2005

Fifty‐six patients with unilateral brainstem infarctions presenting with skew deviation of the eyes were analyzed for static vestibular function in the roll plane. Ischemic lesions were allocated to the level and side of the brainstem by the clinical syndrome and neuroimaging. Two findings of clinical relevance were obtained: (1) All skew deviations were ipsiversive (ipsilateral eye was undermost) with caudal pontomedullary lesions and contraversive (contralateral eye was lowermost) with rostral pontomesencephalic lesions. (2) All skew deviations were associated with concomitant ocular torsion and tilts of subjective visual vertical toward the undermost eye. Thus, skew deviation or more correctly, ocular skew torsion is a sensitive brainstem sign of localizing and lateralizing value. Evidence is presented that the ocular skew torsion sign indicates a vestibular tone imbalance in the roll plane secondary to graviceptive pathway lesions.
Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel
Authors: Engel Andrew G. , Uchitel Osvaldo D. , Walls Timothy J. , Nagel Alexander , Harper C. Michael , Bodensteiner John
Published: January 2005

We describe here a new congenital myasthenic syndrome associated with a kinetic abnormality of the acetylcholine receptor (AChR) channel. The propositus had poor suck and cry after birth. Subsequently, she had intermittent ocular symptoms and fatigued abnormally on exertion. At age 9 years, significant weakness was detected only in the frontalis, levator palpebrae, and neck flexor muscles. Electromyography showed no decrement in limb muscles but single‐fiber examination of the facial muscles was consistent with a neuromuscular transmission defect. The ocular symptoms responded partially to pyridostigmine, but the abnormal fatigability did not. Tests for anti‐AChR antibodies were negative. A younger sister had elements of the same disease. An intercostal muscle specimen was obtained from the propositus at age 9 years for endplate studies. The quantal content of the endplate potential was normal. Miniature endplate currents were abnormally large and their decay time constant was abnormally short. AChR channel properties were studied by analysis of acetylcholine‐induced current noise. The mean single‐channel conductance was increased 1.7‐fold and the mean channel open time was 30% shorter than normal. The number of AChR per endplate was normal. Electron microscopy of most endplates showed no abnormality, but a few were degenerating or simplified. The channel abnormality may stem from a point mutation in an AChR subunit affecting a single amino acid residue lining the pore of the AChR channel. The mechanism by which the physiological abnormality produces clinical symptoms is not known, but possible explanations are considered.
Serum antibodies to GM1, GD1b, peripheral nerve myelin, and Campylobacter jejuni in patients with Guillain‐Barré syndrome and controls: Correlation and prognosis
Authors: Vriesendorp Francine J. , Mishu Ban , Blaser Martin J. , Koski Carol L.
Published: January 2005

Serum antibodies to monosialoganglioside (GM1), disialoganglioside (GD1b), and Campylobacter jejuni, measured by enzyme‐linked immunosorbent assay and serum antibodies to peripheral nerve myelin, measured by the C1 fixation and transfer assay, were studied in 58 acute‐phase patients with Guillain‐Barré syndrome (GBS), 42 disease controls, and 29 normal controls. Anti‐peripheral nerve myelin antibodies were elevated in 57 of 58 patients with GBS compared with controls, whereas only 8.6% had increased antibody titers to GM1 and 10.3% to GD1b. Only low antibody titers (GM1) or no antibodies (GD1b) were found in controls. More GBS patients (17.2%) than controls (7%) had antibodies to C jejuni. Poor recovery with inability to walk at 1 year after onset of symptoms was seen in 3 (5%) of the patients with GBS. All 3 patients had serological evidence of recent C jejuni infection but no antibodies to GM1 or GD1b. GBS patients with antibodies to GM1 or GD1b had excellent recovery. Our data indicate that antibodies to GM1 or GD1b do not necessarily mediate the extensive axonal damage seen in these severely affected patients.
Positron emission tomographic findings in Filipino X‐linked dystonia–parkinsonism
Authors: Eidelberg D. , Takikawa S. , Wilhelmsen K. , Dhawan V. , Chaly T. , Robeson W. , Dahl R. , Margouleff D. , Greene P. , Hunt A. , Przedborski S. , Fahn S.
Published: January 2005

Regional and global metabolic rates for glucose (rCMRGlc and GMR) were estimated using [18F]fluorodeoxyglucose and positron emission tomography in 3 patients with Filipino X‐linked dystonia‐parkinsonism (lubag). In all 3 patients a selective reduction in normalized striatal glucose metabolism (rCMRGlc/GMR) was observed compared with 15 normal volunteer subjects. Presynaptic nigrostriatal function was assessed in these patients using [18F]fluorodopa and positron emission tomography. Striatal rate constants for [18F]fluorodopa uptake were found to be in the normal range in all 3 patients with lubag. These findings suggest that the extrapyramidal manifestations of lubag are metabolically localized to the striatum and that clinical parkinsonism in these patients may be secondary to extranigral factors.
The polymerase chain reaction in the diagnosis of Lyme neuroborreliosis
Authors: Pachner Andrew R. , Delaney Elizabeth
Published: January 2005

The polymerase chain reaction is sensitive and specific in the detection of defined DNA sequences and holds promise for diagnosing the presence of fastidious microorganisms in human infectious diseases. We developed a methodology for nested polymerase chain reaction and hybridization analysis of the cerebrospinal fluid using primers from a genomic Borrelia burgdorferi sequence and applied it to the cerebrospinal fluid (CSF) of patients suspected of having Lyme neuroborreliosis and other diseases. Polymerase chain reaction and hybridization demonstrated extremely high sensitivity for spirochetal DNA, and was highly specific, with a false‐positivity rate of less than 3%. However, the results were negative or indeterminate in 54% of CSF samples from patients with definite or probable disease, indicating an absence, or extremely low level, of spirochetes or spirochetal DNA in a significant percentage of patients with Lyme neuroborreliosis. Polymerase chain reaction and hybridization of the CSF can thus be considered a useful adjunct in diagnosis, but its negativity does not rule out Lyme neuroborreliosis.
β‐Amyloid precursor epitopes in muscle fibers of inclusion body myositis
Authors: Askanas Valerie , Alvarez Renate B. , Engel W. King
Published: January 2005

Sporadic inclusion body myositis (IBM) and hereditary inclusion body myopathy (hIBM) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers that contain 15‐ to 21‐nm cytoplasmic tubulofilaments (CTFs). Those vacuolated muscle fibers also contain abnormally accumulated ubiquitin and β‐amyloid protein (Aβ), and they contain amyloid in β‐pleated sheets as indicated by Congo red and crystal violet positivity. Using several well‐characterized antibodies, we have now demonstrated that, in addition to Aβ, two other epitopes, N‐terminal and C‐terminal, of the β‐amyloid precursor protein (βPP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, immunoreactivities of N‐ and C‐epitopes of βPP closely colocalized with Aβ and ubiquitin immunoreactivities. However, by immunogold electronmicroscopy, even though N‐, C‐, and Aβ epitopes of βPP and ubiquitin colocalized at the amorphous and dense floccular structures, only Aβ was localized to the 6‐ to 10‐nm amyloid‐like fibrils and only ubiquitin was localized to CTFs. βPP immunoreactive structures were often in proximity to CTFs, but CTFs themselves never contained βPP immunoreactivities. The fact that Aβ but not C‐ or N‐terminal epitopes of βPP localized to the 6‐ to 10‐nm amyloid‐like fibrils suggests that free Aβ might be generated during βPP processing and, after aggregation, may be responsible for the amyloid present within IBM muscle fibers. Our study demonstrates that three epitopes of βPP accumulate abnormally in diseased human muscle, and therefore this phenomenon is not unique to Alzheimer's disease, Down's syndrome brain, and Dutch‐type cerebrovascular amyloidosis.
Procedural learning in Parkinson's disease and cerebellar degeneration
Authors: Pascual‐Leone A. , Grafman J. , Clark K. , Stewart M. , Massaquoi S. , Lou J‐S. , Hallett M.
Published: January 2005

We compared procedural learning, translation of procedural knowledge into declarative knowledge, and use of declarative knowledge in age‐matched normal volunteers (n = 30), patients with Parkinson's disease (n = 20), and patients with cerebellar degeneration (n = 15) by using a serial reaction time task. Patients with Parkinson's disease achieved procedural knowledge and used declarative knowledge of the task to improve performance, but they required a larger number of repetitions of the task to translate procedural knowledge into declarative knowledge. Patients with cerebellar degeneration did not show performance improvement due to procedural learning, failed to achieve declarative knowledge, and showed limited use of declarative knowledge of the task to improve their performance. Both basal ganglia and cerebellum are involved in procedural learning, but their roles are different. The normal influence of the basal ganglia on the prefrontal cortex may be required for timely access of information to and from the working memory buffer, while the cerebellum may index and order events in the time domain and be therefore essential for any cognitive functions involving sequences.
Recurrent ascending myelitis: An unusual presentation of herpes simplex virus type 1 infection
Authors: Shyu Woei‐Cherng , Lin Jiann‐Chyun , Chang Bao‐Chy , Harn Horng‐Jyh , Lee Chan‐Chin , Tsao Wen‐Long
Published: January 2005

We report on a healthy female with a unique relapsing transverse myelitis accompanied by herpes simplex virus type 1 (HSV‐1) infection. Magnetic resonance imaging showed cord enlargement and increased signal intensity on T1‐weighted image with gadolinium enhancement from T‐4 to T‐10 during the first attack and from C‐1 to C‐2 during the second episode. She was not diagnosed during the first attack. During the second episode, laboratory studies disclosed IgM and IgG antibodies to HSV at the outset with greater than fourfold increases in antibody levels in the serum and cerebrospinal fluid (CSF). Cells cultured from the CSF were positive for HSV‐1 according to the immunofluoresecnce method. The presence of HVS‐1 DNA in CSF was documented by polymerase chain reaction (PCR) technique. Acylovir was given with a partial recovery. We anticipate that PCR assay of CSF will assist early diagnosis of herpetic central nervous system disorders.
Disequilibrium of unknown cause in older people
Authors: Fife Terry D. , Baloh Robert W.
Published: January 2005

Many older people complain of a sense of unsteadiness when standing or walking and many are fearful of falling. The cause of this disequilibrium is often difficult to determine even after thorough clinical evaluation. To better understand the pathogenesis of this symptom in a community‐dwelling population, we studied 26 patients >75 years old who complained of disequilibrium in whom no cause was evident after clinical evaluation. Each patient and each of 26 age‐matched controls underwent a comprehensive evaluation that included a history and examination, a questionnaire, functional scales, a gait and balance scale, mini‐mental state testing, audiometry, visual acuity, visual tracking, rotational vestibular testing, and quantitative posturography. Although none had Romberg's sign, patients tended to sway more and do poorer on semiquantitative gait and balance testing than did controls. Patients showed few differences from controls for most other measurements. However, 7 patients, designated Group V, had profoundly reduced vestibular function. In the remaining 19 patients (Group D), the average vestibular function was still significantly lower than controls. Sway velocity measured with posturography was increased in the patients compared with controls, particularly in Group V patients. Measures of vestibular function correlated with increased sway velocity both in Group D alone and among all study participants. Quantitative measurement of vestibular function should be considered in older people complaining of disequilibrium, particularly if the cause is not apparent after the initial evaluation.
Short‐term response to dietary therapy in molybdenum cofactor deficiency
Authors: Boles Richard G. , Ment Laura R. , Meyn M. Stephen , Horwich Arthur L. , Kratz Lisa E. , Rinaldo Piero
Published: January 2005

Molybdenum cofactor deficiency was diagnosed in a 3‐month‐old girl who presented with microcephaly, developmental delay, severe irritability, and lactic acidosis. Dietary methionine restriction, with cysteine supplementation, was associated with moderate short‐term clinical improvement, including a resumption in predicted head growth, modest developmental progress, and a reduction in irritability. Clinical relapse was associated with noncompliance of dietary therapy 2 months later. Urinary sulfite levels measured by commercial dipsticks were useful in following therapy. Molybdenum cofactor deficiency is probably frequently underdiagnosed due to the lack of specific clinical or laboratory features. Screening of infants at risk for the presence of urinary sulfites or serum hypouricemia, or both, is both rapid and inexpensive.
A new inherited prion disease (PrP‐P105L mutation) showing spastic paraparesis
Authors: Kitamoto Tetsuyuki , Amano Naoji , Terao Yasu , Nakazato Yoshihiko , Isshiki Toshiyuki , Mizutani Tomohiko , Tateishi Jun
Published: January 2005

We report the clinicopathological findings of 5 patients with an inherited prion disease with a codon 105 (Pro to Leu) mutation. All of the patients had a spastic gait disturbance and progressive dementia without either cerebellar signs, myoclonus, or periodic synchronous discharges. Autopsy of 3 patients revealed numerous amyloid plaques in the cerebral cortex, especially in the motor cortex and the frontal lobe where neuronal loss and severe gliosis were observed in the absence of spongiform changes. The cerebellum was preserved histologically except for only a few amyloid plaques. The pyramidal tracts in the brainstem and spinal cord showed vacuolated changes and a loss of myelin, but no prion protein accumulations. Thus, the prion protein codon 105 mutation is considered to correspond to a new variant to the Gerstmann‐Sträussler syndrome with spastic paraparesis.
Familial parkinsonism with depression: A clinicopathological study
Authors: Bhatia K. P. , Daniel S. E. , Marsden C. D.
Published: January 2005

A family with autosomal dominant inheritance of an early‐onset and rapidly progressive parkinsonian syndrome and associated severe depression is reported. Three members had parkinsonism with depression, 3 had parkinsonism alone, and 2 suffered depression only. Pathological brain examination in 2 members with parkinsonism and depression revealed distinctive changes, with devastation of the substantia nigra, scarce Lewy bodies, and gliosis of the caudate nucleaus and globus pallidus. The clinical and pathological findings were similar to those in four previously described families with autosomal dominant parkinsonism, depression, and alveolar hypoventilation.
Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes
Authors: Thornton Charles A. , Johnson Keith , Moxley Richard T.
Published: January 2005

The genetic basis of myotonic dystrophy is an unstable expansion of CTG repeats located in a gene on chromosome 19 that encodes a putative serine/threonine protein kinase. We studied the somatic mosaicism of the (CTG)n expansion in myotonic dystrophy patients. (CTG)n expansions were 2‐to 13‐fold greater in DNA isolated from skeletal muscle than in DNA from leukocytes in 10 of 11 patients with myotonic dystrophy. Different muscles of the same individual showed similar (CTG)n expansions. In postmortem tissues from an adult patient, (CTG)n expansions in brain, skeletal muscle, cardiac muscle, testes, and liver were all greater than in leukocytes. Normal myotonic dystrophy gene alleles from 7 healthy subjects had the same number of CTG repeats in leukocytes and muscle. The myotonic dystrophy mutation displays pronounced heterogeneity in somatic cells. The (CTG)n expansion observed in peripheral blood leukocytes is not necessarily representative of the repeat expansion in affected tissues, such as skeletal muscle and myocardium. In some patients with myotonic dystrophy, the predictive value of genetic analysis based on leukocyte DNA may be limited.
Absence of hereditary mutations in exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene in families with glioma
Authors: van Meyel Donald J. , Ramsay David A. , Chambers Ann F. , Macdonald David R. , Cairncross J. Gregory
Published: January 2005

Inherited mutations of the p53 and neurofibromin genes are thought to cause two distinct neoplastic disorders in which gliomas occur, the Li‐Fraumeni syndrome and neurofibromatosis type 1. We investigated the possibility that inherited mutations in specific regions of these genes also contributed to the clustering of gliomas in otherwise normal families. Twenty‐six members of 16 families with glioma were screened for germline mutations of exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene using a polymerase chain reaction–single‐strand conformation polymorphism method. No germline mutations were found, suggesting that the genetic basis of familial glioma is distinct from that of gliomas occurring in the Li‐Fraumeni syndrome, and that inherited mutations of the catalytic domain of neurofibromin do not predispose affected glioma families to these tumors.
The clinical correlates of high‐titer IgG anti‐GM1 antibodies
Authors: Kornberg Andrew J. , Pestronk Alan , Bieser Karen , Ho T. W. , McKhann G. M. , Wu H. S. , Jiang Z.
Published: January 2005

Serum IgG anti‐GM1 antibodies have been reported to occur in a variety of disorders, including Guillain‐Barré syndrome and chronic polyneuropathies. Of over 5,000 serums tested in our laboratory, high titers of selective IgG anti‐GM1 antibodies (>1: 1,000) and without binding to sulfatide were found in 35 patients. Clinical correlation revealed that almost all patients had axonal, motor neuropathies. One subgroup was comprised of individuals with an acute motor neuropathy, described either as an acute axonal Guillain‐Barré–like syndrome that was occasionally associated with a prodrome of Campylobacter jejuni enteritis or as Chinese paralysis syndrome. A second group of patients had chronic asymmetric lower motor neuron (LMN) syndromes with no conduction block or other evidence of demyelination. The presence of selective high‐titer IgG anti‐GM1 antibody reactivity in serum is uncommon but when present is strongly associated with acute axonal motor neuropathies or chronic asymmetric LMN syndromes.
Prognostic value of myoclonus status in comatose survivors of cardiac arrest
Authors: Wijdicks Eelco F. M. , Parisi Joseph E. , Sharbrough Frank W.
Published: January 2005

Generalized myoclonus status is common in comatose patients after cardiac resuscitation, but its prognostic value is uncertain. We studied the clinical, radiologic, and pathologic findings in 107 consecutive patients who remained comatose after cardiac resuscitation. Myoclonus status was present in 40 patients (37%). Features more prevalent in patients with myoclonus status were burst suppression on electroencephalograms, cerebral edema or cerebral infarcts on computed tomography scans, and acute ischemic neuronal change in all cortical laminae. All patients with myoclonus status died. Of 67 patients without myoclonus, 20 awakened. We conclude that myoclonus status in postanoxic coma should be considered an agonal phenomenon that indicates devastating neocortical damage. Its presence in comatose patients after cardiac arrest must strongly influence the decision to withdraw life support.
Rapidly evolving myopathy with myosin‐deficient muscle fibers
Authors: Al‐Lozi M. T. , Pestronk A. , Yee W. C. , Flaris N. , Cooper J.
Published: January 2005

Five patients with rapidly evolving, severe weakness had an unusual myopathy with virtually complete loss of myosin in 5 to 40% of muscle fibers. Three of the 5 patients began to develop weakness 1 to 2 weeks after lung transplantation. The fourth became weak after a febrile illness. The fifth presented with diabetic ketoacidosis and weakness. All patients had received corticosteroid therapy. In all cases the weakness was progressive and led to severe disability, with respiratory failure in 4 patients. Initial diagnostic testing did not localize an underlying cause for the weakness. Creatine kinase was normal or minimally elevated. Electromyography generally showed mildly myopathic or nondiagnostic changes. However, muscle biopsy revealed numerous small angular fibers with no myosin ATPase staining at any pH. Immunocytochemical staining and ultrastructural studies confirmed a severe loss of myosin in many fibers. This rapidly evolving myopathy with myosin‐deficient muscle fibers appears to be different clinically and pathologically from previously described syndromes involving rapidly progressive weakness. Slow recovery over a period of months is the most common outcome.
Muscarinic antagonists in the treatment of acquired pendular and downbeat nystagmus: A double‐blind, randomized trial of three intravenous drugs
Authors: Barton Jason J. S. , Huaman Ana G. , Sharpe James A.
Published: January 2005

We performed a double‐blind, randomized trial of intravenous scopolamine, benztropine, and glycopyrrolate in 7 patients with acquired nystagmus and oscillopsia. Five patients had pendular nystagmus and 2, downbeat nystagmus. We recorded eye movements with a magnetic search coil technique and tested visual acuity and motion perception before and after administration of each drug. Scopolamine reduced nystagmus in all patients. Benztropine was moderately effective and glycopyrrolate had a negligible impact. Visual acuity improved only with scopolamine; motion discrimination and oscillopsia improved significantly with scopolamine and benztropine. Pendular and downbeat nystagmus respond to intravenous antagonists of central muscarinic receptors.
Magnetic resonance spectroscopy of N‐acetylaspartate in hypoxic–ischemic encephalopathy
Authors: Graham S. H. , Meyerhoff D. J. , Bayne L. , Sharp F. R. , Weiner M. W.
Published: January 2005

Magnetic resonance imaging and water‐suppressed proton magnetic resonance spectroscopic imaging were used to study N‐acetylaspartate and other metabolites in a patient with severe hypoxic–ischemic encephalopathy. The N‐acetylaspartate signal, a putative marker of neuronal density, was markedly reduced in the forebrain. The relative signal intensity of choline‐containing metabolites, which are more abundant in astrocytes than neurons, was increased. These results support the hypothesis that water‐suppressed proton magnetic resonance spectroscopic imaging measurements of N‐acetylaspartate may be useful for noninvasive detection of selective neuronal loss in a variety of disease states in the human brain.
Neurophysiological properties of pallidal neurons in Parkinson's disease
Authors: Sterio Djordje , Berić Aleksandar , Dogali Michael , Fazzini Enrico , Alfaro George , Devinsky Orrin
Published: January 2005

Neuronal properties of the human globus pallidus (GP) are not known. Since GP is the major output of the basal ganglia, it may be involved in the pathophysiology of Parkinson's disease. We studied 12 patients with medically resistant Parkinson's disease by using single cell recording of the GP during stereotaxic pallidotomy to define neuronal firing rate and its modulation during active and passive movements. Different frequency and pattern of single cell activity was found in globus pallidus externus compared with globus pallidus internus. Discharge rates of 19% of GP cells were modulated by passive contralateral movements. Pallidal units were most often related solely to single joint movement. Different patterns of activity in relation to the two different movements of the same joint were often observed. We identified somatotopically arranged cell clusters that alter discharge rate with related movements. These findings suggest at least a partial somatotopic organization of the human GP and similarity with experimental results in both healthy and MPTP monkeys, providing a rationale for surgical or pharmacological targeting of GP for treating Parkinson's disease.
Functional magnetic resonance imaging of human auditory cortex
Authors: Binder J. R. , Rao S. M. , Hammeke T. A. , Yetkin F. Z. , Jesmanowicz A. , Bandettini P. A. , Wong E. C. , Estkowski L. D. , Goldstein M. D. , Haughton V. M. , Hyde J. S.
Published: January 2005

Magnetic resonance imaging methods recently demonstrated regional cerebral signal changes in response to limb movement and visual stimulation, attributed to blood flow enhancement. We studied 5 normal subjects scanned while listening to auditory stimuli including nonspeech noise, meaningless speech sounds, single words, and narrative text. Imaged regions included the lateral aspects of both hemispheres. Signal changes in the superior temporal gyrus and superior temporal sulcus were observed bilaterally in all subjects. Speech stimuli were associated with significantly more widespread signal changes than was the noise stimulus, while no consistent differences were observed between responses to different speech stimuli. Considerable intersubject variability in the topography of signal changes was observed. These observations confirm the utility of magnetic resonance imaging in the study of human brain structure‐function relationships and emphasize the role of the superior temporal gyrus in perception of acoustic‐phonetic features of speech, rather than processing of semantic features.
Movement‐ and task‐related activations of motor cortical areas: A positron emission tomographic study
Authors: Remy Philippe , Zilbovicius Monica , Leroy‐Willig Anne , Syrota André , Samson Yves
Published: January 2005

Using repeated measurements of regional cerebral blood flow with positron emission tomography, we investigated the regional cortical activations induced in 10 normal subjects, by two different finger motor tasks, i.e., a repeated flexion–extension of all fingers and a repeated flexion–extension of the middle finger. The all‐finger movement only activated the primary sensorimotor cortex (SM) and the supplementary motor area (SMA) contralateral to the movement. However, the activation of the SMA was clearly task related during this motor task, because it was only observed when the movement was triggered by an auditory cue but not when it was self‐paced. The middle finger movement was performed during self‐paced conditions. It induced a much more complex pattern of activation than the all‐finger movement, characterized by a high degree of SM and SMA activation contralateral to the side of the movement, as well as a slight ipsilateral activation of these areas. We suggest that this pattern of cortical activation may reflect the process of individuating finger movement or the early stages of motor learning of this unusual and technically difficult movement. Our data also confirm that the SM activation is closely linked to the intrinsic parameters of the movement; while the SMA may be activated by different aspects of the movement realization and preparation.
Suppression of motor cortical excitability by electrical stimulation over the cerebellum in ataxia
Authors: Ugawa Yoshikazu , Genba‐Shimizu Kieko , Rothwell John C. , Iwata Makoto , Kanazawa Ichiro
Published: January 2005

We studied the effect of electrical stimulation over the cerebellum on electromyographic responses evoked by magnetic stimulation over the cerebral motor cortex in 14 normal volunteers and 32 patients with ataxia due to various disorders. In all the normal subjects, stimulation over the cerebellum significantly reduced the size of electromyographic response in the first dorsal interosseous muscle evoked by magnetic cortical stimulation, when the cerebellar stimulus preceded the cortical stimulus by 5, 6, and 7 msec. This suppression was absent or reduced in ataxic patients who had atrophy of the cerebellar hemispheres as demonstrated by magnetic resonance imaging and in patients with dysfunction of the cerebellothalamocortical pathway who had lesions in the superior cerebellar peduncle or in the motor thalamus. In contrast, suppression was normal in ataxic patients who had pontine lesions that affected the pontocerebellar afferent pathway to the cerebellum. Results were also normal in patients without cerebellar ataxia, such as those with Parkinson's disease, sensory ataxia, and cerebrovascular disease without ataxia. We conclude that electrical stimulation activates cerebellar structures that suppress motor cortical excitability through a cerebellothalamocortical pathway and that the afferent systems to the cerebellum make no or little contribution to the effect. The technique described here would be useful for distinguishing ataxia due to lesions of cerebellar afferent pathway from other types of cerebellar ataxia.
The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease
Authors: Mitsumoto Hiroshi , Ikeda Ken , Holmlund Tomas , Greene Tom , Cedarbaum Jesse M. , Wong Vivien , Lindsay Ronald M.
Published: January 2005

Ciliary neurotrophic factor is the first neurotrophic factor to show survival‐promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary neurotrophic factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary neurotrophic factor (n = 6) resulted in delayed weight gain (p <0.001), grip strength normalized to body weight in the factor‐treated mice was significantly greater (p <0.02) and declined at a slower rate (p < 0.05) compared to that in vehicle‐treated animals. Human ciliary neurotrophic factor (n = 27) produced no change in body weight and reduced paw position and walking pattern abnormalities (p < 0.001 and p < 0.02, respectively). After 4 weeks of treatment, the mean grip strength of human ciliary neurotrophic factor‐treated animals was twice as great (p < 0.001) and declined at a much slower rate (p <0.005) than that of control mice. The time required to run 2.5 ft was less (p < 0.005) and muscle twitch tension was greater (p < 0.002) in ciliary neurotrophic factor‐treated animals. Thus, ciliary neurotrophic factor retarded the disease progression and improved muscle strength in this motor neuron disease model.
Immune complex deposition in the choroid plexus of patients with acquired immunodeficiency syndrome
Authors: Falangola M. F. , Castro‐Filho B. G. , Petito C. K.
Published: January 2005

We identified immune complex deposits in the choroid plexus of approximately 75% of patients with acquired immunodeficiency syndrome (AIDS) who had either normal brains or human immunodeficiency virus encephalitis. Since circulating immune complexes are common in AIDS patients, and since local choroid plexus pathology usually was absent, their likely origin is from the bloodstream. Choroid plexus deposits of immune complexes have been implicated in altering the function of this structure or in enhancing its vulnerability to infection. Therefore, immune complex deposition in the choroid plexus of AIDS patients may be responsible for some of the common alterations in the cerebrospinal fluid and for the frequency of opportunistic infections in this region.
Trinucleotide repeat length and rate of progression of Huntington's disease
Authors: Illarioshkin Sergei N. , Igarashi Shuichi , Onodera Osamu , Markova Elena D. , Nikolskaya Natalya N. , Tanaka Hajime , Chabrashwili Tina Z. , Insarova Nina G. , Endo Kotaro , Ivanova‐Smolenskaya Irina A. , Tsuji Shoji
Published: January 2005

The Huntington's disease gene contains an expanded unstable (CAG)n repeat, and the repeat lengths have been shown to correlate with the age of onset. Using detailed clinical scales, we evaluated the rate of progression of Huntington's disease and its relationship to the number of triplet repeats. We found significant positive correlation between the rate of progression of clinical symptoms (both neurological and psychiatric) and CAG repeat length. These data suggest an important role of expanded trinucleotide repeat length in affecting the pathological process during the enitre course of Huntington's disease.
Dose‐dependent association of apolipoprotein e allele ε4 with late‐onset, sporadic Alzheimer's disease
Authors: Yoshizawa Toshihiro , Yamakawa‐Kobayashi Kimiko , Komatsuzaki Yasuko , Arinami Tadao , Oguni Ei'ichi , Mizusawa Hidehiro , Shoji Shin'ichi , Hamaguchi Hideo
Published: January 2005

We examined the apolipoprotein E (apo E) genotypes in 47 patients with late‐onset sporadic Alzheimer's disease (mean age at onset ± standard deviation, 72.2 ± 6.4 years), 8 with late‐onset familial Alzheimer's disease (75.5 ± 5.1 years), 18 with early‐onset sporadic Alzheimer's disease (52.8 ± 4.7 years), and 10 with early‐onset familial Alzhemer's disease (52.0 ± 6.8 years) in Japan and compared them with genotypes in control subjects. In late‐onset sporadic Alzheimer's disease, apo E‐ε4 frequency increased significantly (ε4 frequency: 0.34 vs 0.095 in controls, p < 0.0001), and the odds ratio, which represents the strength of association between Alzheimer's disease and apo E‐ε4 gene (3 [95% confidence interval, 2–6] in one dose; 43 [95% confidence interval, 12–154] in two doses). This study also suggested that apo E‐ε4 is associated with both late‐onset (ε4: 0.31) and early‐onset familial Alzheimer's disease (ε4: 0.35). In contrast, we found no association between apo E‐ε4 and early‐onset sporadic Alzheimer's disease (ε4: 0.08). These results indicate that the risk of developing late‐onset sporadic Alzheimer's disease is markedly dependent on the dose of apo E‐ε4, while apo E‐ε4 does not appear to be a major risk factor for early‐onset sporadic Alzheimer's disease.
In situ polymerase chain reaction demonstration of JC virus in progressive multifocal leukoencephalopathy, including an index case
Authors: Ueki Keisuke , Richardson Edward P. , Henson John W. , Louis David N.
Published: January 2005

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that is caused by JC papovavirus. The virus can be demonstrated in brains with PML using a variety of techniques. In situ polymerase chain reaction (PCR) is a new method that combines the sensitivity of PCR with the histological localization of in situ hybridization. We here show that in situ PCR can detect JC virus in archival tissue sections of 3 cases of PML, including 1 of the original cases described in 1958 and 1 case that was fixed in formalin for 7 weeks. JC virus DNA was amplified directly on tissue and demonstrated in the characteristic enlarged oligodendrocytes and bizarre astrocytes. These data illustrate the utility of the in situ PCR technique in detecting JC virus in archival sections, including those fixed for prolonged periods, and provide a historical footnote to the original report of PML.
Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease
Authors: Mecocci Patrizia , MacGarvey Usha , Beal M. Flint
Published: January 2005

Oxidative damage to DNA may play a role in both normal aging and in neurodegenerative diseases. We examined whether Alzheimer's disease (AD) is associated with increased oxidative damage to both nDNA and mtDNA in postmortem brain tissue. We measured the oxidized nucleoside, 8‐hydroxy‐2′‐deoxyguanosine (OH8dG), in DNA isolated from three regions of cerebral cortex and cerebellum in 13 AD and 13 age‐matched controls. There was a significant threefold increase in the amount of OH8dG in mtDNA in parietal cortex of AD patients compared with controls. In the entire group of samples there was a small significant increase in oxidative damage to nDNA and a highly significant threefold increase in oxidative damage to mtDNA in AD compared with age‐matched controls. These results confirm that mitochondrial DNA is particularly sensitive to oxidative damage, and they show that there is increased oxidative damage to DNA in AD, which may contribute to the neurodegenerative process.
Extracellular human T‐cell lymphotropic virus type I tax protein induces cytokine production in adult human microglial cells
Authors: Dhib‐Jalbut Suhayl , Hoffman Paul M. , Yamabe Toshio , Sun Di , Xia Jane , Eisenberg Howard , Bergey Gregory , Ruscetti Francis W.
Published: January 2005

Tropical spastic paraparesis (HAM/TSP) is caused by human T‐cell lymphotropic virus type I (HTLV‐I) infection. Although the virus infects T cells in vivo and is capable of infecting microglia in vitro, the inflammatory demyelination has not been linked to virus in central nervous system tissue. Thus, indirect mechanisms (e.g., cytokines) could be involved in demyelination and inflammation. The ability of HTLV‐I Tax protein to induce tumor necrosis factor‐α (TNF‐α), interleukin‐1 β (IL‐1β), and IL‐6 in primary adult human microglia and peripheral blood macrophages (PBMs) was examined by enzyme‐linked immunosorbent assay and reverse transcription–polymerase chain reaction (RT‐PCR). Tax (20 ng/ml) induced TNF‐α in microglia (from undetectable or low basal levels to 215–1,075 pg/ml, mean 576 ± 375 pg/ml, n = 4) and in PBMs (70‐1,900, mean 646 ± 844 pg/ml, n = 4). This induction was dose dependent, Tax specific, and maximal at 8 hours after stimulation. IL‐6 levels in microglia increased from a basal level of 368 ± 194 to 664 ± 270 pg/ml 24 hours after Tax stimulation. In contrast, IL‐1β levels were modestly induced (≤26 pg/ml). An increase in mRNA levels of the three cytokines was observed by semiquantitative RT‐PCR (TNF‐α = 28‐fold; IL‐6 = 5.6‐fold; IL‐1β = 3.6‐fold). Thus, in HAM/TSP, extracellular Tax released from infiltrating T cells could induce cytokine release by microglia and contribute to demyelination and inflammation in the absence of detectable virus.
Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher's syndrome
Authors: Yuki N. , Taki T. , Takahashi M. , Saito K. , Yoshino H. , Tai T. , Handa S. , Miyatake T.
Published: January 2005

We isolated Campylobacter jejuni from 2 patients with Fisher's syndrome subsequent to enteritis. Crude lipopolysaccharide fractions were extracted from the bacteria and separated by thin‐layer chromatography. Monoclonal antibodies to GQ1b ganglioside (GMR 13 and 7F5) reacted with both lipopolysaccharide fractions, indicating that the lipopolysaccharides bear the GQ1b epitope. This is the first report of molecular mimicry between neural tissue components and the antecedent infectious agents of Fisher's syndrome.
Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan
Authors: Muramatsu Taro , Higuchi Susumu , Arai Hiroyuki , Sasaki Hidetada , Yamada Koichi , Hayashida Motoi , Trojanowski John Q.
Published: January 2005

The apolipoprotein E ε4 allele has been associated with both familial and sporadic Alzheimer's disease (AD). Given its possible role in nerve repair and growth, it is plausible that apolipoprotein E may be a common denominator in the pathogenesis of several dementing diseases. Therefore, we investigated ε4 frequencies in demented and nondemented alcoholics, as well as in patients with sporadic AD and controls in Japan. No significant difference in allele frequencies was found between demented and nondemented alcoholics and controls, while a significant association was demonstrated between AD and the ε4 allele. These results support a specific role of ε4 in the pathogenesis of AD, rather than a more general role for ε4 in dementing illnesses.
Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line
Authors: Mosier Dennis R. , Baldelli Pietro , Delbono Osvaldo , Smith R. Glenn , Alexianu Maria E. , Appel Stanley H. , Stefani Enrico
Published: January 2005

The sporadic from of amyotrophic lateral sclerosis (ALS) is an idiopathic and eventually lethal disorder causing progressive degeneration of cortical and spinal motoneurons. Recent studies have shown that the majority of patients with sporadic ALS have serum antibodies that bind to purified L‐type voltage‐gated calcium channels and that antibody titer correlates with the rate of disease progression. Furthermore, antibodies purified from ALS patient sera have been found to alter the physiologic function of voltage‐gated calcium channels in nonmotoneuron cell types. Using wholecell patch‐clamp techniques, immunoglobulins purified from sera of 5 of 6 patients with sporadic ALS are now shown to increase calcium currents in a hybrid motoneuron cell line, VSC4.1. These calcium currents are blocked by the polyamine funnel‐web spider toxin FTX, which has previously been shown to block Ca2+ currents and evoked transmitter release at mammalian motoneuron terminals. These data provide additional evidence linking ALS to an autoimmune process and suggest that antibody‐induced increases in calcium entry through voltage‐gated calcium channels may occur in motoneurons in this disease, with possible deleterious effects in susceptible neurons.
Temporal lobe epilepsy caused by domoic acid intoxication: Evidence for glutamate receptor–mediated excitotoxicity in humans
Authors: Cendes Fernando , Andermann Frederick , Carpenter Stirling , Zatorre Robert J. , Cashman Neil R.
Published: January 2005

We describe the development of temporal lobe epilepsy in an 84‐year‐old man who had suffered domoic acid intoxication. Following intoxication he had nausea, vomiting, confusion, and coma. Generalized convulsions and complex partial status epilepticus progressively developed. After 3 weeks he improved and was seizure free with severe residual memory deficit. Electroencephalograms initially showed periodic epileptiform discharges, later evolving to epileptic abnormalities over frontotemporal regions with diffuse slow waves. Eight months after the intoxication the electroencephalogram was normal. One year after the acute episode, complex partial seizures developed. Electroencephalograms showed epileptic discharges independently over both temporal lobes, with left‐sided predominance. Magnetic resonance imaging revealed a hyperintense T2‐weighted signal and atrophy of both hippocampi; a positron emission tomographic scan showed bitemporal decreased glucose metabolism. Pneumonia developed and the patient died 31/4 years after the intoxication. Autopsy disclosed severe bilateral hippocampal sclerosis. The seizures following acute domoic acid intoxication, the postmortem pathology, and the fact that temprol lobe epilepsy developed 1 year after intoxication indicate that the human hippcampus is also vulnerable to kainate receptor excitotoxicity, and provide strong evidence supporting the role of excitotoxic injury in epileptogenesis. This report provides a unique human parallel to, and validates the animal model of, Kainate‐induced epilepsy as an important tool for studying temporal lobe epilepsy.
Multiple, diverse senile plaque–associated proteins are ligands of an apolipoprotein e receptor, the α2‐macroglobulin receptor/low‐density‐lipoprotein receptor—related protein
Authors: Rebeck G. William , Harr Steven D. , Hyman Bradley T. , Strickland Dudley K.
Published: January 2005

Both apolipoprotein E and its receptor, the low‐density‐lipoprotein receptor‐related protein (LRP), are associated with senile plaques in Alzheimer's disease. We examined the relationship of other LRP‐related molecules to senile plaques. LRP is a multifunctional receptor that blinds and rapidly internalizes at least seven ligands: apolipoprotein E, activated α2‐macroglobulin, tissue and urokinase‐type plasminogen activators, plasminogen activator inhibitor‐1, lipoprotein lipase, and lactoferrin. Using immunohistochemistry, we showed that all of these ligands, representing a diverse group of otherwise apparently unrelated proteins, accumulate on senile plaques. We also studied expression of the receptor‐associated protein, a physiological inhibitor of LRP, in the hippocampal formation from normal subjects and Alzheimer's disease patients. Receptor‐associated protein colocalizes with LRP on neuronal soma, but not on neuronal processes or reactive astrocytes. It is not present on senile plaques. These results suggest that senile plaque‐associated LRP can bind its ligands, but clearance of these compounds may be impaired in the vicinity of senile plaques.