bluuebunny/crossref_metadata_2025 huggingface dataset:
Apolipoprotein E genotype in diverse neurodegenerative disorders
Authors: Schneider Julie A. , Gearing Marla , Robbins Ronen S. , De l'Aune William , Mirra Suzanne S.
Published: January 2005

While the apolipoprotein E (ApoE) ϵ4 allele is a recognized risk factor for Alzheimer's disease (AD), an association of ϵ4 with other neurodegenerative diseases (NDs) has not been extensively explored. We examined 51 cases of neuropathologically confirmed ND. After eliminating 18 cases exhibiting pathology sufficient to warrant an additional diagnosis of AD, three disorders characterized by τ‐related cytoskeletal pathology, i.e., Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, showed increased ϵ4 frequencies. Since the number of cases within each category was small, these increased ϵ4 frequencies were not statistically significant. β‐Amyloid (βA4) immunoreactive diffuse plaques were observed in many of these cases. While we cannot eliminate the possibility that these patients were destined to develop AD, these changes may merely reflect an independent association of ϵ4 with amyloid deposition. These preliminary data affirm the need for further study of well‐characterized cases to explore the relationship of ApoE to cytoskeletal pathology and ND.
Reduced expression of peptide‐loaded HLA class I molecules on multiple sclerosis lymphocytes
Authors: Li Fangqin , Linan Mercedes J. , Stein Marchion C. , Faustman Denise L.
Published: January 2005

Lymphocytes from patients with HLA class II–linked autoimmune disease such as type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Graves' have recently been shown to have a Decemberrease in the expression of self‐peptide–filled HLA calss I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multiple sclerosis in some cases are also associated with the presence of certain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fresh peripheral blood mononuclear cells (PBMCs) and newly produced Epstein‐Barr virus (EBV)‐transformed cell lines from multiple sclerosis patients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a Decemberrease in the amount of conformationally correct peptide‐filled HLA class I molecules on the cell surface compared with matched controls detectable by flow cytometry. To demonstrate the independence of this defect from exogenous serum factors, newly produced EBV‐transformed cell lines from B cells of patients with multiple sclerosis maintained the defect. In addition, DR2 +/+, +/–, and –/– EBV –transformed B cells from these patients similarly demonstrated the self‐antigen presentation defect. Analysis of a set of discordant multiple sclerosis twins revealed the class I defect was exclusively found on the affected twin lymphocytes, suggesting a role of this class I complex in disease expression. These data indicate that multiple sclerosis patients have abnormal presentation of self‐antigens. This phenomenon, common to a number of HLA‐linked autoimmune disorders, may be associated with failed self‐tolerance and improper T‐cell education secondary to faulty HLA class I assembly controlled by HLA class II linked genes.
Acute axonal Guillain‐Barré syndrome with IgG antibodies against motor axons following parenteral gangliosides
Authors: Illa Isabel , Ortiz Nicolau , Gallard Eduard , Juarez Candido , Grau Josep M. , Dalakas Marinos C.
Published: January 2005

We studied 7 patients with an acute motor axonal Guillain‐Barré syndrome (GBS), manifested 5 to 15 days after parenteral injection of a commercial ganglioside preparation given for nonspecific pain syndromes. The serum IgG and IgM antibody response to ganglioside was studied serially and the recognition of epitopes on the peripheral nerves and motor end‐plates was examined using biotinylated IgG extracted from the patient's serum. Sera from 8 patients treated with the same ganglioside preparation who did not develop neuropathy and from 25 patients with classic GBS never treated with gangliosides were studied concurrently. All patients with ganglioside‐related GBS had a rather severe axonal degeneration, incomplete recovery, and high IgG, but not IgM, antiganglioside antibody titers, ranging from 1:320 to 1:10,240. Seven (28%) of the 25 GBS patients had IgG antibody titers, ranging from 1:160 to 1:10,240. None of the ganglioside‐treated patients who did not develop GBS and none of the 50 disease control subjects had IgG GM1 antibodies. Purified IgG from the patients with high GM1 antibodies, but not from the others, recognized epitopes at the nodes of Ranvier and the distal motor nerve terminals at the end‐plate. We conclude that exogenous ganglioside injections can be immunogenic, triggering IgG antiganglioside antibodies with specificity for motor nerve terminals. In some patients with axonal GBS such antibodies may be Marchkersor mediators of axonal involvement.
Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy
Authors: Greenberg Steven M. , William Rebeck G. , Vonsattel Jean Paul G. , Gomez‐Isla Teresa , Hyman Bradley T.
Published: January 2005

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular deposition of the amyloid β‐peptide, leading to intracerebral hemorrhage in severe cases. Other than rare familial cases, the only identified risks for CAA are advancing age and accompanying Alzheimer's disease. We tested whether the apolipoprotein E ϵ4 (apoE ϵ4) allele was associated with CAA and hemorrhage and whether this association was independent of Alzheimer's disease. The apoE ϵ4 genotype was determined without knowledge of the pathology for 93 postmortem cases systematically graded for severity of CAA and for 15 patients with CAA‐associated intracerebral hemorrhage. We found a significant and independent effect of the apoE genotype in both cohorts. Among the postmortem cases, the presence of apoE ϵ4 increased the odds ratio 13.1‐fold. In the cohort of CAA‐associated cerebral hemorrhages, the apoE ϵ4 allele frequency was 0.40, significantly greater than the control frequency of 0.14. The increase in CAA remained even after controlling for the presence of Alzheimer's disease, suggesting that apoE ϵ4 is a risk factor for CAA and CAA‐related hemorrhage, independent of its association with Alzheimer's disease.
Creutzfeldt‐Jakob disease after liver transplantation
Authors: Créange Alain , Gray Françoise , Cesaro Pierre , Adle‐Biassette Homa , Duvoux Christophe , Cherqui Daniel , Bell Jeanne , Parchi Piero , Gambetti Pierluigi , Degos Jean‐Denis
Published: January 2005

We report a 57‐year‐old woman who died from Creutzfeldt‐Jakob disease 2 years after a liver transplantation. The liver donor had no history of neurological disease. In one albumin donor, possible Creutzfeldt‐Jakob disease developed 3 years later. The patient initially had cerebellar symptoms. Neuropathology included “Kuru‐type” plaques and prion protein (PrP) deposits involving the cerebellum predominantly. The patient was homozygote valine at codon 129 of the PrP gene while the liver was homozygote methionine. This observation raises the possibility of transmission of Creutzfeldt‐Jakob disease by the graft itself or the associated albumin transfusions and, on a wider extent, by nonneural tissue.
A search for human T‐cell leukemia virus type I in the lesions of patients with tropical spastic paraparesis and polymyositis
Authors: Tangy Frédéric , Vernant Jean‐Claude , Coscoy Laurent , Ossondo Marlène , Bellance RéMi , Zaninovic Vladimir , Cartier Luis , Brahic Michel , Ozden Simona
Published: January 2005

We searched for the presence of human T‐cell leukemia virus type I (HTLV‐I) sequences in central nervous system and muscle lesions of 3 patients with tropical spastic paraparesis/HTLV‐I—associated myelopathy (TSP/HAM) and 3 patients with HTLV‐I—associated polymyositis. Proviral DNA coding for the Tax protein was found by polymerase chain reaction amplification in DNA extracted form lesions of every patient with TSP/HAM or HTLV‐I—associated polymyositis. In contrast, viral RNA was found occasionally by in situ hybridization in muscle lesions of some patients with polymyositis, but was never found in central nervous system lesions of TSP/HAM patients.
Paroxysmal dyskinesias: Clinical features and classification
Authors: Demirkiran Meltem , Jankovic Joseph
Published: January 2005

We studied 46 patients with paroxysmal dyskinesia and classified them according to phenomenology, duration of attacks, and etiology. There were 13 patients, 7 females, who had paroxysmal kinesigenic dyskinesia (PKD), 10 with attacks lasting 5 minutes or less (short lasting) and 3 with attacks lasting longer than 5 minutes (long lasting). Twentysix patients, 18 females, had paroxysmal nonkinesigenic dyskinesia (PNKD), 9 with short‐lasting and 17 with longlasting PNKD. Five patients, 3 females, had paroxysmal exertion‐induced dyskinesia (PED), 3 with short‐lasting PED and the other 2 with long‐lasting PED. In addition, there was 1 patient with paroxysmal hypnogenic dyskinesia (PhD) and 1 with paroxysmal superior oblique myokymia. Only 2 patients, 1 with PKD and 1 with PhD, had family history of paroxysmal dyskinesias. No specific cause could be identified in 21 patients; in the other 23 patients the etiologies included the following: psychogenic (9 patients), cerebrovascular diseases (4), multiple sclerosis (2), encephalitis (2), cerebral trauma (2), peripheral trauma (2), migraine (1), and kernicterus (1). Nine of 10 (90%) patients with PKD improved with medications, mostly anticonvulsants, compared with only 7 of 19 (37%) with PNKD. This new classification, based chiefly on precipitating events, allowed appropriate categorization of the attacks in all our patients with paroxysmal dyskinesias.
Clinical correlates of {18F}fluorodopa uptake in five grafted Parkinsonian patients
Authors: Remy Philippe , Samson Yves , Hantraye Philippe , Fontaine Anne , Defer Gilles , Mangin Jean‐François , Fénelon Gilles , Gény Christian , Ricolfi Frédéric , Frouin Vincent , N'Guyen Jean‐Paul , Jeny Roland , Degos Jean‐Denis , Peschanski Marc , Cesaro Pierre
Published: January 2005

To assess the efficacy of fetal mesencephalic grafts in Parkinson's disease, it is important to know if the grafted cells survive and are functional. Positron emission tomography (PET) and {18F}fluorodopa ({18F}dopa) have been used to demonstrate the survival of the grafted cells, but the relationship of {18F}dopa uptake changes in the grafted striatum to motor function remains unclear. We investigated this question with 16 serial PET scan in 5 severe parkinsonian patients unilaterally grafted in whom we found a significant and progressive increase of the {18F}dopa uptake in the grafted putamen. The number of patients was too small to assess the sensitivity of {18F}dopa PET scans in individual patients. Yet, by analyzing the 16 serial PET scans we found a correlation between the {18F}dopa uptake (Ki) in the grafted putamen and the percentage of daily time spent “on,” suggesting that Ki changes have a functional meaning. In addition, the Ki values were correlated with the contralateral finger dexterity to the same extent in both the grafted and nongrafted putamen. These results indicate that {18F}dopa uptake reflects the motor function of the opposite side of the body, similarly in the grafted and ungrafted putamen, at least in terms of these tasks. Finally, extrapolating from these correlations offers the suggestion that clinical optimal results of the graft could be achieved if the graft brings the Ki values in the putamen to about two standard deviations of mean control values.
Urinary myelin basic protein—like material as a correlate of the progression of multiple sclerosis
Authors: Whitaker J. N. , Kachelhofer R. D. , Bradley E. L. , Burgard S. , Layton B. A. , Reder A. T. , Morrison W. , Zhao G. J. , Paty D. W.
Published: January 2005

In the multicenter, randomized, placebo‐controlled trial of alternate‐day injections of recombinant interferon beta‐1b in relapsing‐remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24‐hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein‐like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing‐remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24‐hour specimens were collected showed that the patients with relapsing‐remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate Marchker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.
Apolipoprotein E genotypes and age of onset in early‐onset familial Alzheimer's disease
Authors: Levy‐Lahad Ephrat , Lahad Amnon , Wijsman Ellen M. , Bird Thomas D. , Schellenberg Gerard D.
Published: January 2005

The effect of the apolipoprotein E (APOE) ϵ4 allele on age of onset was analyzed in two groups of families with early‐onset Alzheimer's disease (AD), (1) Volga German (VG) kindreds, in which AD is caused by an unknown locus and (2) early‐onset non‐VG families showing evidence of linkage to chromosome 14. The ϵ4 allele did not have a detectable effect on age of onset in either group. This finding suggests some forms of early‐onset familial AD are not modifiable by APOE status, or that AD can be caused by APOE‐independent pathways.
Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood
Authors: Kemp G. J. , Taylor D. J. , Barnes P. R. J. , Wilson J. , Radda G. K.
Published: January 2005

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using 31P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three‐fold greater than in control subjects. However, the initial rate of ATP turNovemberer at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.
Dopa‐responsive parkinsonism phenotype of Machado‐Joseph disease: Confirmation of 14q CAG expansion
Authors: Tuite P. J. , Rogaeva E. A. , St George‐Hyslop P. H. , Lang A. E.
Published: January 2005

The subtype IV of Machado‐Joseph disease (MJD), characterized by parkinsonism variably combined with ataxia, distal atrophy, and sensory loss, has been all but ignored in recent reports of MJD, including those describing the molecular biologic substrate of the disease. We have demonstrated expansion of the CAG trinucleotide repeat of the MJD1 gene located on chromosome 14q32.1 in 2 patients of Azorean descent who presented with levodopa‐responsive atypical parkinsonism. Previous publications have documented the presence of this expanded repeat in the other more common MJD phenotypes (I‐III). To our knowledge, this is the first molecular biologic confirmation of the presence of the MJD1 gene in the subtype IV phenotype. Patients presenting with parkinsonism and peripheral neuropathy should be screened for this genetic defect.
Reversible dementia and apparent brain atrophy during valproate therapy
Authors: Papazian Oscar , Canizales Elizabeth , Alfonso Israel , Archila Ricardo , Duchowny Michael , Aicardi Jean
Published: January 2005

Two children developed severe cognitive and behavioral deterioration suggestive of a degenerative disease while being treated with sodium valproate for idiopathic, localization‐related epilepsy with centrotemporal spikes. Magnetic resonance imaging revealed Marchked central and generalized cortical and cerebellar atrophy. In both patients, clinical symptoms and signs cleared in a few weeks following valproate withdrawal. The magnetic resonance imaging appearance improved within 3 months in 1 of the patients and normalized in both after 6 and 12 months. No metabolic changes were associated with the clinical or imaging abnormalities. Although the mechanism of this rare idiosyncratic complication of valproate therapy is unknown, we advocate discontinuing valproate therapy in all epileptic patients with neuromental deterioration or brain atrophy of unknown etiology.
Neurodevelopmental effects of X monosomy: A volumetric imaging study
Authors: Reiss Allan L. , Mazzocco Michèle M. M. , Greenlaw Ronald , Freund Lisa S. , Ross Judith L.
Published: January 2005

Thirty girls with Turner syndrome (TuS) were compared with 30 individually age‐matched controls on volumtric brain measures derived from magentic resonance imaging and on measures of psychological functioning. As expected, girls with TuS performed more poorly on visual‐spatial and intellectual measures relative to controls, and were rated by their parents as having more significant problems in attention and social behaviors. Although no group differences in overall cerebral or subcortical volumes were observed, the regional distribution of gray and white matter differed across groups in both right and left parietal regions. Differences in total tissue volume ratios were seen for both right and left parietal regions. In general, girls with TuS had a smaller proportion of tissue (gray and white) within the right and left parietal regions, and a larger proportion of tissue within the right inferior parietal‐occipital region relative to girls in the control group. These data suggest a potentially important role for X chromosome genes and/or sex steroids in the development and specialization of brain structure and function.
Resolution‐dependent estimates of lesion volumes in magnetic resonance imaging studies of the brain in multiple sclerosis
Authors: Filippi M. , Horsfield M. A. , Campi A. , Mammi S. , Pereira C. , Comi G.
Published: January 2005

In this study, we investigated the relationship between multiple sclerosis lesion volumes measured from magnetic resonance imaging scans and image‐slice thickness. The lesion volume was computed using a semiautomated thresholding technique from axial scans of the brain of varying slice thickness. Ten patients were studied, and in all cases the computed lesion volume increased with decreasing slice thickness (p = 0.01). Linear extrapolation from our data allowed the lesion volume at very small slice thickness to be estimated; this was found to be on average 20% greater than that obtained using a slice thickness of 5 mm. Furthermore, there were considerable differences in the percentage of change in lesion volume from patient to patient, and it would appear that there is a larger variation with slice thickness for patients with smaller lesions and higher lesion loads.
The effect of deprenyl and levodopa on the progression of Parkinson's disease
Authors: Olanow C. W. , Hauser R. A. , Gauguster L. , Malapira T. , Koller W. , Hubble J. , Bushenbark K. , Lilienfeld D. , Esterlitz J.
Published: January 2005

We have performed a 14‐month, prospective, randomized, double‐blind, placebo‐controlled study to evaluate the effect of deprenyl and levodopa/carbidopa (Sinemet) on the progression of signs and symptoms in patients with mild Parkinson's disease (PD). One hundred one untreated PD patients were randomly assigned to one of the following four treatment groups: Group I, deprenyl + Sinemet; Group II, placebo‐deprenyl + Sinemet; Group III, deprenyl + bromocriptine; and Group IV, placebo‐deprenyl + bromocriptine. The final visit was performed at 14 months, i.e., 2 months after withdrawal of deprenyl or its placebo and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration in Unified Parkinson's Disease Rating Score (UPDRS) between untreated baseline and final visits was used as an index of disease progression. Placebo‐treated patients deteriorated by 5.8 ± 1.4 points, while deprenyl‐treated patients deteriorated by 0.4 ± 1.3 points (p < 0.001). This effect was sufficiently powerful that a significant deprenyl effect could be detected in the subgroup of 41 patients randomized to Sinemet (p < 0.01) as well as in the 23 patients who completed a 14‐day washout of Sinemet or bromocriptine (p < 0.05). No difference in the extent of deterioration was detected in patients randomized to Sinemet versus bromocriptine. This study demonstrates that deprenyl attenuates deterioration in UPDRS score in patients with early PD. These findings are not readily explained by the drug's symptomatic effects and are consistent with the hypothesis that deprenyl has a neuroprotective effect.
Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy
Authors: Williamson Anne , Spencer Susan S. , Spencer Dennis D.
Published: January 2005

Hippocampal depth electrodes are often used to localize seizure onset in patients who may have temporal lobe epilepsy (TLE). A number of features of the spontaneous seizures and of their ictal onset patterns can be analyzed from these recordings. We compared a number of the typical electroencephalographic (EEG) changes at seizure onset with several cellular parameters recorded in dentate granule cells from the same 14 patients diagnosed with medial temporal sclerosis (MTS) to examine the pathophysiological correlates of this spontaneous EEG activity in this form of TLE. The intracellularly recorded parameters include the propensity to fire evoked epileptiform bursts, the absence of evoked inhibitory potentials, the presence of polysynaptic excitatory postsynaptic potentials, and the presence of spontaneous excitatory activity. We noted several correlations between the EEG data and the intracellular recordings. The absence of synaptically evoked bursts was correlated with the presence of low‐voltage fast activity at seizure onset. In addition, the loss of inhibitory postsynaptic potentials was correlated with the presence of periodic spiking pre‐ictally. Several other correlations were also noted. These data indicate that EEG findings may be predictive of anatomical and cellular pathological changes and provide clues to the physiological mechanisms involved in this form of epilepsy.
Experimental status epilepticus alters γ‐aminobutyric acid type A receptor function in CA1 pyramidal neurons
Authors: Kapur Jaideep , Coulter Douglas A.
Published: January 2005

There is a reduction of β‐aminobutyric acid (GABA)‐mediated inhibition in the CA1 pyramidal region of the hippocampus during status epilepticus (SE). The cellular basis of this loss of GABA‐mediated inhibition is not known. This study tested the possibility that GABA type A (GABAA) receptor function in CA1 pyramidal neurons was reduced or blocked during SE, at least in part by postsynaptic cellular mechanisms. GABAA receptor currents (IGABA) were studied by whole‐cell patch‐clamp techniques in CA1 pyramidal neurons acutely dissociated from rats undergoing lithium/pilocarpine‐induced limbic status epilepticus (SE neurons) and from naive rats (naive neurons). SE neurons had more depolarized resting membrane potential (−17.3 mV) compared with naive neurons (−56 mV). IGABA was absent in 47% of SE neurons and reduced in 55% of the remainder, compared with naive neurons. The reduction in IGABA in SE neurons resulted from a combination of factors, including reduced potency and reduced efficacy of GABA in activating chloride channels, and diminished driving force for the GABA‐induced chloride currents once activated. These postsynaptic cellular mechanisms resulted in a net reduction or loss in GABA‐mediated inhibition and may explain previous in vivo findings reporting a loss of inhibition in hippocampus during limbic SE.
The role of reading activity on the modulation of motor cortical outputs to the reading hand in braille readers
Authors: Pascual Alvaro , Wassermann Eric M. , Sadato Norihiro , Hallett Mark
Published: January 2005

We studied the cortical motor output maps of the first dorsal interosseous (FDI) of both hands and the abductor digitiminimi of the reading hand in 6 blind proficient Braille readers. The maps were generated using transcranial magnetic stimulation. We compared the maps obtained on a day in which they worked as Braille proofreaders (reading Braille for approximately 6 hours) with the maps obtained on a day they took off from work. On the work day, the maps for the FDI of the reading hand were significantly larger after the working shift than in the morning after having been off work for 2 days. These changes were not seen for the same muscle on the day off work or on any of the 2 days in the other two muscles studied. These results illustrate the rapid modulation in motor cortical outputs in relation to preceding activity and emphasize the importance of precise timing in studies of the neurophysiological correlates of skill acquisition.
Enhanced expression of microtubule‐associated protein 2 in large neurons of cortical dysplasia
Authors: Yamanouchi Hideo , Zhang Weixian , Jay Venita , Becker Laurence E.
Published: January 2005

To evaluate neuronal cytoarchitectural changes in cortical dysplasia, we examined microtubule‐associated protein 2 (MAP2) expression in surgically resected specimens obtained from 20 patients (age range, 3 months to 10 years) treated for intractable epilepsy. Large neurons were investigated in the specimens from all patients and showed significantly strong immunoreactivity with antibodies against MAP2 in the perikaryon and proximal portion of their processes. In situ hybridization with MAP2 antitense riboprobe showed increased hybridization signal intensities in the large neurons, which correlated with the pattern of immunoreactivity for MAP2. We conclude that MAP2 is strongly expressed in the large neurons in cortical dysplasia. The results of preliminary immunoblotting in 1 patient with focal cortical dysplasia showed that the low‐molecular‐weight form of MAP2 (MAP2c) was strongly expressed in the dysplastic cortex, suggesting that MAP2c may be a major component contributing to the increased expression of MAP2 in the large neurons of cortical dysplasia. Since it has been suggested that MAP2 plays a crucial role in the branching and remodeling of neuronal processes, increased expression of MAP2 may reflect activated plasticity of the large neurons in cortical dyspasia.
Familial hemiplegic migraine, nystagmus, and cerebellar atrophy
Authors: Elliott Michael A. , Peroutka S. J. , Welch S. , May Eugene F.
Published: January 2005

Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by transient hemiplegia during the aura phase of a migraine attack. Nystagmus has been reported in individuals affected with this disorder, but the origin of the ocular motility findings is unknown. A three‐generation family with FHM is described and clinical histories are outlined. Ocular motility evaluations were performed on 7 family members, 5 with a history of hemiplegic migraine and 2 without history of migraine. All affected family members had abnormal eye movements consistent with vestibulocerebellar dysfunction. Magnetic resonance imaging scans in affected family members revealed cerebellar vermian atrophy. DNA linkage analysis revealed a common marker in all the affected family members on chromosome 19. We suggest that the hemiplegic migraine attacks and the cerebellar degeneration are linked genetically and that the eye movements are not the ischemic sequelae of recurrent migraine. Strikingly similar ocular motility findings and cerebellar degeneration are reported in both FHM and a genetically related disorder, hereditary paroxysmal cerebellar ataxia (HPCA). The significance of these similarities is discussed along with a proposed pathophysiology for FHM.
Clinical, neuroimaging, and pathologic features of progressive nonfluent aphasia
Authors: Turner R. S. , Kenyon L. C. , Trojanowski J. Q. , Gonatas N. , Grossman M.
Published: January 2005

We report the clinical, neuroimaging, and neuropathologic features of progressive nonfluent aphasia (PNFA), a rare neurodegenerative syndrome most notable for its distinct language disturbance. Longitudinal observations of 3 patients revealed progressively telegraphic speech and writing, followed by gradual deterioration of sentence comprehension, and finally, preterminal mutism and dementia. Magnetic resonance imaging revealed cortical atrophy most pronounced in anterior regions of the left hemisphere. Functional neuroimaging demonstrated reduced cerebral activity most prominently in left frontal and temporal regions. At necropsy, microscopic pathology of brain was most consistent with the diagnosis of “dementia lacking distinctive histology” (DLDH). A review of published primary progressive aphasia cases with adequate clinical and hietopathological descriptions reveals that the most common pathology underlying PNFA is DLDH. PNFA is one example of a family of clinical syndromes with similar underlying histopathology that affects different regions of the frontal lobe.
Deficiency of complex II of the mitochondrial respiratory chain in late‐onset optic atrophy and ataxia
Authors: Taylor Robert W. , Birch‐Machin Mark A. , Schaefer Jochen , Taylor Louise , Shakir Raad , Ackrell Brian A. C. , Cochran Bruce , Bindoff Laurence A. , Jackson Margaret J. , Griffiths Philip , Turnbull Douglass M.
Published: January 2005

Defects of the mitochondrial respiratory chain are increasingly being recognized as an important cause of neurological disease in humans. In many of these patients, the biochemical defect results from an abnormality of the mitochondrial genome. Respiratory chain defects involving complex II, which is entirely encoded by the nuclear genome, are comparatively rare. We report the clinical and biochemical findings in 2 elderly sisters who presented with late‐onset neurodegenerative disease. In both patients, a partial deficiency of complex II (approximately 50% of control values) was shown to be present in mitochondria from muscle and platelets. The enzyme defect was not expressed in cultured skin fibroblasts or immortalized lymphocytes. There was an overexpression of the 70‐kd flavoprotein subunit in muscle mitochondria from both patients, although we showed that this subunit is present in normal amounts in mitochondrial membranes. Our studies highlight the diversity of the clinical presentation of respiratory chain disease and that complex II deficiency should enter the differential diagnosis of certain patients with late‐onset neurodegenerative disease.
Myelin basic protein and human coronavirus 229E cross‐reactive T cells in multiple sclerosis
Authors: Talbot Pierre J. , Paquette Jean‐Sébastien , Ciurli Cristina , Antel Jack P. , Ouellet France
Published: January 2005

Multiple sclerosis (MS) is an inflammatory demyelinating neurological disease in which autoreactive T lymphocytes sensitized to myelin components of the central nervous system are postulated to contribute to pathogenesis. The possible relevance of molecular mimicry between a human coronavirus and the myelin basic protein component of myelin in the generation of this autoimmune reaction was evaluated. Myelin basic protein– and virus‐reactive T‐cell lines were established from 16 MS patients and 14 healthy donors and shown to be mostly CD4+. In contrast to healthy donors, several T‐cell lines isolated from MS patients showed cross‐reactivity between myelin and coronavirus antigens. Overall, 29% of T‐cell lines from MS patients (10 donors) but only 1.3% of T‐cell lines from normal control subjects (2 donors) showed an HLA‐DR‐restricted cross‐reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens. Moreover, reciprocal reactivities were only observed in MS patients (4 donors). This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease.
Intramuscular interferon beta‐1a for disease progression in relapsing multiple sclerosis
Authors: Jacobs Lawrence D. , Cookfair Diane L. , Rudick Richard A. , Herndon Robert M. , Richert John R. , Salazar Andres M. , Fischer Jill S. , Goodkin Donald E. , Granger Carl V. , Simon Jack H. , Alam John J. , Bartoszak David M. , Bourdette Dennis N. , Braiman Jonathan , Brownscheidle Carol M. , Coats Michael E. , Cohan Stanley L. , Dougherty David S. , Kinkel Revere P. , Mass Michele K. , Munschauer Frederick E. , Priore Roger L. , Pullicino Patrick M. , Scherokman Barbara J. , Weinstock‐Guttman Bianca , Whitham Ruth H.
Published: January 2005

The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta‐1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double‐blinded, placebo‐controlled, multicenter phase I11 trial of interferon beta‐la. Interferon beta‐la, 6.0 million units (30 μg), was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta‐la treatment produced a significant delay in time to sustained EDSS progression (p equals; 0.02). The Kaplan‐Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta‐la‐treated group. Patients treated with interferon beta‐la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium‐enhanced brain lesions on magnetic resonance images (pvalues ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo‐treated patients versus 0.61 in interferon beta‐la‐treated patients. There were no major adverse events related to treatment. Interferon beta‐ la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium‐enhanced lesions on brain magnetic resonance images. This treatment may alter the hndamen‐ tal course of relapsing multiple sclerosis.
Human α‐tocopherol transfer protein: Gene structure and mutations in familial vitamin E deficiency
Authors: Hentati Afif , Deng Han‐Xiang , Hung Wu‐Yen , Nayer Muhammad , Ahmed M. Said , He Xiaoxuan , Tim Richard , Stumpf David A. , Siddique Teepu
Published: January 2005

Familial vitamin E deficiency (AVED) causes ataxia and peripheral neuropathy that resembles Friedreich's ataxia. AVED is thought to be caused by a defect in the transport of vitamin E in liver cells, which is the probable function of αtocopherol transfer protein (αTTP). We have cloned the cDNA and several genomic phage clones covering the entire human αTTP gene and determined the junctions between the five exons and four introns that composed the gene for human αTTP. Three mutations in three unrelated North American families with AVED were identified. Two mutations, 485delT and 513insTT, cause a frame shift and a premature stop codon and the third mutation 574G→A would substitute Arg192 to His in αTTP. The 2 patients with a severe form of AVED were homozygous with 485delT and 513insTT, respectively, while the patient with a mild form o f the disease was compound heterozygous with 513insTT and 574G→A. These findings have identified the underlying genetic defect in AVED and have confirmed the role of αTTP in AVED.
Risk of stroke during long‐term anticosgulant therapy in patients after myocardial infarction
Authors: Azar Aida J. , Koudstaal Peter J. , Wintzen Axel R. , Bergen Paul F. Van , Jonker Jan J. , Deckers Jaap W.
Published: January 2005

Myocardial infarction survivors have an increased risk of stroke, which is reduced with long‐term anticoagulant therapy. However, an estimated 10‐times increase in risk of bleeding during such treatment has been reported. We evaluated the risk of stroke in patients after a myocardial infarction and examined the relationship of the risk of intracranial hemorrhage or cerebral infarction and the intensity of anticoagulant therapy. The study population consisted of 3,404 post‐myocardial infarction patients who took part in a randomized, double‐blind, placebo‐controlled trial. Patients were randomized to treatment with anticoagulants (international normalized ratio range, 2.8–4.8) or matching placebo. Mean follow‐up was more than 3 years. The incidence of stroke analyzed on “intention‐to‐treat” was 0.7 per 100 patient‐years in the anticoagulant patients against 1.2 in placebo, a hazard ratio of 0.60, with 95% confidence interval of 0.40 to 0.90. In the anticoagulation group, 15 patients had cerebral infarction and 17 an intracranial bleeding, 3 of which occurred after withdrawal of treatment. In the placebo group, the numbers were 43 and 2. Of the 14 intracranial bleeds during anticoagulation, 6 occurred at an international normalized ratio between 3.0 and 4.0 and 8 at greater than 4.0. These results confirm that long‐term anticoagulant therapy substantially reduces the risk of stroke in post‐myocardial infarction patients. The increased risk of bleeding complications associated with anticoagulant therapy is offset by a marked reduction in ischemic events. The risk of intracranial bleeding is directly related to the intensity of anticoagulant treatment.
The role of spreading depression in focal ischemia evaluated bv dffusion mapping
Authors: Takano Kentaro , Latour Lawrence L. , Formato James E. , Carano Richard A. D. , Helmer Karl G. , Hasegawa Yasuhiro , Sotak Christopher H. , Fisher Marc
Published: January 2005

This study investigated the role of spontaneous and induced spreading depression (SD) on the evolution of focal ischemia in vivo. We induced focal ischemia in 12 rats using the middle cerebral artery suture occlusion (MCAO) method. Chemical stimulation of nonischemic ipsilateral cortex by potassium chloride application (KCl group; n = 7) and saline (NaCI group; n = 5) was performed at 15, 30, 45, and 60 minutes following MCAO, and SD was detected electrophysiologically. Ischemic lesion volumes assessed over 15‐minute intervals, evaluated by continuous apparent diffusion coefficient (ADC) of water mapping, demonstrated that the ischemic region increased significantly during 15‐minute time epochs with a single SD episode (36.5 ± 12.9 mm3 mean ± SD) or multiple SD episodes (39.8 ± 22.3) compared with those without SD (13.9 ± 11.5) (p = 0.0009). Infarct volume at postmortem 24 hours after MCAO was significantly larger in the KCl group, with more total SDs (237.8 ± 13.8) than the NaCl group (190.5 ± 12.6) (p = 0.0001). This study demonstrates that ischemia‐related and induced SDs increase significantly ischemic lesion volume in vivo, supporting the hypothesis for a causative role of SD in extending focal ischemic injury.
Sensory nerve pathology in multifocal motor neuropathy
Authors: Corse Andrea M. , Chaudhry Vinay , Crawford Tom O. , Cornblath David R. , Kuncl Ralph W. , Griffin John W.
Published: January 2005

The nosological status of multifocal motor neuropathy remains controversial. The clinical and electrodiagnostic hallmarks suggest selective motor fiber involvement. In this study, we asked to what extent sensory nerves might be involved pathologically in multifocal motor neuropathy. Examination of sensory nerve biopsy specimens from II patients did reveal pathological findings in all, but they were very mild. An increased number of thinly myelinated, large‐caliber fibers was the unifying feature common to each specimen. By electron microscopy, each biopsy specimen had thinly myelinated fibers surrounded by minor onion bulbs. Active demyelination, though scant, was seen in 3 nerves. Myelinated fiber density was normal. Subperineurial edema and inflammation were not present. We conclude that multifocal motor neuropathy is not an exclusively motor abnormality, although it appears to be so clinically and electrophysiologically. The frequent, albeit mild, pathological abnormalities in sensory fibers suggest that the demyelinating pathophysiology also affects sensory fibers, but to a lesser degree than motor fibers. Some investigators maintain that multifocal motor neuropathy is within the spectrum of chronic inflammatory demyelinating polyneuropathy. The very mild degree of sensory fiber involvement, the absence of inflammation or edema, and the distinctive clinical features support the concept of multifocal motor neuropathy as distinct from chronic inflammatory demyelinating polyneuropathy.
Disorders of affective and linguistic prosody in children after early unilateral brain damage
Authors: Trauner Doris A. , Ballantyne Angela , Friedland Susan , Chase Christopher
Published: January 2005

Prosody is that quality of speech that imparts meaning by changes in intonation, pitch, and stress. The right hemisphere (RH) appears to be dominant for affective prosody in adults, while the left hemisphere (LH) mediates the more linguistic aspects of nonverbal communication. Few similar studies have been reported of individuals who suffered early unilateral brain damage, when brain reorganization or plasticity might be expected to play a role in ameliorating the adverse effects of focal brain damage. In this study, comprehension and expression of affective and linguistic prosody were tested in subjects with documented unilateral brain damage of pre‐ or perinatal onset and in matched controls. Both RH‐ and LH‐lesion groups demonstrated difficulty on tasks involving expression of affective prosody, and on tests of linguistic prosody, compared with controls. Only the RH‐lesion group was impaired on an affective comprehension task. The results indicate that even after very early unilateral brain damage, prosodic deficits may be present. However, only for affective comprehension does the side of the lesion appear to determine such deficits. The findings suggest that during brain development there is not clear brain lateralization for prosody and there may be bilateral representation for these skills during early development. There may be limitations to the ability of the developing brain to reorganize after early injury.
Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes
Authors: Rottach Klaus G. , Riley David E. , DiScenna Alfred O. , Zivotofsky Ari Z. , Leigh R. John
Published: January 2005

We studied dynamic properties of horizontal, vertical, and oblique eye movements in 23 patients with the following parkinsonian syndromes: idiopathie parkinsonism (PD), multiple system atrophy (MSA), pure akinesia (PA), progressive supranuclear palsy (PSP), and cortical‐basal ganglionic degeneration (CBGD). Compared with age‐matched controls, only PSP patients showed slowing of saccades. Patients in all groups showed saccadic hypometria that was most marked vertically. The trajectories of saccades made to diagonal target jumps were deviated toward the horizonal plane, due to the vertical hypometria; this was most marked in PA and PSP groups. Saccade latency was only increased in the CBGD group. Sinusoidai smooth pursuit did not differentiate between controls and patients; however, with step‐ramp stimuli, pursuit eye acceleration was impaired in all patient groups compared with controls. The vestibulo‐ocular reflex, with or without visual enhancement, was similar in patients and controls. These findings indicate that (1) in parkinsonian syndromes apart from PSP, the saccade‐generating brainstem burst neurons are probably spared, but the signals that they receive, specifying the size and direction of saccades, are flawed; and (2) measurements of the gain and trajectory of oblique saccades, and initiation of smooth pursuit, may aid in diagnosing these different types of parkinsonism.
Experimental sensory neuropathy induced by sensitization with ganglioside GD1b
Authors: Kusunoki Susumu , Shimizu Jun , Chiba Atsuro , Ugawa Yoshikazu , Hitoshi Seiji , Kanazawa Ichiro
Published: January 2005

Three of six rabbits immunized with purified GD1b developed ataxic sensory neuropathy. They laid on the floor with their limbs splayed out, and their movements were awkward; but muscle power, tonus, and superficial sensation appeared to be intact. Sciatic nerve motor conduction studies were normal. Axonal degeneration was present in the dorsal column of the spinal cord, in the dorsal roots, and in the sciatic nerve. Some of the nerve cell bodies in the dorsal root ganglia had degenerated and disappeared. No demyelinative lesions or mononuclear cell infiltrations were seen in those regions. No pathological changes were present in the other three immunized rabbits that showed no clinical symptoms. Control rabbits inoculated only with adjuvants showed neither clinical symptoms nor pathological changes. Anti‐GD1b antibody was raised in the sera from all six rabbits immunized with GD1b. The monoclonal anti‐GD1b antibody GGR12 immuno‐stained about one‐half the rabbit primary sensory neurons. Sensitization with GD1b, therefore, may cause ataxic sensory neuropathy in rabbits due to antibody‐mediated damage to the primary sensory neurons.