bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of interferon‐β on blood—brain barrier disruptions demonstrated by constrast‐enhanced magnetic resonance imaging in relapsing—remitting multiple sclerosis
Authors: Stone Lael A. , Frank Joseph A. , Albert Paul S. , Bash Craig , Smith Mary E. , Maloni Heidi , McFarland Henry F.
Published: January 2005

Magnetic resonance imaging (MRI) has been a valuable tool to understand the pathophysiology and natural history of multiple sclerosis (MS), and increasing attention is focusing on the use of MRI findings as outcome measures in treatment trials in MS. The recently completed trial of interferon‐β‐1b (IFN‐β1b) demonstrated a decrease in accumulation of diseased tissue on T2‐weighted images and a reduction in new lsions on T2‐weighted images. To examine the effect of IFN‐β1b on blood‐brain barrier (BBB) breakdown, and to provide additional insights into the usefulness of MRI in the evolution of effectiveness of experimental treatments in MS, we used the contrast‐enhanced lesion frequency of 7‐month baseline MRIs compared with the enhanced lesion frequency for 6‐month treatment period MRIs in 14 relapsing‐remitting (RR) MS patients. Longer baselines were also available for analysis in a subset of 8 patients, as these patients had been followed by monthly MRI in a natural history study for up to 4 years prior to the current study. A significant reduction in the total or new enhancing lesion frequency was detected in the patients analyzed as a whole, and 13 of 14 of the patients demonstrated a reduction in enhancing lesion frequency on treatment over the 6 months studied. These findings suggest that IFN‐β has a mechanism of action that at least temporarily inhibits the opening of the BBB in RRMS patients. This trial also illustrates the usefulness of a baseline versus treatment trial design to evaluate the effect of drug therapy in MS.
Recovery from wernicke's aphasia: A positron emission tomographic study
Authors: Weiller Cornelius , Isensee Christian , Rijntjes Michel , Huber Walter , Müller Stefan , Bier Dirk , Dutschka Klaus , Woods Roger P. , Noth Johannes , Diener Hans Christoph
Published: January 2005

Changes in the organization of the brain after recovery from aphasia were investigated by measuring increases in regional cerebral blood flow (rCBF) during repetition of pseudowords and during verb generation. Six right‐handed patients who had recovered from Wernicke's aphasia caused by an infarction destroying the left posterior perisylvian language zone were compared with 6 healthy, right‐handed volunteers. In the control subjects, strong rCBF increases were found in the left hemisphere in the posterior part of the superior and middle temporal gyrus (Wernicke's area), and during the generation task in lateral prefrontal cortex (LPFC) and in inferior frontal gyrus (Broca's area). There were some weak right hemisphere increases in superior temporal gyrus and inferior premotor cortex. In the patients, rCBF increases were preserved in the frontal areas. There was clear right hemisphere activation in superior temporal gyrus and inferior premotor and lateral prefrontal cortices, homotopic to the left hemisphere language zones. Increased left frontal and right perisylvian activity in patients with persisting destruction of Wernicke's area emphasizes redistribution of activity within the framework of a preexisting, parallel processing and bilateral network as the central mechanism in functional reorganization of the language system after stroke.
Motor reorganization in acquired hemidystonia
Authors: Ceballos‐Baumann A. O. , Passingham R. E. , Marsden C. D. , Brooks D. J.
Published: January 2005

Regional cerebral blood flow (rCBF) was measured with H215O positron emission tomography in 5 patients with acquired hemidystonia (AHD) due to structural lesions of the basal ganglia or posterior thalamus contralateral to the dystonic limb. Patients were scanned at rest and when performing paced joystick movements in freely chosen directions with the dystonic and then the unaffected arm. Findings were compared with those of 5 age‐matched controls performing joystick movements with the right arm. At rest, there was decreased activity in ventroanterior thalamus, posterior thalamus, angular gyrus ipsilateral to the lesion, and bilateral frontoorbital cortex. At a similar level of significance, increased resting activity was found in lentiform nucleus, hippocampus, and anterior insula contralateral to the lesion. Using the affected arm, AHD cases showed significant overactivity of contralateral prefrontal, lateral premotor cortex, rostral supplementary motor area, anterior cingulate area 32, bilateral sensorimotor cortex (SMC) and insula, mesial parietal cortex, and ipsilateral cerebellum. There was similar frontal overactivity when the unaffected arm performed the joystick movements, though SMC and insula overactivity was contralateral rather than bilateral. The associated frontal overactivity on movement is consistent with acquired dystonia being a syndrome of thalamofrontal disinhibition due to structural disruption of basal ganglia inhibitory control. Our findings also suggest that cortical activation during movement of the unaffected limb is abnormal in acquired hemidystonia.
Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: Correlation with magnetic resonance imaging
Authors: Hartung Hans‐Peter , Reiners Karlheinz , Archelos Juan J. , Michels Marco , Seeldrayers Pierrette , Heidenreich Fedor , Pflughaupt Karl W. , Toyka Klaus V.
Published: January 2005

Adhesion molecules are important in T‐cell trafficking to sites of inflammation. We determined levels of circulating vascular cell adhesion molecule‐1 (VCAM‐1), L‐selectin, and E‐selectin in the serum of 147 patients with definite multiple sclerosis of the remitting‐relapsing or secondary progressive type. Soluble VCAM‐1 and L‐selectin concentrations were increased compared to levels in a large group of control subjects. Levels were highest in patients with gadolinium‐enhancing lesions on magnetic resonance imaging (VCAM‐1: 1,011 ± 276 vs 626 ± 87 ng/ml; L‐selectin: 1,130 ± 272 vs 793 ± 207 ng/ml [mean ± standard deviation]; p > 0.0001 vs patients without enchancing lesions). Serum levels of soluble tumor necrosis factor receptor (60 kd) were also raised (2.64 ± 1.23 vs 2.17 ± 0.69 ng/ml in subjects with other neurological diseases and 2.1 ± 0.77 ng/ml in healthy control subject; p < 0.05). Soluble VCAM‐1 and L‐selectin levels were correlated to concentrations of soluble tumor necrosis factor receptor. In 13 patients with viral encephalitis, similar observations were made. Raised levels of soluble VCAM‐1 and L‐selectin probably reflect cytokine‐induced endothelial cell and T‐lymphocyte/monocyte activation occurring in the process of T‐cell migration into the central nervous system. Tumor necrosis factor‐alpha may be critically involved.
Striatal 3,4‐dihydroxyphenylalanine decarboxylase in aging: Disparity between postmortem and positron emission tomography studies?
Authors: Kish Stephen J. , Zhong Xiaohui H. , Hornykiewicz Oleh , Haycock John W.
Published: January 2005

Recent positron emission tomography (PET) studies using 3,4‐[18F]fluorodihydroxyphenylalanine ([18F]fluorodopa) have reported little or no Decemberrement in dopaminergic function in human striatum (caudate and putamen) during aging. In contrast, previous postmortem studies have reported Marchked age‐dependent Decemberreases in the activity of dopa Decemberarboxylase (DDC), a variable upon which the PET determinations depend. Using quantitative blot immunolabeling techniques, we measured DDC protein concentrations in postmortem striata of 28 neurologically normal subjects ranging in age from 17 to 103 years. We found a significant, albeit modest, age‐dependent Decemberrease in the concentration of DDC protein in caudate (r = −0.50, p < 0.05) but not in putamen (r = −0.16, p > 0.05), with mean values of the 87‐year‐old group being 27% (caudate) and 12% (putamen) lower than those of the 30‐year‐old group. The absence of a robust effect of aging upon striatal DDC protein is consistent with the [18F]fluorodopa‐PET studies that report either no change or only a relatively small Decemberrease in striatal 18F accumulation during aging. To the extent that aging is associated with a substantial loss of striatal dopaminergic nerve terminals, the present results also suggest that DDC protein synthesis may be upregulated in those dopaminergic neurons that survive the aging process and, therefore, that striatal [18F]fluorodopa uptake indices may provide an overestimate of the number of dopaminergic nerve terminals during physiological aging.
Decreased single‐photon emission computed tomographic {123I}β‐CIT striatal uptake correlates with symptom severity in parkinson's disease
Authors: Seibyl J. P. , Marchek K. L. , Quinlan D. , Sheff K. , Zoghbi S. , Zea‐Ponce Y. , Baldwin R. M. , Fussell B. , Smith E. O. , Charney D. S. , Hoffer P. B. , Innis R. B.
Published: January 2005

Previous studies have utilized single‐photon emission computed tomography (SPECT) to demonstrate decreased {123I}β‐CIT striatal uptake in idiopathic Parkinson disease (PD) patients. The present study extendss this work by examining SPECT outcome measures in a larger group of PD patients with varying disease severity. Twenty‐eight l‐dopa‐responsive PD patients (Hoehn‐Yahr stages 1–4) and 27 healthy controls had SPECT scans at 18 to 24 hours after injection of {123I}β‐CIT. Specific to nondisplaceable striatal uptake ratios (designated V3″) were correlated with Hoehn‐Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. Linear discriminant function analyses utilizing striatal uptakes, putamen‐to‐caudate ratios, and ipsilateral‐contralateral asymmetry indices were performed. Decreased striatal tracer uptake (V3″) was correlated with total UPDRS score for both contralateral and ipsilateral striatum. Putamen uptake was relatively more reduced than caudate with mean putamen:caudate ratios of 0.50 ± 0.17 and 0.82 ± 0.09 for PD patients and controls, respectively. Ipsilateral:contralateral asymmetry was significantly greater in PD patients than controls. Discriminant function analysis utilizing V3″ for ipsilateral and contralateral caudate and putamen correctly classified all 55 cases. These data demonstrate Marchked differences in {123I}β‐CIT SPECT measures in healthy controls and PD patients. The significant correlation of SPECT measures with motor severity suggests {123I}β‐CIT may be a useful Marchker of disease severity in PD.
Reduction of β‐amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease
Authors: Motter R. , Vigo‐Pelfrey C. , Kholodenko D. , Barbour R. , Johnson‐Wood K. , Galasko D. , Chang L. , Miller B. , Clark C. , Green R. , Olson D. , Southwick P. , Wolfert R. , Munroe B. , Lieberburg I. , Seubert P. , Schenk D.
Published: January 2005

In this clinical study, the cerebrospinal fluid (CSF) level of a Novemberel form of the β‐amyloid peptide (Aβ) extending to position 42 (Aβ42) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF Aβ42 levels, total Aβ peptides, microtubule‐associated protein τ, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF Aβ42 levels were found to be significantly lower in AD patients relative to controls, whereas total Aβ levels were not. Aβ42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, τ levels were increased in AD patients; however, neither Aβ42 nor τ levels were apparently influenced by the ApoE genotype.
Oxidative damage to protein in sporadic motor neuron disease spinal cord
Authors: Shaw Pamela J. , Ince Paul G. , Falkous Gavin , Mantle David
Published: January 2005

The recent discovery that defects in the gene encoding copper‐zinc superoxide dismutase (SOD1) are associated with some cases of familial motor neuron disease has heightened interest in the possibility that free radical mechanisms may contribute to selective motor neuron injury. Sporadic and familial motor neuron diseases are clinically and pathologically very similar and may share common pathophysiological mechanisms. Thus the role of free radical mechanisms as a contributory factor to motor neuron injury in the common sporadic form of motor neuron disease requires urgent exploration, particularly as this may provide an avenue for therapy aimed at retarding pathological progression. We investigated oxidative damage to proteins in the lumbar spinal cord by quantifying the protein carbonyl level from 19 patients with sporadic motor neuron disease, 8 neurologically normal control subjects, and 11 neurological disease control subjects, most of whom had slowly progressive neurodegenerative disease. In sporadic motor neuron disease the mean protein carbonyl level in the spinal cord was increased by 119% (p < 0.02) compared to normal control subjects and by 88% (p < 0.04) compared to the neurological disease control subjects. These data contribute to the emerging evidence that oxidative damage may play a contributory role in the neuronal death in sporadic motor neuron disease. This mechanism may be particularly important in a subset of patients with motor neuron disease.
Genetic control of multiple sclerosis: Increased production of lymphotoxin and tumor necrosis factor‐α by HLA‐DR2+ T cells
Authors: Zipp Frauke , Weber Frank , Huber Susanne , Sotgiu Stefano , Czlonkowska Anna , Holler Ernst , Albert Ekkehard , Weiss Elisabeth H. , Wekerle Hartmut , Hohlfeld Reinhard
Published: January 2005

Lymphotoxin (LT) and tumor necrosis factor‐α (TNF‐α) play an important role in the pathogenesis of multiple sclerosis (MS). MS is associated with the HLA‐DR2, Dw2, DQ6 HLA class II haplotype. Because both LT and TNF‐α are encoded in the HLA region, the HLA association of MS may be related to the production of these cytokines. To test this hypothesis, we investigated the production of LT, TNF‐α, and interferon‐γ (IFN‐γ) by CD4+ T‐cell lines (TCLs) specific for myelin basic protein (MBP) or tetanus toxoid (TT) isolated from MS patients and normal controls. After stimulation with specific antigen but not mitogen, TCLs from HLA‐DR2+ donors produced significantly more LT and TNF‐α, than TCLs from DR2− donors. In contrast, HLA‐DR2+ and DR2− TCLs did not differ in the production of IFN‐γ, a cytokine also produced by T cells but not encoded in the HLA region. Increased secretion of LT and TNF‐α was unrelated to the specificity (MBP vs TT), MHC restriction (HLA‐DR2 vs other DR molecules), or source (MS vs normal) of the TCLs. There was no significant association of the cytokine production with individual LT or TNF‐α alleles, indicating that the increased production of these cytokines may be linked to other polymorphic genes in this region. The results suggest that the association of MS with HLA‐DR2 implies a genetically determined propensity of T cells to produce increased amounts of LT and TNF‐α.
Significance of spikes recorded on electrocorticography in nonlesional medial temporal lobe epilepsy
Authors: Tran T. A. , Spencer S. S. , Marks D. , Javidan M. , Pacia S. , Spencer D. D.
Published: January 2005

Whether spikes recorded by intraoperative electrocorticography imply active epileptogenicity has not been adequately addressed. We performed preresection and postresection electrocorticography on 47 patients with nonlesional medial temporal lobe epilepsy who were undergoing surgery for the treatment of medically refractory epilepsy. A standard anteromedial temporal lobectomy was performed on all patients, with no additional resection, regardless of electrocorticographic findings. Patients were divided into two groups: Group I (no seizures or rare seizures) and Group II (recurrent seizures). Recorded spikes were analyzed for distribution and spike discharge rate. On preresection electrocorticography, 83% of Group I and 82% of Group II had spikes in the anterior temporal lobe. The spike discharge rate was equally distributed between high frequency and low frequency for both groups (not significant). Although spikes localized to the posterior temporal neocortex were seen more in Group II (64%) than Group I (39%), this was not a significant difference (p > 0.1). Most of these patients had a low‐frequency spike discharge rate. On postresection electrocorticography, 80% of Group I and 75% of Group II had residual spikes. The majority of these had a lowfrequency spike discharge rate and were localized to the Marchgin of resection. We found no correlation between residual spikes on preresection and postresection electrocorticography and outcome. These findings do not support the role of intraoperative electrocorticography in guiding mesial temporal lobe resection.
Early copper therapy in classic Menkes disease patients with a novel splicing mutation
Authors: Kaler Stephen G. , Buist Neil R. M. , Holmes Courtney S. , Goldstein David S. , Miller Richard C. , Gahl William A.
Published: January 2005

To correlate genotype with response to early copper histidine therapy in Menkes disease, an X‐linked disorder of copper transport, we performed mutational analysis in 2 related males who began treatment at the age of 10 days and prenatally at 32 weeks' gestation, respectively. A G to T transversion at the —1 exonic position of a splice donor site was identified, predicting a glutamine to histidine substitution at codon 724 of the Menkes copper‐transporting ATPase gene. The Q724H mutation disrupts proper splicing and generates five mutant transcripts that skip from one to four exons. None of these transcripts is predicted to encode a functional copper transport protein. Copper histidine treatment normalized circulating copper and ceruloplasmin levels but did not improve the baseline deficiency of dopamine‐β‐hydroxylase, a copper‐dependent enzyme. At the age of 36 months, the first patient was living and had neurodevelopmental abilities ranging from 10 to 15 months. The second patient also showed delayed neurodevelopment and died of pulmonary complications at the age of 5 1/2 months. We conclude that early copper histidine therapy does not normalize neurological outcome in patients with the Q724H splicing mutation, and suggest that preservation of some residual Menkes ATPase activity may be a general prerequisite for significant clinical efficacy from such treatment.
Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions
Authors: Gilman Sid , Sima Anders A. F. , Junck Larry , Kluin Karen J. , Koeppe Robert A. , Lohman Mary E. , Little Roderick
Published: January 2005

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCAl mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [18F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [llC]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCAl gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.
Wolfram syndrome: Hereditary diabetes mellitus with brainstem and optic atrophy
Authors: Scolding Neil J. , Kellar‐Wood Helen F. , Shaw C. , Shneerson John M. , Antount Nagui
Published: January 2005

Wolfram syndrome was originally described as a combination of familial juvenile‐onset diabetes mellitus and optic atrophy. Other neurological features subsequently emerged, and “DIDMOAD” (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) became a commonly accepted acronym. Here, we describe 4 further cases from 2 families, in whom there occurred previously unrecognized neurological features, central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure (fatal in 1 case), startle myoclonus (in 2 unrelated cases), axial rigidity, and Parinaud's syndrome. Magnetic resonance images revealed striking brainstem atrophy affecting, in particular, the pons and midbrain. The mitochondrial DNA from 3 cases (and relatives) showed no evidence of any of the previously reported abnormalities. These neurological and neuroradiological features, in conjunction with (1) analyses showing the neurodegenerative origin of optic atrophy, deafness, diabetes insipidus, and incontinence, (2) other previously reported neurological complications (including anosmia, ataxia, epilepsy, and neuropsychiatric and cognitive abnormalities), and (3) the very small number of published postmortem studies, indicate that Wolfram syndrome should be reemphasized as a unique hereditary neurodegenerative disorder with prominent optic atrophy and diabetes mellitus.
Aβ‐peptide length aid apolipoprotein E genotype in Alzheimer's disease
Authors: Gearing Marla , Mori Hiroshi , Mirra Suzanne S.
Published: January 2005

Apolipoprotein ∈ (ApoE)ε4 allele, a risk factor for the development of Alzheimer's disease (AD), is associated with increased amyloid deposition. We examined cerebral cortex in 68 AD cases using antibodies to βbeta;‐amyloid (Aβbeta;) peptides of different length (Aβbeta;1−40 and Aβbeta;l−42) and found that the increased plaque frequency observed with ε4 genotypes may be largely attributed to an increase in Aβbeta;1−40‐positive plaques. Indeed, both the number of Aβbeta;1−40‐positive plaques, as well as the ratio of Aβbeta;I−40/ Aβbeta;1−42‐positive plaques, increased with ε4 dosage. In contrast, the frequency of Aβbeta;1−42‐immunoreactive plaques was similar for ε3/ε3,ε3/ε4 and ε4/ε4 genotypes. ApoE may influence Aβbeta; length by facilitating Aβbeta; 1−40 deposition onto Aβbeta;1−42‐seeded plaques or by modulating the activity of a putative carboxypeptidase that forms Aβbeta;1−40 from Aβbeta;1−42 in situ.
Impact of aerobic training on fitness and quality of life in multiple sclerosis
Authors: Petajan Jack H. , Gappmaier Eduard , White Andrea T. , Spencer Mark K. , Mino Lizbeth , Hicks Richard W.
Published: January 2005

Fifty‐four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (Vo2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 × 40‐minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in Vo2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very‐low‐density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.
Anti‐GD1a ganglioside antibodies in peripheral motor syndromes
Authors: Carpo Marinella , Nobile‐Orazio Eduardo , Meucci Nicoletta , Gamba Massimo , Barbieri Sergio , Allaria Silvia , Scarlato Guglielmo
Published: January 2005

High titers of anti‐GD 1a antibodies have been found in patients with Guillain‐Barŕe syndrome or motor neuropathy. To determine the possible diagnostic relevance of these antibodies, we measured serum anti‐GD 1a IgG and IgM antibodies by enzyme‐linked immunosorbent assay in 195 patients with different motor syndromes and in 335 control subjects. Moderately high antibody titers (I/ 1,280‐1/5,120) were occasionally found in patients with chronic inflammatory demyelinating polyneuropathy (5%), multifocal motor neuropathy (18%), lower motor neuron disease (3.8%), or amyotrophic lateral sclerosis (1.8%) and in immunological control subjects (1.2%), while titers of 1/20,480 or higher were only found in 2 patients with Guillain‐Barri! syndrome (IgG in both) and 2 with motor neuropathy and IgMλ monoclonal gam‐mopathy improving with immunotherapy. In both motor neuropathy patients and the Guillain‐Barŕe syndrome patient who were retested during recovery, anti‐GD 1a titers decreased concomitantly with clinical improvement. High anti‐GD 1a antibody titers may be found in several motor syndromes but only markedly increased anti‐GD 1a titers are strictly associated with potentially treatable dysimmune neuropathies.
Human T‐lymphotropic virus type I‐associated myelopathy and tax gene expression in CD4+ T lymphocytes
Authors: Moritoyo Takashi , Reinhart Todd A. , Haase Ashley T. , Moritoyo Hiroyoko , Izumo Shuji , Osame Mitsuhiro , Sato Eiichi
Published: January 2005

Infection by human T‐lymphotropic virus type I (HTLV‐I) is associated with adult T‐cell leukemia and a slowly progressive disease of the central nervous system (CNS), HTLV‐I‐associated myelopathy/tropical spastic paraparesis, characterized pathologically by inflammation and white matter degeneration in the spinal cord. One of the explanations for the tissue destruction is that HTLV‐I infects cells in the CNS, or HTLV‐I‐infected CD4+ T lymphocytes enter the CNS, and this drives local expansion of virus‐specific CD8+ cytotoxic T lymphocytes, which along with cytokines cause the pathological changes. Because both in the circulation and in the cerebrospinal fluid, CD8+ cytotoxic T lymphocytes are primarily reactive to the product of the HTLV‐I tax gene, we sought evidence of expression of this gene within cells in the inflammatory lesions. After using double‐label in situ hybridization techniques, we now report definitive localization of HTLV‐I tax gene expression in CD4+ T lymphocytes in areas of inflammation and white matter destruction. These findings lend support to a hypothetical scheme of neuropathogenesis in which HTLV‐I tax gene expression provokes and sustains an immunopathological process that progressively destroys myelin and axons in the spinal cord.
Effect of lazabemide on the progression of disability in early Parkinson's disease
Authors: Kieburtz
Published: January 2005

Lazabemide (Ro 19‐6327) is a relatively short‐acting, reversible, and selective type B monoamine oxidase inhibitor that is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg/day during a 6‐week study of 201 patients with early untereated Parkinson's disease (PD). We now assess whether or not lazabemide influences the progression of disability in untreated PD. Patients (N = 321) were assigned by randomization to one of five treatment groups (placebo, 25 mg, 50 mg, 100 mg, or 200 mg/day) and followed systematically for up to 1 year. The risk of reaching the primary end point (the onset of disability sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with placebo‐treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not placebo‐treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not differ among the treatment groups. At dosages ranging from 25 to 200 mg/day, lazabemide was well tolerated and delayed the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of benefits were similar to those observed after 1 year of deprenyl (selegiline) treatment in the DATATOP clinical trial.
Motor neuron disease: A paraneoplastic process associated with anti‐Hu antibody and small‐cell lung carcinoma
Authors: Verma Ashok , Berger Joseph R. , Snodgrass Susan , Petito Carol
Published: January 2005

Although isolated lower motor neuron disease has been reported as a paraneoplastic complication, it has not been previously described in association with anti‐Hu antibody. We report a 51‐year‐old man in whom weakness heralded the presence of a small‐cell cancer of the lung. His neurological disorder was characterized by an unremitting progression of limb, neck, and chest wall weakness and wasting that commenced and remained predominant in the upper limbs. Electrophysiological studies demonstrated widespread denervation and examination of a muscle biopsy specimen showed evidence of acute and chronic denervation. High titers of anti‐Hu antibody were detected in the serum and cerebrospinal fluid. Neither objective measures of strength nor titers of anti‐Hu antibody responded to corticosteroids, cyclophosphamide, intravenous immunoglobulins, or plasmapheresis. Death from the complications of motor neuron disease ensued 23 months after the onset of weakness. Autopsy revealed tumor in the lung and on pleural and peritoneal surfaces. There was a loss of anterior horn cells in the spinal cord. Despite the absence of symptomatic cerebellar disease, a decrease in the number of Purkinje cells was also detected.
Neurodegenerative disorders with extensive tau pathology: A comparative study and review
Authors: Feany Mel B. , Dickson Dennis W.
Published: January 2005

Many neurodegenerative disorders with onset in mid to late adult life present diagnostic challenges to clinicians and pathologists alike. A distinguishing neuropathological feature has traditionally been the presence or absence of neurofibrillary tangles. Recent biochemical and molecular biological studies have identified the microtubule‐binding protein tau as the predominant component of these and related inclusions, and have provided powerful new reagents for the study of neurodegenerative diseases. Several diseases previously considered distinct pathophysiological entities contain similar tau‐immunoreactive lesions, but qualitative and regional anatomical differences in vulnerability can differentiate the disorders. Comparison of tau‐immunoreactive lesions in three relatively uncommon neurodegenerative diseases—progressive supranuclear palsy, Pick's disease, and corticobasal degeneration—illustrates the types of analyses that demonstrate unexpeceted pathological similarities, but also fundamental differences between these disorders. These results have important implications for the differential diagnosis of disorders containing tau‐immunoreactive lesions, including Alzheimer's disease.
Sequence of mitochondrial DNA in patients with multiple sclerosis
Authors: Chalmers R. M. , Harding A. E. , Robertson N. , Compston D. A. S.
Published: January 2005

The excess female transmission of multiple sclerosis (MS) and the observation of an MS‐like illness in patients with Leber's hereditary optic neuropathy who carry a mitochondrial DNA mutation may indicate that mitochondrial genes contribute to the genetic susceptibility to MS. We sequenced the protein‐ and RNA‐coding sequences of 9 patients with MS who had a family history of MS consistent with maternal transmission. Four base‐pair (bp) changes of particular interest were identified. Those at bp 4216 and 4917 may play a role in the etiology of Leber's hereditary optic neuropathy. Two others, at bp 11447 and 14766, were found in all MS patients sequenced. Restriction enzyme analysis used to screen 175 unrelated MS patients and 233 healthy control subjects showed that each of these changes was present in MS patients at a similar frequency to control subjects. The 4216 and 4917 changes were at a higher frequency in north European control subjects than previously documented. We conclude that variation in mitochondrial DNA is unlikely to contribute to susceptibility to MS. The etiology of the overlap between Leber's hereditary optic neuropathy and MS remains unexplained.
Altered mental status in thrombotic thrombocytopenic purpura is secondary to nonconvulsive status epilepticus
Authors: Garrett William T. , Bleck Thomas P. , Chang Cherylee W. J.
Published: January 2005

Thrombotic thrombocytopenic purpura (TTP) is a syndrome with numerous neurological manifestations including altered mental status and seizures. At least 10% of the patients with TTP seen at our institution had non‐convulsive status epilepticus as a cause of or associated with their altered mental status. We propose that altered mental status secondary to nonconvulsive status epilepticus requiring electroencephalographic diagnosis and antiepileptic medication occurs in a substantial proportion of patients with TTP.
Lambert‐eaton myasthenic syndrome immunoglobulins react with multiple types of calcium channels in small‐cell lung carcinoma
Authors: Meriney Stephen D. , Hulsizer Susan C. , Grinnell Alan D. , Lennon Vanda A.
Published: January 2005

Barium currents through voltage‐gated calcium (Ca2+) channels were studied in the small‐cell lung carcinoma cell line NCI‐H345 using patch clamp techniques. Pharmacological dissection of whole‐cell barium currents revealed that 23% of the current was sensitive to nitrendipine, 35% to ω‐conotoxin GVIA, and between 10 and 39% to ω‐Aga‐IVA. This implies that these cells express L‐, N‐, and P‐type calcium channels. Only large cells expressed current that was sensitive to ω‐Aga‐IVA. The size dependency of this P‐type channel expression may reflect the cell cycle stage. Cell‐attached recordings revealed three unitary conductances: 5 to 6 pS, 10 to 12 pS, and 20 to 23 pS. The largest conductance channel (20‐23 pS) was sensitive to bay K 8644 and is presumed to represent L‐type calcium channels. The frequency of observing the medium conductance channel (10‐12 pS) was reduced by exposure to ω‐conotoxin GVIA and may represent N‐type channels. Incubation of cells with Lambert‐Eaton myasthenic syndrome IgG for 24 to 48 hours removed up to 71% of the whole‐cell current. Incubation with control human IgG (normal or myasthenia gravis) had no effect. Lambert‐Eaton maysthenic syndrome IgG did not selectively target one “presynaptic” type of calcium channel, but rather appeared to target many of the calcium channel types that are expressed on small‐cell lung carcinoma cells.
Acute and chronic effects of hypoxia on the developing hippocampus
Authors: Owens James , Robbins Carol A. , Wenzel H. Jurgen , Schwartzkroin Philip A.
Published: January 2005

Perinatal hypoxia i associated with both seizures arising acutely and the subsequent development of temporal lobe epilepsy (as determined retrospectively). We terefore attempted to identify acute and chronic morphological and/or electrophysiological hippocampal pathologies assiciated with experimentally induced hypoxia in immature rats. Pups were exposed to 15 minutes of hypoxia on 3 successive days (starting on postnatal dya 8; P8), or to 60 minutes of hypoxia on P10 with either one or multiple hupoxia‐induced seizures. For animals experiencing multiple seizures, flurothyl seizure threshold was significantly lower than that of controls at 60 to 80 days, but not at 10 days, after hypoxia. Acutely, there was a treatment‐related increase in the number and the density of pyknotic dentate and hilar neurons, in particular in animals experiencing multiple seizures. However, 60 to 80 days after the multiple‐sezure protocol, the number of dentate and hilar neurons did not differ between expermental and control animals at any time point. These results indicate that early postnatal hupoxia and hypoxia‐induced seizure episodes decrease seizure threshold in the adult but produce minimal acute or chronic morphological or functional chages in the hippocampus.
Sequestration of RNA in Alzheimer's disease neurofibrillary tangles and senile plaques
Authors: Ginsberg Stephen D. , Crino Peter B. , Lee Virginia M.‐Y. , Eberwine James H. , Trojanowski John Q.
Published: January 2005

The polypeptide composition of neurofibrillary tangles (NFTs) and senile plaques (SPs) has been characterized extensively within the Alzheimer's disease (AD) brain. Because few data exist on the nonproteinaceous components of these lesions, we sought to determine if NFTs, neuropil threads (NTs), and SPs contain RNA species. To acoomplish this, acridine orange (AO) histofluorescence was employed, alone or in combination with thioflavine S (TS) staining and immunohistochemistry to identify RNAs in paraffin‐embedded tissue sections of hippocampus and entorhinal cortex. Postmortem brain samples came from 32 subjets including AD and elderly Down's syndrome (DS) patints, age‐matched normal controls, and non‐AD diseased controls. AO stained the cytoplasm of normal hippocampal and entorhinal neurons in all of the cases, while NFTs, NTs, and SPs were AO‐positive in the same regions of AD and DS brains. Cytoplasmic AO histofluorescence was abolished with RNase, but not DNase or proteinase K, indicating the relative specificity of AO for RNA species. Quantitative analysis of double‐labeled sections demonstrated that approximately 80% of TS‐positive NFTs also were AO‐positive, whereas approximately 55% of TS‐stained SPs contained AO labeling. These novel observations demosntrate the presence of RNAs in NFTs, NTs, and SPs.
Imaging of axonal damage in multiple sclerosis: Spatial distribution of magnetic resonance imaging lesions
Authors: Narayanan S. , Fu L. , Pioro E. , De Stefano N. , Collins D. L. , Francis G. S. , Antel J. P. , Matthews P. M. , Arnold D. L.
Published: January 2005

We performed magnetic resonance imaging and magnetic resonance spectroscopic imaging on 28 patients with multiple sclerosis stratified for disability and clinical course (relapsing with at least partial remissions or secondary progressive disease). Lesions were segmented on the conventional proton density and T2‐weighted magnetic resonance images, and lesion distribution images were generated for each patient. The conventional magnetic resonance and spectroscopic images were transformed into a standard brain‐based stereotaxic coordinate space, allowing comparison of images from different patients on a voxel‐by‐voxel basis. The spatial distribution of lesions in the transformed magnetic resonance images did not differ significantly between the relapsing and the progressive disease groups. We then generated from the individual data sets, group lesion probability distribution images for the relapsing and the progressive disease groups. The spatial distribution of metabolites was characterized with respect to lesion distribution using the magnetic resonance spectroscopic images transformed into stereotaxic space and averaged. The neuronal marker N‐acetylaspartate was diffusely lower in the multiple sclerosis patients than in normal control subjects. Comparison of the averaged metabolite and T2‐weighted lesion probability images confirmed loss of N‐acetylaspartate in regions of both high and low lesion probability. This suggests that diffuse axonal volume loss or dysfunction extends beyond the inflammatory lesions of multiple sclerosis, perhaps due to microscopic disease or wallerian degeneration along projection pathways of axons traversing the lesions.
Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia
Authors: Browne Susan E. , Bowling Allen C. , Macgarvey Usha , Baik M. Jay , Berger Stephanie C. , Muquit Miratul M. K. , Bird Edward D. , Beal M. Flint
Published: January 2005

The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase‐corrected complex II‐III activity was markedly reduced in both HD caudate (−29%) and putamen (−67%), and complex IV activity was reduced in HD putamen (−62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8‐hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.
Allelic heterogeneity of mediterranean myoclonus and the cystatin B gene
Authors: Labauge Pierre , Ouazzani RÉDa , M'Rabet Amel , Grid Djamel , Genton Pierre , Dravet Charlotte , Chkili Taieb , Beck Corrine , Buresi Catherine , Baldy‐Moulinier Michel , Malafosse Alain
Published: January 2005

Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Anothe form has been described in Finland, the so‐called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht‐Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht‐Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht‐Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.
CAG repeat number governs the development rate of pathology in Huntington's disease
Authors: Penney John B. , Vonsattel Jean‐Paul , Macdonald Marcy E. , Gusella James F. , Myers Richard H.
Published: January 2005

We compared the number of CAG repeats, the age at death, and the severity of neuropathology in 89 Huntington's disease brains. We found a linear correlation between the CAG repeat number and the quotient of the degree of atrophy in the striatum (the brain region most severely affected in Huntington's disease) divided by age at death, with an intercept at 35.5 repeats. The largest CAG repeat length, therefore, at which no pathology is expected to develop is 35.5. These results imply that striatal damage in Huntington's disease is almost entirely a lineaar function of the length of the polyglutamine stretch beyond 35.5 glutamines multiplied by the age of the patient. Thus, it is predicted that the pathological process develops linearly from birth. Analysis of other measures of striatal function could test this hypothesis and might determine when treatment for CAG repeat diseases should start.
Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease
Authors: Minoshima Saroshi , Giordani Bruno , Berent Stanley , Frey Kirk A. , Foster Norman L. , Kuhl David E.
Published: January 2005

This study investigated cerebral glucose metabolism in very early Alzheimer's disease, before a clinical diagnosis of probable Alzheimer's disease is possible, using [18F]fluorodeoxyglucose positron emission tomography. First, 66 patients with probable Alzheimer's disease with a spectrum of dementia severity (Mini‐Mental State Examination score, 0–23) were recruited and studied. Cortical metabolic activity was analyzed topographically using three‐dimensional stereotactic surface projections. Regression analysis was performed for each brain pixel to predict metabolic patterns of very early disease. Predictions were tested prospectively in a group of 8 patients who complained only of memory impairment without general cognitive decline (Mini‐Mental State Examination score, 25 · 1) at the time of scanning but whose condition later progressed to probable Alzheimer's disease. Both results were compared to cerebral metabolic activity in 22 age‐similar normal control subjects. Prediction and analysis of actual patients consistently indicated marked metabolic reduction (21–22%) in the posterior cingulate cortex and cinguloparietal transitional area in patients with very early Alzheimer's disease. Mean metabolic reduction in the posterior cingulate cortex was significantly greater than that in the lateral neocortices or parahippocampal cortex. The result suggests a functional importance for the posterior cingulate cortex in impairment of learning and memory, which is a feature of very early Alzheimer's disease.
Early‐onset Alzheimer's disease with a presenilin‐1 mutation at the site corresponding to the volga German presenilin‐2 mutation
Authors: Crook Richard , Ellis Ronald , Shanks Megan , Thal Leon J. , Perez‐Tur Jordi , Baker Matt , Hutton Mike , Haltia Tuomas , Hardy John , Galasko Douglas
Published: January 2005

We describe a new mutation causing Alzheimer's disease (AD) in presenilin‐1 (N135D) that is at the homologous site to the presenilin 2 mutation (N141I) in Volga German kindreds. The phenotype of PS1 N135D is an early‐onset (34–38 years) disease. The mutation forms part of, and extends, the α‐helical array of mutations in transmembrane 2 of the presenilins and leads to the suggestion that disruption of this helical face is the molecular insult that leads to disease.