bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in down Syndrome
Authors: Iwatsubo Takeshi , Mann David M. A. , Odaka Asano , Suzuki Nobuhiro , Ihara Yasuo
Published: January 2005

The chronological relationship regarding deposition of amyloid β protein (Aβ) species, Aβ40 and Aβ42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years. The frontal cortex was probed with two end‐specific monoclonals that recognize Aβ40 or Aβ42(43). All senile plaques detected with an authentic β monoclonal were also Aβ42(43) positive, but only a varying proportion was Aβ40 positive. In young (≤ 50 years old) brains there were many Aβ42(43)‐positive, Aβ40‐negative diffuse plaques, but only few Aβ40‐positive senile plaques (mean, 6.3% of total number of senile plaques). The 2 youngest Down syndrome brains showed only diffuse plaques that were all Aβ42(43) positive but Aβ40 negative. Old (≤ 50 years old) brains contained many mature senile plaques with amyloid cores in addition to diffuse and immature plaques and the proportion of Aβ40‐positive senile plaques was increased (mean, 42% of total). Cerebral amyloid angiopathy was more abundant in old Down syndrome brains and was positive for both Aβ40 and Aβ42(43). In cerebral amyloid angiopathy, Aβ40 predominated over Aβ42(43) in both staining intensity and number of positive vessels. These results indicate that (1) the Aβ species intially deposited in the brain as senile plaques is Aβ42(43) and Aβ40 only appears a decade later, and (2) in cerebral amyloid angiopathy Aβ40 appears as early as Aβ42(43).
Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia
Authors: Ceballos‐Baumann A. O. , Passingham R. E. , Warner T. , Playford E. D. , Marsden C. D. , Brooks D. J.
Published: January 2005

Regional cerebral blood flow was measured using H215O and positron emission tomography in a group of 6 patients with idiopathic torsion dystonia and in a group of 6 control subjects. Subjects were scanned while at rest and when performing paced joystick movements in freely chosen directions with the right hand. Patients with idiopathic torsion dystonia showed significant overactivity in the contralateral lateral premotor cortex, rostral supplementary motor area, Brodmann area 8, anterior cingulate area 32, ipsilateral dorsolateral prefrontal cortex, and bilateral lentiform nucleus. Significant underactivity was found in the caudal supplementary motor area, bilateral sensorimotor cortex, posterior cingulate, and mesial parietal cortex. These results are consistent with inappropriate overactivity of striatofrontal projections and impaired activity of motor executive areas in idiopathic torsion dystonia and may explain the simultaneous dystonic posturing and bradykinesia evident in these patients.
In vitro evidence for a dual role of tumor necrosis factor‐α in human immunodeficiency virus type 1 encephalopathy
Authors: Wilt Susan G. , Milward Elizabeth , Zhou Jia Min , Nagasato Kunihiko , Patton Heather , Rusten Ray , Griffin Diane E. , O'Connor Michael , Dubois‐Dalcq Monique
Published: January 2005

Microglial cell activation, myelin alteration, and abundant tumor necrosis factor (TNF)‐α message have been observed in the brains of some human immunodeficiency virus type 1 (HIV ‐ 1)vinfected and demented patients. We therefore used cultures of purified human microglia and oligodendrocytes derived from adult human brain to examine the role of TNF‐α in HIV‐1 encephalopathy. Human microglia synthesize TNF‐α message and protein in vitro. When these cells were infected with HIV‐1 JrFL and maintained in the presence of TNF‐α antibodies, soluble TNF‐α receptors, or the TNF‐α inhibitor pentoxifylline, viral replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF‐Rl, which has been implicated in cytotoxicity, and TNF‐R2. While TNF‐α may enhance HIV‐1 replication in an autocrine manner, it is not toxic for microglia. In contrast, recombinant human TNF‐α causes oligodendrocyte death in a dose‐dependent manner. In situ detection of DNA fragmentation in some cells indicated that oligodendrocyte death may occur by apoptosis. Addition of live microglia or medium conditioned by these cells also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF‐α inhibitors. We propose that TNF‐α plays a dual role in HIV‐1 encephalopathy, enhancing viral replication by activated microglia and damaging oligodendrocytes. Thus, TNF‐α inhibitors may alleviate some ofthe neurological manifestations of acquired immunodeficiency syndrome.
Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results
Authors: Palmini André , Gambardella Antonio , Andermann Frederick , Dubeau Francois , da Costa Jaderson C. , Olivier André , Tampieri Donatella , Gloor Pierre , Quesney Felipe , Andermann Eva , Paglioli Eduardo , Paglioli‐Neto Eliseu , Andermann Ligia Coutinho , Leblanc Richard , Kim Hyoung‐Ihl
Published: January 2005

Cortical dysplastic lesions (CDyLs) are often associated with severe partial epilepsies. We describe the electrographic counterpart of this high degree of epileptogenicity, manifested by continuous or frequent rhythmic epileptogenic discharges recorded directly from CDyLs during intraoperative electrocorticography (ECoG). These ictal or continuous epileptogenic discharges (I/CEDs) assumed one of the following three patterns: (1) repetitive electrographic seizures, (2) repetitive bursting discharges, or (3) continuous or quasicontinuous rhythmic spiking. One or more of these patterns were present in 23 of 34 patients (67%) with intractable partial epilepsy associated with CDyLs, and in only 1 of 40 patients (2.5%) with intractable partial epilepsy associated with other types of structural lesions. I/CEDs were usually spatially restricted, thus contrasting with the more widespread interictal ECoG epileptic activity, and tended to colocalize with the magnetic resonance imaging–defined lesion. Completeness of excision of cortical tissue displaying I/CEDs correlated positively with surgical outcome in patients with medically intractable seizures; i.e., three‐fourths of the patients in whom it was entirely excised had favorble surgical outcome; in contrast, uniformly poor outcome was observed in those patients in whom areas containing I/CEDs remained in situ. We conclude that CDyLs are highly and intrinsically epileptogenic, and that intraoperative ECoG identification of this intrinsically epileptogenic dysplastic cortical tissue is crucial to decide the extent of excision for best seizure control.
Lyme neuroborreliosis
Authors: Garcia‐Monco Juan Carlos , Benach Jorge L.
Published: January 2005

Neuroborreliosis, an infection of the nervous system caused by spirochetes of the genus Borrelia, has achieved worldwide attention in the last decade as part of the clinical spectrum of Lyme disease. This disorder, caused by Borrelia burgdorferi, has increased in incidence to become the most frequent arthropod‐borne infection in North America and Europe. As a result of this rapid rise in incidence and of its protean neurological manifestations, this disease has created an important challenge to modern neurology. The diverse manifestations of neuroborreliosis require that it be included in the differential diagnosis of many neurological disorders. This review takes a chronological approach to clinical neuroborreliosis to summarize its most important aspects. The limitations as well as the benefits of laboratory diagnosis are also considered, with the aim of providing assistance in this area. Recent advances in neuroimmunology regarding the pathogenesis of neuroborreliosis that may elucidate its protean clinical spectrum are summarized.
Low platelet mitochondrial complex I and complex II/III activity in early untreated parkinson's disease
Authors: Haas Richard H. , Nasirian Fatemeh , Nakano Kazutoshi , Ward David , Pay Mary , Hill Robert , Shults Clifford W.
Published: January 2005

Following the discovery of inhibition of electron transport complex I by the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), which produces a parkinsonian syndrome in humans, monkeys, and mice, several laboratories have reported abnormalities of complex I and other electron transport complexes (ETCs) in various tissues from patients with Parkinson's disease (PD). Criticism of the significance of these findings in the etiology of PD has centered on whether drug treatments or the debilitation of the disease process itself produced the low ETC activities. We present results from a blinded study of platelet mitochondrial ETC activities in 18 early untreated PD patients and 18 age‐ and sex‐matched controls and in 13 spousal controls. Lower complex I activity in platelet mitochondria of PD patients was seen in early untreated disease and thus cannot be due to debilitation or drug therapy. Home environmental factors seem an unlikely explanation for the reduced complex I activity in PD patients but have not been excluded. Complex II/III activity was also reduced by 20% in PD compared with age‐/sex‐matched controls. The low complex I and II/III activities in platelet mitochondria appear to be related to the etiology of PD.
Expression of heme oxygenase‐1 in the senescent and alzheimer‐diseased brain
Authors: Schipper H. M. , Cissé S. , Stopa E. G.
Published: January 2005

Heme oxygenase‐1 is a cellular stress protein expressed in brain and other tissue in response to oxidative challenge and other noxious stimuli. Using immunohistochemistry and immunofluorescent labeling in conjunction with laser scanning confocal microscopy, we observed intense immunoreactivity of heme oxygenase‐1 in neurons of the hippocampus and temporal cortex of Alzheimer‐diseased (AD) brain relative to age‐matched control specimens. Furthermore, we demonstrated consistent colocalization of heme oxygenase‐1 to glial fibrillary acidic protein–positive astrocytes, neurofibrillary tangles, and senile plaques in the AD specimens. In AD hippocampus, approximately 86% of glial fibrillary acidic protein–positive astrocytes expressed heme oxygenase‐1, whereas only 6.8% of hippocampal astrocytes in normal senescent control specimens were immunopositive for heme oxygenase‐1 (p < 0.0001). In regions other than the hippocampus and neocortex, such as the substantia nigra, the proportion of astrocytes expressing heme oxygenase‐1 in the experimental group (12.8%) was not significantly different from that in the controls (6.4%, p > 0.05). Robust 32‐kd bands corresponding to heme oxygenase‐1 were observed by Western blotting of protein extracts derived from AD temporal cortex and hippocampus after sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Heme oxygenase‐1 bands were very faint or absent in protein extracts prepared from control specimens. These results indicate that heme oxygenase‐1 is significantly overexpressed in neurons and astrocytes of AD hippocampus and cerebral cortex relative to control brains. Upregulation of heme oxygenase‐1 in AD brain supports the contention that the affected tissues are experiencing chronic oxidative stress. In addition, the excessive generation of carbon monoxide, a metabolite of heme degradation, may participate in the pathogenesis of AD.
Tonic vibration reflex and muscle afferent block in writer's cramp
Authors: Kaji Ryuji , Rothwell John C. , Katayama Mari , Ikeda Tomoko , Kubori Tamotsu , Kohara Nobuo , Mezaki Takahiro , Shibasaki Hiroshi , Kimura June
Published: January 2005

Patients with focal dystonia take advantage of certain cutaneous or proprioceptive sensory inputs to alleviate their symptoms (“sensory trick”). We examined the effects of increasing muscle spindle activity by the tonic vibration reflex maneuver and Decemberreasing it by intramuscular injection of lidocaine. The vibration was applied to the palm or the tendon of forearm muscles in 15 patients with writer's cramp and 15 age‐matched normal subjects. In 11 patients, the vibration induced dystonic postures or movements typical of those seen during writing. Normal subjects showed either no response to the vibration or a gradually developing tonic vibration reflex only in the wrist and finger flexors, which produced visible movements with a significantly longer latency (12.5 ± 6.7 seconds [mean ± standard deviation]) than what was observed in the patients (2.7 ± 2.5 seconds, p < 0.0001). Local injection of lidocaine (0.5%, 5–40 ml/muscle) attenuated the tendon reflex with relatively little effect on the M response. Injection into muscles with increased activity produced Marchked reduction of dystonic movements and significant clinical improvement in 13 patients, whereas injection into the other muscles had no effect. The clinical benefit lasted for 1 to 24 hours after injection. In 13 patients who had additional injections of 10% ethanol, which blocks sodium channels for a longer period than does lidocaine, the duration of action was prolonged to 5 to 21 days. These findings suggest that muscles causing dystonic movements have abnormal sensitivities to vibration at rest and that muscle afferents may play a pivotal role in producing dystonic movements. Local injection of lidocaine or ethanol reduces the effectiveness of muscle spindle afferent and may provide a means of treating patients with writer's cramp without causing unwanted weakness.
Frontal lobe phosphorus metabolism and neuropsychological function in aging and in alzheimer's disease
Authors: Smith Charles D. , Creed Pettigrew L. , Avison Malcolm J. , Kirsch John E. , Tinkhtman Alexander J. , Schmitt Frederick A. , Wermeling Daniel P. , Wekstein David R. , Marchkesberry William R.
Published: January 2005

31P Magnetic resonance spectroscopy of the frontal lobe was performed in 17 patients with Alzheimer's disease (AD), 8 elderly controls (EC), and 17 young controls (YC). The phosphocreatine/inorganic phosphate (PCr/Pi) ratio in AD (2.32 ± 0.26 SD) was significantly lower than in EC (2.65 ± 0.41). In AD patients, a correlation was observed between the PCr/Pi ratio and the dementia rating scale (r = −0.50, p = 0.04). A significant positive correlation between PCr/Pi ratio and age was observed in both AD (r = 0.67, p 0.003) and YC (r = 0.63, p 0.006) groups, however, suggesting caution in interpretation of this ratio in AD. We did not find differences between AD, EC, or YC in any other spectroscopic measure. A significant sex difference in the phosphomonoester/phosphodiester ratio (PME/PDE) ratio was observed in AD brain. Females had a lower PME/PDE ratio than males.
Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy
Authors: Sivakumar K. , Cervenáková L. , Dalakas M. C. , Leon‐Monzon M. , Isaacson S. H. , Nagle J. W. , Vasconcelos O. , Goldfarb L. G.
Published: January 2005

Accumulation of β‐amyloid protein (Aβ) occurs in some muscle fibers of patients with inclusion body myopathy and resembles the type of amyloid deposits seen in the affected tissues of patients with Alzheimer's disease and cerebrovascular amyloidosis. Because mutations in exons 16 and 17 of the β‐amyloid precursor protein (βAPP) gene on chromosome 21 have been identified in patients with early‐onset familial Alzheimer's disease and Dutch‐type cerebrovascular amyloidosis, we searched for mutations of the same region in patients with familial inclusion body myopathy. Sequencing of both alleles in 8 patients from four unrelated families did not reveal any mutations in these exons. The amyloid deposition in familial forms of inclusion body myopathy may be either due to errors in other gene loci, or it is secondary reflecting altered βAPP metabolism or myocyte degeneration and cell membrane degradation.
Proton nuclear magnetic resonance spectroscopic imaging of human temporal lobe epilepsy at 4.1 T
Authors: Hetherington Hoby , Kuzniecky Ruben , Pan Jullie , Mason Graeme , Morawetz Richard , Harris Cheryl , Faught Edward , Vaughan Thomas , Pohost Gerald
Published: January 2005

We performed proton magnetic resonance spectroscopic imaging (MRSI) at high magnetic field (4.1 T) to study N‐acetylaspartate, creatine, and choline levels in the brains of normal control subjects and patients with intractable temporal lobe epilepsy. We compared the results of MRSI to those of other presurgical techniques to determine the sensitivity of this method in the lateralization of the epileptic focus. The normal hippocampal creatine—N‐acetylaspartate ratio was 0.71 ± 0.14 with no differences between left and right. Using the mean control hippocampal creatine—N‐acetylaspartate ratio plus 2 standard deviations to identify statistically significant changes, we found lateralizing metabolic abnormalities corresponding to the operated temporal lobe in all patients. Four patients (40%) had contralateral abnormalities, and 2 of them had bilateral independent seizure onset confirmed by intracranial electroencephalographic studies. Statistically significant increases in the choline—N‐acetylaspartate ratio in comparison to healthy volunteers were observed in 8 of the 10 patients. With the creatine—N‐acetylaspartate ratio, MRSI demonstrated a 100% sensitivity compared to magnetic resonance imaging, which identified pathology in 70% of the patients. These findings suggest that proton MRSI yields a distinctive metabolic profile in patients with temporal lobe epilepsy and is sensitive in detecting bilateral metabolic abnormalities in some patients. These preliminary findings suggest that MRSI is more sensitive than magnetic resonance imaging in the lateralization of epileptic foci in temporal lobe epilepsy.
Recovery of hypermetria after a cerebellar stroke occurs as a multistage process
Authors: Manto M. , Jacquy J. , Hildebrand J. , Godaux E.
Published: January 2005

In a prospective study, we repeatedly recorded fast goal‐directed wrist movements of 8 patients who had experienced an acute cerebellar hypermetria due to a stroke and who had subsequently recovered clinically. Movements and the associated agonist and antagonist electromyographic (EMG) activities were recorded before and after addition of inertial loads. Four stages characterized the recovery process. At stage 1, hypermetria was present in the basal state and was not modified by the addition of inertial loads. At stage 2, hypermetria, which was present in the basal state, was enlarged by mass addition. At stage 3, hypermetria was absent in the basal state, but was revealed by an inertial load increase. At stage 4, as in healthy subjects, there was no hypermetria without or with addition of inertial loads. At stage 1, the patients presented several defects. (1) Facing an increased inertia, they could not increase their agonist EMG activity. (2) The onset latency of their antagonist EMG activity was delayed. (3) Facing an increased inertia, they could not increase their antagonist EMG activity. Among these three defects, the first disappeared at stage 2, the second at stage 3, and the third at stage 4.
Apolipoprotein E ϵ4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis
Authors: Mui Stina , William Rebeck G. , McKenna‐Yasek Diane , Hyman Bradley T. , Brown Robert H.
Published: January 2005

Apolipoprotein E allele 4 (apo E ϵ4) is known to be in genetic disequilibrium with Alzheimer's disease and is associated with an earlier age at onset of dementia. Whether apo E ϵ4 is a specific risk factor for Alzheimer's disease or is a more general susceptibility factor that shifts the age at onset of neurodegenerative diseases to earlier ages is unknown. To test these possibilities, we determined the apolipoprotein E genotypes of subjects with familial or sporadic amyotrophic lateral sclerosis (ALS). ApoE allele frequencies of the the apoE gene of the ALS subjects (n = 170, ϵ2 = 0.071, ϵ3 = 0.771, ϵ4 = 0.159) were found to be comparable to the allele frequencies of the general population. Furthermore, no significant association was observed between the age at onset or the duration of ALS and the inheritance of apoE ϵ4: subjects with at least one copy of ϵ4 (sporadic ALS: n = 15, onset at 57.7 ± 13.9 years; familial ALS: n = 23, onset at 53.6 ± 9.5 years, duration [n = 14] of 2.6 ± 1.6 years) had comparable ages at onset and durations to subjects without ϵ4 (sporadic ALS: n = 28, onset at 53.1 ± 17.0 years; familial ALS: n = 56, onset at 50.8 ± 12.1 years, duration [n = 30] of 1.9 ± 0.8 years). The lack of association of apoE ϵ4 with the age at onset and the duration of ALS suggests that apoE ϵ4 does not have a global effect on the pathogenesis of other neurodegenerative diseases.
Cerebral transport and metabolism of 1‐11C‐D‐glucose during stepped hypoglycemia
Authors: Powers William J. , Dagogo‐Jack Samuel , Markham Joanne , Larson Kenneth B. , Dence Carmen S.
Published: January 2005

Attempts to measure blood‐to‐brain glucose transport and cerebral glucose metabolism with 11C‐glucose have been hampered by methods that require jugular venous sampling or do not adequately account for the efflux of labeled metabolites from the brain. We performed eight positron emission tomography studies with 1‐11C‐d‐glucose in macaques at arterial plasma glucose concentrations of 8.43 to 1.51 μmol ml−1 (152–27 mg dl−1) using a model that includes a fourth rate constant to account for regional egrees of all 11C‐metabolites. Values for blood‐to‐brain glucose influx, cerebral glucose metabolism, and brain free glucose concentration agreed closely with values obtained in mammals by other investigators. Values for net extraction fraction corresponded closely to simultaneously measured arteriovenous values. We demonstrated that utilization of a model that includes a fourth rate constant to account for regional egress of all 11C‐metabolites with positron emission tomography and 1‐11C‐d‐glucose provides accurate measurements of blood‐to‐brain glucose transport and cerebral glucose metabolism in vivo without need for jugular venous sampling, even under conditions of severe hypoglycemia.
Localization of subclinical ictal activity by functional magnetic resonance imaging: Correlation with invasive monitoring
Authors: Detre John A. , Sirven Joseph I. , Alsop David C. , O'Connor Michael J. , French Jaqueline A.
Published: January 2005

Functional magnetic resonance imaging (fMRI) with susceptibility‐based contrast was used to detect focal changes in cerebral blood flow and metabolism in a patient with focal epilepsy. The patient presented with frequent partial motor seizures involving his right lower face that spread to produce speech arrest and occasionally right arm jerking. Consciousness was never impaired during these events. A multislice echoplanar technique was used to acquire 16 contiguous axial slices every 4 seconds for 11 minutes. Although no overt seizures were observed or reported by the patient during the scanning, a time series analysis of the functional data revealed focal signal‐intensity changes in the posterior left frontal lobe, which correlated well both in duration and spatial localization with ictal activity subsequently recorded by invasive electrophysiological monitoring. The spatial localization of fMRI was more accurate than electroencephalography recorded from a subdural grid in predicting the site of successful surgical therapy. These results illustrate the potential of functional MRI for localizing seizure foci with high spatial and temporal resolution. Such studies can be readily combined with high‐resolution anatomical imaging, task‐activation studies, and other magnetic resonance techniques.
Movement‐related cortical potentials in writer's cramp
Authors: Deuschl G. , Toro C. , Matsumoto J. , Hallett M.
Published: January 2005

Movement‐related cortical potentials in response to simple, self‐paced, brisk index finger abduction movements were recorded in patients with simple and complex writer's cramp and compared with those of age‐matched control subjects. Analysis of the movement‐related cortical potential waveforms showed that the Bereitschaftspotential, the peak of the negative slope, and the frontal peak of the motor potential did not differ in the two groups, except for the average amplitude of the early part of the negative‐slope peak, which was decreased in the patient group during the interval of 300 to 200 msec prior to electromyographic onset. This finding was restricted to the electrodes overlying the contralateral and midline central electrodes. Movement‐related cortical potentials from patients and control subjects could be equally accounted for by a four‐dipole source model with sources located in the contralateral and ipsilateral sensorimotor regions and the supplementary motor area. There was a trend for a reduction in the strength of the sensorimotor sources active during the premotor period in the patient group, but the difference did not reach a significant level for any individual source. No differences were found between the movement‐related cortical potentials elicited by movements of the affected and unaffected hand, or between those of patients with simple or complex hand cramps. This result suggests a deficiency of contralateral motor cortex activation just prior to the initiation of voluntary movements in patients with focal dystonia.
Familial subarachnoid hemorrhage: Distinctive features and patterns of inheritance
Authors: Bromberg Jacoline E. C. , Rinkel Gabriel J. E. , Algra Ale , van Duyn Cornelia M. , Greebe Paut , Ramos Lino M. P. , van Gijn Jan
Published: January 2005

To delineate the distinctive features of familial subarachnoid hemorrhage, we compared gender and age at the time of subarachnoid hemorrhage, as well as site and number of aneurysms, in patients with familial subarachnoid hemorrhage (at least 1 first‐degree relative with subarachnoid hemorrhage) and patients with sporadic subarachnoid hemorrhage (no subarachnoid hemorrhage in first‐ or second‐degree relatives), in a prospective, hospital‐based series of patients. In addition we studied the pattern of inheritance in 17 families with familial subarachnoid hemorrhage. Mean age at the time of hemorrhage in patients with the familial form was 6.8 years lower than that in those with the sporadic form, and middle cerebral artery aneurysms occurred more often in patients with familial disease. Sex distribution and number of aneurysms were similar in the two groups. Inheritance was compatible with autosomal dominant transmission in some families, and with autosomal recessive or multifactorial transmission in others. In our 5 families as well as in all 18 previously reported families with two affected generations, the age at the time of subarachnoid hemorrhage was invariably lower in later generations, which is suggestive of anticipation. We conclude that familial subarachnoid hemorrhage is a separate entity with occurrence at a young age, predilection for aneurysms of the middle cerebral artery, and variable modes of inheritance, including autosomal dominant inheritance with possible anticipation.
Intravenous antigen adrmnistration as a therapy for autoimmune demyelinating disease
Authors: Racke Michael K. , Critchfield Jeffrey M. , Quigley Laura , Cannella Barbara , Raine Cedric S. , McFarland Henry F. , Lenardo Michael J.
Published: January 2005

Experimental allergic encephalomyelitis is a prototypic autoimmune disease characterized by central nervous system inflammation and demyelination. Previously, we demonstrated that intravenous administration of high doses of myelin basic protein abrogated the clinical and pathological signs of experimental allergic encephalomyelitis by causing the deletion of encephalitogenic, CD4+ myelin basic protein‐specific T cells through antigen‐induced programmed cell death. In the present study, we further characterized the ability of intravenous antigen administration to attenuate an immune response by myelin basic protein‐reactive encephalitogenic T cells. We demonstrated that multiple injections of myelin basic protein ace required to achieve a therapeutic response, and that this form of therapy is effective even after prolonged chronic disease. These studies showed that although interleukin‐2–stimulated cell cycling is an important factor leading to T‐cell death, the administration of exogenous interleukin‐2 with antigen can result in the aggravation of clinical disease compared to administration of antigen alone. More importantly, administration of myelin basic protein alone without interleukin‐2 was sufficient to reduce autoreactive T cells and clinical disease in experimental autoimmune encephalomyelitis. Our experiments support the rationale for antigen‐specific therapy aimed at inducing the programmed death of autoreactive T cells in autoimmune diseases, potentially including the human demyelinating disease multiple sclerosis.
Strength in Parkinson's disease: Relationshp to rate of force generation and clinical status
Authors: Corcos Daniel M. , Chen Chiung‐Mei , Quinn Niall P. , McAuley John , Rothwell John C.
Published: January 2005

Maximum elbow flexor and extensor muscle strength was measured in 9 patients with Parkinson's disease on and off antiparkinsonian medication. In addition, the rate of force generation, the rate of actively returning force to resting levels, and passive release of force “relaxation” were measured in submaximal contractions. The measures of strength and contraction time were correlated with changes in clinical status as measured by the Unified Parkinson's Disease Rating Scale. When patients were off medication, their reduction in strength was significantly greater in extension than flexion. The reduction in flexion strength did not reach statistical significance. The extensor weakness was primarily due to decreased tonic activation of the extensor muscles and not to muscle coactivation. Muscle relaxation time was much more prolonged than was force generation time or active force return time. The increase in relaxation time and the decrease in extensor strength both correlated with changes in clinical status. Finally, changes in extensor torque correlated with the time to actively return force, suggesting that reduced strength is related to a reduced ability to generate rapid contractions in some patients with Parkinson's disease. These results suggest that there is an asymmetric distribution of muscle weakness in Parkinson's disease and that selected measures of muscle strength and muscle relaxation correlate with changes in clinical status.
Bell's palsy–associated blepharospasm relieved by aiding eyelid closure
Authors: Chuke John C. , Baker Robert S. , Porter John D.
Published: January 2005

The efficacy of the blink reflex is maintained by adaptive control mechanisms. We describe a 39‐year‐old woman with the rare complication of blepharospasm‐like symptoms appearing contralateral to an eyelid weakened by facial nerve palsy. The hyperexcitable blink reflex may be a maladaptive consequence of adaptive systems but was not accompanied by an expected increase in main sequence slope. Eyelid spasms were eliminated by the implantation of a gold weight to assist closure of the paretic eyelid. We suggest that aiding closure of the weak eyelid in this case caused a reduction in blink system excitability via the same compensatory mechanisms that initially produced the eyelid spasm. Data also suggest that blinkadaptive systems act via changes in reflex excitability and/or main sequence relationships, and that these may be regulated either synergistically or independent of one another.
Mitochondrial defect in Huntington's disease caudate nucleus
Authors: Gu M. , Gash M. T. , Mann V. M. , Javoy‐Agid F. , Cooper J. M. , Schapira A. H. V.
Published: January 2005

Although the Huntington's disease (HD) gene defect has been identified, the structure and function of the abnormal gene product and the pathogenetic mechanisms involved in producing death of selective neuronal populations are not understood. Indirect evidence from several sources indicates that a defect of energy metabolism and consequent excitotoxicity are involved in HD. Toxin models of HD may be induced by 3‐nitropropionic acid or malonate, both inhibitors of succinate dehydrogenase, complex II of the mitochondrial respiratory chain. We analyzed mitochondrial respiratory chain function in the caudate nucleus (n = 10) and platelets (n = 11) from patients with HD. In the caudate nucleus, severe defects of complexes II and III (53–59%, p < 0.0005) and a 32–38% (p < 0.01) deficiency of complex IV activity were demonstrated. No deficiencies were found in platelet mitochondrial function. The mitochondrial defect identified in HD caudate parallels that induced by HD neurotoxin models and further supports the role of abnormal energy metabolism in HD. The relationship of the mitochondrial defect to the role of huntingtin is not known.
Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1
Authors: Goldfarb L. G , Vasconcelos O. , Platonov F. A. , Lunkes A. , Kipnis V. , Kononova S. , Chabrashvili T. , Vladimirtsev V. A. , Alexeev V. P. , Gajdusek D. C.
Published: January 2005

A Siberian kindred with spinocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene. The kindred includes 1,484 individuals, 225 affected and 656 at risk, making this collection the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele containing a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles had 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 55 repeats were found in 26 atrisk relatives. The number of CAG repeats in the mutated allele was inversely correlated with age at disease onset. Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients with low CAG repeat numbers, but severely complicated the course of illness in patients with a larger number of repeat units. One female mutation carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical manifestation corresponded to the size of the larger allele.
Upregulation of Bcl‐2 protein in the myasthenic thymus
Authors: Onodera Jun‐ichi , Nakamura Shozo , Nagano Isao , Tobita Muneshige , Yoshioka Masaru , Takeda Atsushi , Oouchi Masahiro , Itoyama Yasuto
Published: January 2005

We examined the expression of Fas antigen and Bcl‐2 protein in thymic tissue surgically resected from 10 patients with myasthenia gravis, using immunocytochemical techniques. Histologically, thymic tissues from 7 myasthenia gravis patients showed hyperplasia, while 3 other patients had thymomas. In hyperplastic thymic tissue, immunoreactivity for Fas antigen was observed mainly in the network of medullary epithelial cells. In contrast, expression of Fas antigen was rare in the cortex. Fas antigen was also detected to some degree in thymoma tissue from 3 patients. Bcl‐2 protein was highly expressed in the medullary thymocytes in the hyperplastic thymic tissue, whereas its staining was quite low in myasthenia gravis thymomas. The number of Bcl‐2‐positive thymocytes in the medulla was significantly greater in the hyperplastic myasthenia gravis thymic tissue than in the control thymic tissue. These findings suggest that Bcl‐2 protein may be upregulated in the myasthenia gravis thymus and that this phenomenon may be related to impaired apoptotic cell death of autoreactive thymocytes in myasthenia gravis.
The effect of ethanol on alcohol‐responsive essential tremor: A positron emission tomography study
Authors: Boecker Henning , Wills Adrian J. , Ceballos‐Baumann Andres , Samuel Michael , Thompson Philip D. , Findley Leslie J. , Brooks David J.
Published: January 2005

We used H215O positron emission tomography (PET) to investigate the effect of ethyl alcohol on regional cerebral blood flow in 6 patients with alcohol‐responsive essential tremor and 6 age‐matched control subjects. The patients were scanned while at rest and during involuntary postural tremor of the extended right arm. Normal control subjects were scanned at rest and during passive wrist oscillation of the right arm at tremor frequency. Regional cerebral blood flow associated with these conditions was measured before and after oral administration of 2 to 3 units of alcohol. The mean blood alcohol level was 35.3 ± 20.0 mg/dl in the patient group and caused marked suppression of tremor; it was 33.9 ± 12.9 mg/dl in the control group. Similar to previous PET studies on essential tremor patients, tremor compared with rest was associated with bilateral cerebellar activation including the cerebellar vermis. This pattern of activation differed from passive wrist oscillation where ipsilateral cerebellar activation was observed. Ethanol ingestion led to bilateral decreases of cerebellar blood flow in both tremor patients and normal subjects, and this was associated with suppression of tremor in the patients. Alcohol‐associated increases of regional cerebral blood flow were observed in the inferior olivary nuclei in the patients but not in the control subjects. We conclude that alcohol‐induced suppression of essential tremor is mediated via a reduction of cerebellar synaptic overactivity resulting in increased afferent input to the inferior olivary nuclei.
Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis
Authors: Orell Richard W. , Habgood James , Rudge Petter , Lane Russell J. M. , de Belleroche Jackie S.
Published: January 2005

Mutations of the copperlzinc superoxide dismutase (SOD‐1) gene are present in around 20% of patients with a family history of amyotrophic lateral sclerosis. The finding of these mutations in patients with sporadic amyotrophic lateral sclerosis is rare. We describe a family with amyotrophic lateral sclerosis associated with the SOD‐1 mutation Asp 101 Asn. This mutation was previously described as occurring in a patient with sporadic disease. We discuss the difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the consequent implications on the neurogenetic advice given to other family members.
Cost‐effectiveness analysis: What is it and how it influence neurology
Authors: Holloway Robert G.
Published: January 2005

Cost‐effectiveness analysis (CEX) refers to a set of research methods that consider the resources consumed by a medical technology in decisions about how best to use the technology. This analytic method is an evolving, controversial, and often misunderstood field in health services research. The basic set of principles underlying CEA is deceptively simple, but sufficient methodological challenges and controversies exist that have, thus far, limited its use in the development of health policy and in bedside decision making. Nonetheless, neurologists like other specialty groups may feel concerned that the results from such analyses may prove unfavorable to their specialty and the patients they serve. This article reviews the fundamental notions surrounding CEA, provides examples from the literature with particular relevance to the neurological community, and highlights critical issues for neurologists regarding the future of CEA.
Campylobacter jejuni infections and anti‐GM1 antibodies in guillain‐barré syndrome
Authors: Jacobs Bart C. , van Doorn Pieter A. , Tio‐Gillen Anne P. , Visser Leo H. , van der Meché Frans G. A. , Schmitz Paul I. M. , Herbrink Paul , Hooijkaas Herbert
Published: January 2005

The group of patients with Guillain‐Barré syndrome (GBS) is very heterogenous with regard to antecedent infections, immunological parameters, clinical manifestations, and response to treatment. In this study, the presumed pathogenic factors anti‐GM1 antibodies and Campylobacter jejuni infections were related to the clinical characteristics. Serum from 154 patients with GBS, 63 patients with other neurological diseases (OND), and 50 normal controls (NC) were tested for the presence of antibodies against GM1 and C. jejuni. Anti‐GM1 antibodies were detected in 31 (20%) GBS patients, 5 (8%) OND patients, and in none of the NC. Evidence for a recent C. jejuni infection was found in 49 (32%) GBS patients and less often in OND patients (11%) or NC (8%). In GBS patients, the presence of anti‐GM1 antibodies was significantly associated with C. jejuni infections. The subgroup of GBS patients with anti‐GM1 antibodies suffered more often from a rapidly progressive and more severe neuropathy with predominantly distal distribution of weakness, without deficits of cranial nerves or sensory distrubances. The subgroup with C. jejuni infection also more often had a severe pure motor variant of GBS. Recovery of the patients with anti‐GM1 antibodies and C. jejuni infection was not as good after plasma exchange compared with intravenous immunoglobulins.
Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging
Authors: Hugg James W. , Kuzniecky Ruben I. , Gilliam Frank G. , Faught R. Edward , Morawetz Richard B. , Hetherington Hoby P.
Published: January 2005

We studied 10 medically intractable temporal lobe epilepsy (TLE) patients prior to surgery using proton magnetic resonance spectroscopic imaging (MRSI) to localize seizure foci. We found significantly elevated creatine/N‐acetylaspartate (Cr/NAA) unilaterally in 8 and bilaterally in 2 patients. Five patients have been studied again 1 year after surgery. In the 2 patients with bilateral temporal seizure onsets, MRSI showed normalization of Cr/NAA in the unoperated contralateral tissue following surgical elimination of seizures. This study suggests that metabolic recovery can occur in contralateral temporal areas following surgical treatment of partial epilepsy.
In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease
Authors: Kuhl D. E. , Minoshima S. , Fessler J. A. , Ficaro E. P. , Wieland D. M. , Koeppe R. A. , Frey K. A. , Foster N. L.
Published: January 2005

To map presynaptic cholinergic terminal densities in normal aging (n = 36), Alzheimer's disease (AD) (n = 22), and Parkinson's disease (PD) (n = 15), we performed single‐photon emission computed tomography using [123I]iodoben‐zovesamicol (IBVM), an in vivo marker of the vesicular acetylcholine transporter. We used coregistered positron emission tomography with [18F]fluorodexyglucose for metabolic assessment and coregistered magnetic resonance imaging for atrophy assessment. In controls (age, 22–91 years), cortical IBVM binding declined only 3.7% per decade. In AD, cortical binding correlated inversely with dementia severity. In mild dementia, binding differed according to age of onset, but metabolism did not. With an onset age of less than 65 years, binding was reduced severely throughout the entire cerebral cortex and hippocapus (about 30%), but with an onset age of 65 years or more, binding reductions were restricted to temporal cortex and hippocampus. In PD without dementia, binding was reduced only in parietal and occipital cortex, but demented PD subjects had extensive cortical binding decreases similar to early‐onset AD. We conclude that cholinergic neuron integrity can be monitored in living AD and PD patients, and that it is not so devastated in vivo as suggested by postmortem choline acetylransferase activity (50–80%).
Neuronal activity and early neurofibrillary tangles in Alzheimer's disease
Authors: Hatanpää Kimmo , Brady Daniel R. , Stoll James , Rapoport Stanley I. , Chandrasekaran Krish
Published: January 2005

We studied neuronal activity and its relation to the accumulation of neurofibrillary tangles in Alzheimer's disease (AD) neurons by in situ hybridization to cytochrome oxidase subunit III messenger RNA, a marker of mitochondrial energy metabolism. In AD midtemporal cortex, levels of cytochrome oxidase subunit III messenger RNA were decreased by 26% in neurons bearing early‐stage neurofibrillary tangles as compared to tangle‐free neurons (p. < 0.01). However, levels of 12S ribosomal RNA, also encoded by mitochondrial DNA, and of total messenger RNA were decreased only in later stages of tangle development. Comparing tangle‐free neurons of 4 AD brains to tangle‐free neurons of 3 control brains, levels of cytochrome oxidase subunit III messenger RNA were found to be 25% lower (p < 0.001) in AD tangle‐free neurons. Because energy metabolic needs of neurons are mainly determined by synaptic input, the observed decreases in cytochrome oxidase subunit III messenger RNA likely reflect downregulation due to impaaired synaptic function in AD. Thus, a failure in synaptic transmission may precede tangle formation. A further decline in neuronal activity is seen as tangle formation progresses. However, these results can also be viewed as showing the viability and continuing activity, albeit at a lower level, of neurons in the early stages of neurofibrillary pathology.
MELAS associated with a mutation in the valine transfer RNA gene of mitochondrial DNA
Authors: Taylor R. W. , Chinnery P. F. , Haldane F. , Morris A. A. M. , Bindoff L. A. , Turnbull D. M. , Wilson J.
Published: January 2005

We describe a patient with the mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) phenotype in whom initial investigations in skeletal muscle failed to show any histochemical or biochemical defect. Subsequent analyis of the mitochondrial genome identified a new heteroplasmic mutation in the valine transfer RNA gene, the first described in this region.
Clinical outcomes assessment in multiple sclerosis
Authors: Rudick Richard , Fischer Jill , Antel Jack , Confavreux Christian , Cutter Gary , Ellison George , Lublin Fred , Miller Aaron , Petkau John , Rao Stephen , Reingold Stephen , Syndulko Karl , Thompson Alan , Wallenberg Joy , Weinshenker Brain , Willoughby Ernest
Published: January 2005

This article represents initial deliberation of an international task force appointed by the US National Multiple Sclerosis Society to develop recommendations for optimal clinical assessment tools for multiple sclerosis clinical trials. Presented within this article are the key issues identified by the task force during its initial year of deliberation. These include the precise purpose for a clinical assessment tool, the clinical dimensions to be measured in a multidimensional outcome measure, desirable attributes of an optimal clinical outcome measure, the complexities of multidimensional outcome measures, the relative merits of categorical clinical ratings and quantitative functional assessments, and a number of other important design issues that relate to the use of a multidimensional outcome measure. An action plan for analysis of existing data is summarized, as are the plans for more detailed recommendations from the task force.
Immunosuppression‐induced leukoencephalopathy from tacrolimus (FK506)
Authors: Small Steven L. , Bramblett Gregory T. , Eidelman Benjamin H. , Fukui Melanie B.
Published: January 2005

Tacrolimus (FK506) has recently been approved for immunosuppressionin organ transplantation, although its use is accompanied by a wide spectrum ofneurotoxic side effects. We describe the clinical, radiological, and pathological features of 3 cases of tacrolimus‐related leukoencephalopathy. The syndrome of immunosuppression‐related leukoencephalopathy is proposed as an uncommon neurological syndrome occurring in patintw with organ transplants involving demyelination, in particular in the parieto‐occipital region and centrum semiovale. Although the syndrome is not associated with a particular (absolute) serum level of tacrolimus, it resolves spontaneously upon decreasing the dose. The tacrolimus‐related syndrome has a similar radiographic and pathologic appearance as the analogous syndrome that occurs in patients taking cyclosporine.