bluuebunny/crossref_metadata_2025 huggingface dataset:
Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity
Authors: DeKosky Steven T. , Scheff Stephen W.
Published: January 2005

Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age‐matched control brains (n = 9; postmortem time, < 13 hours). Further decline in synaptic number was seen in age‐matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini‐Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini‐Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined. The loss of neuronal connectivity, indexed by loss of synapses, predicted the degree of cognitive impairment in the patients who underwent biopsy and indicated a degree of structural change in AD brain not likely to be affected by pharmacotherapy.
Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double‐blinded, placebo‐controlled clinical trial
Authors:   The Multiple Sclerosis Study Group, Wolinsky
Published: January 2005

Patients with clinically definite multiple sclerosis, mild to moderately severe neurological disability (entry score on the Expanded Disability Status Scale (EDSS) between 3.0 and 7.0), and a progressive course defined by an increase in the EDSS of between 1 and 3 grades in the year prior to entry were randomized to receive either cyclosporine (n = 273) or placebo (n = 274) in a 2‐year, double‐blinded, multicenter trial. Treatment groups at entry proved balanced for age, gender, duration of illness, and neurological disability. Cyclosporine dosage was adjusted for toxicity and a median trough whole‐blood level was maintained between 310 and 430 ng/ml. The mean increase in EDSS score was 0.39 ± 1.07 grades for cyclosporine‐treated patients and 0.65 ± 1.08 grades for placebo‐treated patients from entry until the time of early withdrawal or completion of the study (p = 0.002). Of three primary efficacy criteria, cyclosporine delayed the time to becoming wheelchair bound (p = 0.038; relative risk, 0.765), but statistically significant effects were not observed for “time to sustained progression” or on a composite score of “activities of daily living.” Active treatment did have a favorable effect on several secondary measures of disease outcome. A large and differential withdrawal rate (44% for cyclosporine‐treated patients, 32% for placebo‐treated patients) complicated the analysis but did not appear to explain the observed effect of cyclosporine in delaying disease progression. Multivariate analysis did not show institutional effects but did demonstrate substantial effects of baseline neurological disability on outcome. Nephrotoxicity and hypertension were common troublesome toxicities and accounted for most of the excess loss of patients in the cyclosporine arm of the study. Thus, chronic cyclosporine therapy was associated with a statistically significant but clinically modest delay of progression of disability in a group of patients with multiple sclerosis selected for moderately severe and progressive disease. Close supervision by physicians familiar with cyclosporine is mandatory to minimize known adverse effects, particularly nephrotoxicity, when considering the use of this immunosuppressant.
N‐Methyl‐D‐Aspartate antagonist reduces stroke size and regional glucose metabolism
Authors: Simon Roger , Shiraishi Kazuya
Published: January 2005

Pharmacological inhibition of cell excitation during focal ischemia was studied in the rat middle cerebral artery occlusion model. The potent and selective N‐methyl‐D‐aspartate antagonist CGS 19755, administered 5 minutes prior to or 5 minutes following permanent middle cerebral artery occlusion, caused a substantial decrease in infarct size, which was associated with reduction of postischemic cerebral glucose hypermetabolism. These data support a role for excitation‐induced hypermetabolism in the pathogenesis of infarction following focal cerebrovascular occlusion.
Nationwide survey of HTLV‐I–associated myelopathy in Japan: Association with blood transfusion
Authors: Osame Mitsuhiro , Janssen Robert , Kubota Hiroaki , Nishitani Hiroshi , Igata Akihiro , Nagataki Shigenobu , Mori Masataka , Goto Ikuo , Shimabukuro Hiromi , Khabbaz Rima , Kaplan Jonathan
Published: January 2005

To study the epidemiology of human T‐cell lymphotropic virus type I (HTLV‐I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan, we conducted two nationwide surveys between October 1986 and March 1989. A total of 710 patients with HAM (definite HAM, 589; probable HAM, 121) were reported. Of the 589 patients with definite HAM, 69%0 were residents of the areas with the highest prevalence HTLV‐I in Japan. To determine the importance of blood transfusion in the pathogenesis of HAM/TSP, we performed a case‐control study in the Kagoshima district in southern Japan. Significantly more patients with HAM reported a history of blood transfusion (26/129, or 20%) than did subjects in a health survey of the general population (41/1,290, or 3%; odds ratio = 7.7, p < 0.001) or than did hospitalized neurological patients (6/119, or 5%; odds ratio = 4.8, p < 0.001). Furthermore, the cumulative percentages of the intervals between blood transfusion and the onset of the symptoms of HAM fit a lognormal curve, suggesting that transfusion was an important common exposure. Blood transfusion probably transmitted HTLV‐I to the patients with transfusion‐associated HAM because there was a significant decrease in the number of patients with the transfusion‐associated HAM who received blood after implementation of nationwide screening of blood donors in 1986 (p = 0.004). In the first 2 years, screening the blood supply in Japan appears to have decreased the number of reported patients with HAM by 16%.
Macrophages but not schwann cells express ia antigen in experimental autoimmune neuritis
Authors: Schmidt Beate , Stoll Guido , Hartung Hans‐Peter , Heininger Kurt , Schäfer Bärbel , Toyka Klaus V.
Published: January 2005

This study was designed to identify which cells express major histocompatibility complex class II (Ia) antigen in experimental autoimmune neuritis and may therefore be antigen presenters. Serial 1‐μm‐thick cryosections of ventral roots of animals with experimental autoimmune neuritis were labeled with Ox6 antibody against rat Ia, the ED1 antibody to identify monocytes/macrophages and an antiserum against S100, a marker for Schwann cells. Ia‐positive cells were predominantly present before overt clinical signs and demyelination (day 12). At later stages when many axons were demyelinated, their number was markedly reduced. Few Ia‐positive cells that had extending long processes, which over some distance were in immediate contact with several myelin sheaths, were scattered in normal‐appearing nerve roots at these later time points. Most of the Ia‐positive cells could be identified as ED1‐positive leanmonocytes/macrophages, but in contrast most phagocytic macrophages in advanced stages of myelin degradation no longer expressed Ia. Ia‐positive structures were invariably negative for S100 at early and late stages of experimental autoimmune neurities, indicating that Schwann cells did not express identifiable Ia antigen. These findings contrast with reports of expression of major histocompatibility complex class II antigens by Schwann cells in human neuropathies. Furthermore they do not support the notion that aberrant Ia expression by Schwann cells plays a major pathogenic role in experimental autoimmune disease of the peripheral nervous system.
Chronic encephalitis, epilepsy, and cerebrovascular immune complex deposits
Authors: Andrews John M. , Thompson Joel A. , Pysher Theodore J. , Walker Marian L. , Hammond M. Elizabeth
Published: January 2005

Refractory epilepsy, electroencephalographic abnormalities, progressive hemiplegia, and contralateral hemicerebral atrophy developed in a previously healthy 3‐year, 9‐month‐old girl. Extensive laboratory testing showed elevated serum antinuclear antibody titers, cerebrospinal fluid oligoclonal bands, and elevated immunoglobulin G (IgG): albumin ratio, IgG index, and IgG synthesis rate: Pathological study of a subtotal hemispherectomy specimen revealed widespread cerebral vasculitis with immunofluorescence staining for IgG, IgM, IgA, C3, and C1q, and ultrastructural evidence of vascular injury in addition to severe cortical atrophy with marked neuronal loss. Cerebrospinal fluid abnormalities in other reported patients siuggest that immunological abnormalities may not be unique to this girl. These data suggest possible immunopathogenetic mechanisms in these patients.
DNA cytosine methylation in brain of patients with Alzheimer's disease
Authors: Schwob Netanel G. , Nalbantoglu Josephine , Hastings Kenneth E. M. , Mikkelsen Tom , Cashman Neil R.
Published: January 2005

We developed a novel quantitative assay to test the hypothesis that defects in DNA cytosine methylation might be responsible for the brain chromatin abnormalities and transcriptional alterations observed in patients with Alzheimer's disease (AD). We found no significant difference in percent methylation of CCGG sites from brain DNA of 44 patients with AD compared with 20 normal subjects. These results, however, would not exclude genomic redistribution of methylcytosine in AD, or disturbed methylation of a limited population of critical brain‐specific genes.
Dissociated neglect behavior following sequential strokes in the right hemisphere
Authors: Daffner Kirk R. , Ahern Geoffrey L. , Weintraub Sandra , Mesulam M‐Marsel
Published: January 2005

A 42‐year‐old woman suffered two focal right hemisphere strokes, sequentially damaging different components of a proposed cerebral network for the spatial distribution of attention. Her first stroke was centered in the right frontal lobe and resulted in left hemispatial neglect but only for tasks that emphasize exploratory‐motor components of directed attention. A second stroke occurred 20 days later in the parietal lobe and led to the emergence of perceptual‐sensory aspects of neglect. This case strongly supports the existence of a distributed anatomic‐functional network subserving directed attention.
A clinical triad to diagnose paraneoplastic retinopathy
Authors: Jacobson Daniel M. , Thirkill Charles E. , Tipping Stuart J.
Published: January 2005

Two elderly men developed photosensitivity and light‐induced glare, transient visual symptoms, and progressive visual loss several months before small cell carcinoma of the lung was discovered. Both patients had impaired visual acuity and color vision, ring scotomas, and attenuated retinal arteriole caliber. Electroretinography demonstrated abnormal cone and rod‐mediated responses. Antiretinal antibodies were identified in their serum. Their visual sensory function improved following therapy with immunosuppressive agents. The triad of photosensitivity, ring scotomatous visual field loss, and attenuated retinal arteriole caliber should alert one to a paraneoplastic disorder affecting the retina.
Ubiquitin immunoreactivity in kuru plaques in Creutzfeldt‐Jakob disease
Authors: Suenaga Toshihiko , Hirano Asao , Llena Josefina F. , Ksiezak‐Reding Hanna , Yen Shu‐Hui , Dickson Dennis W.
Published: January 2005

Cerebellar kuru plaques in 2 cases of Creutzfeldt‐Jakob disease were studied immunohistochemically. Similar to cerebellar senile plaques in Alzheimer's disease, many kuru plaques contained ubiquitin‐positive, tau‐negative small granular elements, presumably representing dystrophic neurites. Our results suggest that similar mechanisms are involved in neuritic changes in cerebellar plaques in Creutzfeldt‐Jakob and Alzheimer's diseases despite differences of amyloid proteins in the plaques.
Vasoactive peptide release in the extracerebral circulation of humans during migraine headache
Authors: Goadsby P. J. , Edvinsson L. , Ekman R.
Published: January 2005

The innervation of the cranial vessels by the trigeminal nerve, the trigeminovascular system, has recently been the subject of study in view of its possible role in the mediation of some aspects of migraine. Since stimulation of the trigeminal ganglion in humans leads to facial pain and flushing and associated release of powerful neuropeptide vasodilator substances, their local release into the extracerebral circulation of humans was determined in patients who had either common or classic migraine. Venous blood was sampled from both the external jugular and the cubital fossa ipsilateral to the side of headache. Plasma levels of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene‐related peptide were determined using sensitive radioimmunoassays for each peptide, and values for the cubital fossa and external jugular and a control population were compared. A substantial elevation of the calcitonin gene‐related peptide level in the external jugular but not the cubital fossa blood was seen in both classic and common migraine. The increase seen in classic migraine was greater than that seen with common migraine. The other peptides measured were unaltered. This finding may have importance in the pathophysiology of migraine.
Relapse of infant botulism
Authors: Glauser Tracy A. , Maguire Henry C. , Sladky John T.
Published: January 2005

We report on 3 infants who had relapse of infant botulism after apparent resolution of clinical symptoms. This group represented 5% of the infants with confirmed infant botulism who were treated at our institution since 1976. The exact cause for these relapses was unclear, but three potential mechanisms are examined. There were no historical, clinical, or electrophysiological predictors of relapse. Although at the time of writing recovery from relapse appeared complete, close follow‐up of patients recovering from a bout of infant botulism is necessary.
Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor–reactive T cells
Authors: Sommer N. , Willcox N. , Harcourt G. C. , Newsom‐Davis J.
Published: January 2005

We compared T‐cell proliferative responses to acetylcholine receptor (AChR) and to purified protein derivative (PPD) (of tuberculin) of hyperplastic thymus, thymoma, and blood cells from patients with myasthenia gravis (MG). Hyperplastic MG thymus cells gave significantly higher and more consistent responses to AChR than parallel cultures of autologous blood cells, whereas responses to PPD showed an opposite trend. Thus there was a preferential localization of AChR‐‐reactive T cells in the hyperplastic MG thymus. Furthermore, there was a strong correlation between blood and thymus cell responses to PPD (but not to AChR), arguing that the hyperplastic MG thymus contains a sample of sesitized peripheral T cells. By contrast, both AChR–and PPD–responsive T cells were almost undetectable in thymus from nonmyasthenic patients, which is evidently much less receptive to circulating T cells. Cells from MG thymomas showed the highest stimulations by AChR but did not consistently react to PPD. However, the uninvolved thymus adjacent to these thymomas behaved almost identically to the hyperplastic samples described above. Our interpretation is that AChR‐specific T cells are initially sensitized in the MG thymoma but are selectively trapped in the hyperplastic thymus after being primed elsewhere.
Substantia nigra: A site of action of muscle relaxant drugs
Authors: Turski Lechoslaw , Klockgether Thomas , Schwarz Michael , Turski Waldemar A. , Sontag Karl‐Heinz
Published: January 2005

Sites of action of centrally active muscle relaxant drugs are not well defined. Clinical experience with such drugs suggests that the spinal cord may be one of the important regions from which pathologically increased muscle tone may be relieved. Supraspinal centers that may also be involved in the expression of muscle relaxant action have not yet been defined. We report here that microinjections of therapeutically relevant muscle relaxants into the midbrain tegmentum of genetically spastic rats decrease muscle tone. The substantia nigra is the region from which midazolam, baclofen, and tizanidine (drugs used clinically in the treatment of spasticity), or gamma‐vinyl‐GABA, (−)‐2‐amino‐7‐phosphonoheptanoate, and [D‐pro2‐D‐phe7‐D‐trp9]‐substance P (experimental drugs active in animal models of spasticity), reduce muscle tone in genetically spastic rats and Hoffmann reflexes in normal rats. The effects of muscle relaxant drugs are topographically restricted to the substantia nigra pars reticulata and are receptor specific. These observations disclose a previously unknown function of the substantia nigra in mediating muscle relaxation.
Spinal cord compression with paraplegia in xanthomatosis due to normocholesterolemic sitosterolemia
Authors: Haranaka I. , Yasuda H. , Hidaka H. , Harada N. , Kobayashi M. , Okabe H. , Matsumoto K. , Hukuda S. , Shigeta Y.
Published: January 2005

A 48‐year‐old woman with a 30‐year history of tendinous xanthomatosis developed paraplegia. The magnetic resonance image revealed extramedullary tumors. The analysis of her sera and tumors revealed increased amount of plant sterols, especially sitosterol, and the diagnosis of sitosterolemia was made. This is the first reported case of a patient with sitosterolemia who had the neurological complication of spinal cord compression due to extramedullary sitosterolemic xanthomas.
α1‐Antichymotrypsin as a possible biochemical marker for Alzheimer‐type dementia
Authors: Matsubara Etsuro , Hirai Shunsaku , Amari Masakuni , Shoji Mikio , Yamaguchi Haruyasu , Okamoto Koichi , Ishiguro Koji , Harigaya Yasuo , Wakabayashi Katsumi
Published: January 2005

We measured serum α1‐antichymotrypsin levels in 38 patients with Alzheimer‐type dementia, 89 control subjects, 2 subjects with Down's syndrome, 20 with vascular dementia, 18 with Parkinson's disease, 14 with spinocerebellar degeneration, 15 with cerebrovascular disease without dementia, and 14 with Duchenne muscular dystrophy. Cerebrospinal fluid (CSF) levels of α1‐antichymotrypsin were also measured in 15 patients with Alzheimer‐type dementia, 26 control subjects, 6 with vascular dementia, 7 with cerebrovascular disorder, and 11 with degenerative disorders. In control subjects, there were no age‐related changes or sex differences. Serum and CSF levels were significantly and specifically higher in patients with Alzheimer‐type dementia than in other subjects (serum, p <0.001; CSF, p <0.05). Serum levels of α1‐antichymotrypsin were significantly elevanted in the early stage of Alzheimer‐type dementia, whereas there was no definite correlation between serum levels and the degree of dementia. CSF levels of α1‐antichymotrypsin tended to parallel the severity of dementia. Serum levels were not correlated with CSF levels. These data indicate that serum and CSF levels of α1‐antichymotrypsin might be independently upregulated in Alzheimer‐type dementia. We concluded that the measurement of serum levels of α1‐antichymotrypsin could be useful as a screening marker for Alzheimer‐type dementia. In addition, CSF levels also could be a useful marker for Alzheimer‐type dementia, because they might reflect the state of dementia.
Normal dystrophin in McLeod myopathy
Authors: Danek Adrian , Witt Thomas N. , Stockmann H. B. A. C. , Weiss Barbara J. , Schotland Donald L. , Fishbeck Kenneth H.
Published: January 2005

Dystrophin and its gene were studied in a patient with McLeod syndrome. This X‐linked recessive myopathy has been localized to Xp21, as the Duchenne muscular dystrophy gene locus, which codes for dystrophin. Histopathological study of the patient's muscle showed mild subclinical myopathy. Immunological studies of dystrophin in two separate biopsy specimens and analysis of dystrophin gene DNA from a blood sample did not detect and abnormality. This suggests that the Duchenne muscular dystrophy gene, albeit close to the McLeod locus, is not involved in McLeod myopathy.
The functional anatomy of motor recovery after stroke in humans: A study with positron emission tomography
Authors: Chollet F. , Di Piero V. , Wise R. J. S. , Brooks D. J. , Dolan R. J. , Frackowiak R. S. J.
Published: January 2005

We have studied regional cerebral blood flow changes in 6 patients after their recovery from a first hemiplegic stroke. All had a single well‐defined hemispheric lesion and at least a brachial monoparesis that subsequently recovered. Each patient had 6 measurements of cerebral blood flow by positron tomography with 2 scans at rest, 2 during movement of fingers of the recovered hand, and 2 during movement of fingers of the normal hand. When the normal fingers were moved, regional cerebral blood flow increased significantly in contralateral primary sensorimotor cortex and in the ipsilateral cerebellar hemisphere. When the fingers of the recovered hand were moved, significant regional cerebral blood flow increases were observed in both contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres. Other regions, namely, insula, inferior parietal, and premotor cortex, were also bilaterally activated with movement of the recovered hand. We have also demonstrated, by using a new technique of image analysis, different functional connections between the thalamic nuclei and specific cortical and cerebellar regions during these movements. Our results suggest that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.
Acceleration of scrapie in trisomy 16↔diploid aggregation chimeras
Authors: Epstein Charles J. , Foster Dallas B. , DeArmond Stephen J. , Prusiner Stanley B.
Published: January 2005

We studied the susceptibility to prion infection of the trisomy 16↔diploid chimeric mouse, a putative model of Down syndrome. When weanling chimeras were inoculated intracerebrally with scrapie prions, the time until appearance of the first symptoms of scrapie was reduced by 17 days (from a mean control time of 153 days) and the time to death was reduced by 30 days (from control time of 170 days). Our results with trisomy 16 chimeras argue that the susceptibility to central nervous system degeneration caused by prions can be modulated by chromosome imbalance.
Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging
Authors: Berkovic Samuel F. , Andermann Frederick , Olivier André , Ethier Roméo , Melanson Denis , Robitaille Yvon , Kuzniecky Ruben , Peters Terence , Feindel William
Published: January 2005

The value of magnetic resonance imaging in the detection of hippocampal sclerosis has been controversial. We studied 10 patients aged 22.5 ± 6.0 years with intractable temporal lobe epilepsy selected because of a history of a prolonged childhood convulsion, which is characteristic of a group of patients in whom hippocampal sclerosis is a constant finding. All 10 patients showed reduction in size of one hippocampus associated with increased signal intensity on T2‐weighted magnetic resonance images. These changes were reliably detected on coronal spin‐echo images, perpendicular to the long axis of the hippocampus. Appreciation of the normal imaging anatomy of the hippocampus allowed correct interpretation of the relative changes in signal intensities of the hippocampus and adjacent temporal horn on sequential echo images. The side of the abnormal hippocampus on magnetic resonance imaging accorded with the electroencephalographic localization in all 10 patients, and with the lateralization of the early convulsions in all 6 patients where this was known. Temporal lobectomy was performed in all 10 patients. Hippocampal sclerosis was confirmed in the 3 patients in whom hippocampal tissue was available for histological examination. The value of this technique was reinforced by the excellent postoperative results, with 80% being seizure free at a mean follow‐up time of 33 ± 4 months.
Loss of high‐affinity agonist binding to M1 muscarinic receptors in Alzheimer's disease: Implications for the failure of cholinergic replacement therapies
Authors: Flynn Donna D. , Weinstein David A. , Mash Deborah C.
Published: January 2005

Cholinergic replacement therapies have yielded little or no clinical improvement in Alzheimer's disease (AD). Since the number of postsynaptic muscarinic receptors remains unchanged in the cerebral cortex, the involvement of other neurotransmitter systems may account for this limited efficacy. Alternatively, there may be a defective coupling of the muscarinic receptor with its nucleotide‐binding protein in AD, which would severely limit the ability of cholinergic agonists to activate intracortical second messengers. To address this possibility, we assessed the ability of the putative M1 muscarinic receptor to form high‐affinity agonist‐receptor complexes with guanine nucleotide regulatory proteins in postmortem frontal cortex. Agonist affinity states of the M1 muscarinic receptor were measured by carbachol/[3H]‐pirenzepine competition. M1 muscarinic receptors exhibited both high (KH) and low (KL) affinities for the agonist carbachol. High‐affinity agonist binding to M1 receptors in postmortem frontal cortex samples from subjects with AD was reduced, demonstrated by an increase in the KH value. Low‐affinity agonist binding (KL value) was unchanged in AD and was not significantly different from the KL value for the uncoupled receptor determined in the presence of guanine nucleotides. The increase in the KH value resulted in a 70% decrease in the average KL/KH ratio for AD as compared to control samples. Choline acetyltransferase activities correlated significantly with the KL/KH ratios (r = 0.73,p < 0.001). These data suggest that the KL/KH ratio for muscarinic agonists may serve as a neurochemical marker of disease severity. The reduced ability of the M1 receptor subtype to form a high‐affinity agonist state in AD may account for the failure of cholinergic replacement therapies to improve specific features of memory and cognition.
Abnormal cerebral glucose metabolism in long‐term survivors of childhood acute lymphocytic leukemia
Authors: Phillips Peter C. , Moeller James R. , Sidtis John J. , Dhawan Vijay , Steinherz Peter G. , Strother Steven C. , Ginos James Z. , Rottenberg David A.
Published: January 2005

Chemotherapy and radiation treatment of the central nervous system may cause delayed neurotoxicity in children with acute lymphocytic leukemia. We evaluated 12 long‐term survivors of childhood leukemia using [18F]fluorodeoxyglucose positron emission tomography, computed tomography scans, clinical neurological examinations, and neuropsychological tests. Regional cerebral metabolic rate for glucose (rCMRGIc) values for white matter were lower in the older long‐term survivors (> 18 years old) treated with cranial radiation and intrathecal chemotherapy than in normal control subjects or survivors who had been treated with intrathecal chemotherapy alone. The ratio of white matter: cortex rCMRGlc values was lower than control values in the long‐term survivors treated with cranial radiation and intrathecal chemotherapy, regardless of age, but not in those treated with intrathecal chemotherapy alone. By contrast, thalamic rCMRGlc values were lower than control values in older survivors regardless of treatment, and the ratio for thalamus: cortex rCMRGIc values was lower in all the treatment groups than in control subjects. The highest rCMRGIc values were found in the youngest children, indicating an important effect of age on cerebral glucose metabolism. No neuropsychological deficits were identified in patients treated only with intrathecal chemotherapy; however, lower IQ scores were found in the long‐term survivors who had been treated with cranial radiation and intrathecal chemotherapy. Treatment of the central nervous system with cranial radiation and intrathecal chemotherapy may cause prolonged alterations in white‐matter and thalamic rCMRGIc, which may permit the identification and assessment of neurotoxicity in long‐term survivors of acute lymphocytic leukemia by [18F]fluorodeoxyglucose positron emission tomography.
A genetic study of idiopathic focal dystonias
Authors: Waddy H. M. , Fletcher N. A. , Harding A. E. , Marsden C. D.
Published: January 2005

A genetic study of idiopathic focal dystonias was undertaken by examining 153 first‐degree relatives of 40 index patients with torticollis (14 patients), other focal cranial dystonias (16 patients), and writer's cramp (10 patients). Nine relatives with dystonia were identified in 6 families; 8 of these had symptoms such as clumsiness or tremor, but none were aware of any dystonia. A further 4 relatives, now deceased, were affected by history. Overall, 25% of index patients had relatives with dystonia. The results of segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrance as a common cause for focal dystonia. Segregation ratios were not significantly different from those ratios observed in generalized or segmental dystonia in the United Kingdom, and it is possible that a single autosomal dominant gene mutation is responsible for inherited dystonia in the majority of patients irrespective of distribution or severity.
Mitochondrial DNA deletions in inherited recurrent myoglobinuria
Authors: Ohno Kimji , Tanaka Masashi , Sahashi Ko , Ibi Tohru , Sato Wataru , Yamamoto Tomoko , Takahashi Akira , Ozawa Takayuki
Published: January 2005

We describe two brothers with inherited recurrent exertional myoglobinuria and alcohol intolerance associated with distinct morphological abnormalities of muscle mitochondria and multiple deletions of muscle mitochondrial DNA. Patient 1 (26 years old) and patient 2 (21 years old) had recurrent episodes of myoglobinuria provoked by strenuous exercise or alcohol intake, from the age of 18 years. Although their serum lactate and pyruvate levels were normal at rest, they were significantly elevated by aerobic exercise. Histochemistry of their biopsied limb muscles showed ragged‐red fibers and cytochrome c oxidase–negative fibers as well as degenerating and regenerating fibers. Electron microscopy showed pronounced accumulation of abnormal mitochondria containing paracrystalline inclusions and moderate increases of glycogen particles. The enzyme activities of the electron‐transfer complexes in the isolated muscle mitochondria of patient 2 were within normal ranges. Southern blot analysis revealed multiple deletions of mitochondrial DNA, some of which were common between the patients. Polymerase chain reaction of their muscle mitochondrial DNA detected multiple abnormal fragments indicating mitochondrial DNA deletions. We propose that a defect of the mitochondrial energy‐transducing system due to multiple mitochondrial DNA deletions is a novel genetic cause of inherited recurrent myoglobinuria.
Late onset dementia with argyrophilic grains and subcortical tangles or atypical progressive supranuclear palsy?
Authors: Masliah Eliezer , Hansen Lawrence A. , Quijada Sylvia , Deteresa Richard , Alford Michael , Kauss Joachim , Terry Robert
Published: January 2005

Most clinically demented elderly patients are found at autopsy to have Alzheimer's disease, multi‐infarct dementia, Parkinson's disease, Pick's disease, or Creutzfeldt‐Jakob disease. We studied 5 patients clinically characterized by late onset dementia whose brains showed no pathological evidence of Alzheimer's disease, or any other specific neuropathological diagnosis. We found argyrophilic grains, coiled bodies, abundant Alz‐50‐positive and thioflavine S‐negative neurofibrillary tangles, and neuropil threads in the hippocampus, entorhinal cortex, locus ceruleus, substantia nigra, subthalamic nucleus, and inferior olives, Ultrastructurally, the grains, threads, and tangles were composed of straight tubulofilamentous structures, 25 nm in diameter, similar to those found in patients with progressive supranuclear palsy but different from the paired helical filaments of patients with Alzheimer's disease. These findings suggest that the late onset dementia with argyrophilic grains syndrome is also characterized by the presence of tangles and threads with the topographical distribution of progressive supranuclear palsy.
Percutaneous electrical stimulation of corticospinal pathways at the level of the pyramidal decussation in humans
Authors: Ugawa Y. , Rothwell J. C. , Day B. L. , Thompson P. D. , Marsden C. D.
Published: January 2005

Stimulation over the base of the skull can activate descending motor pathways to produce electromyograpnic (EMG) responses in muscles of the arm and leg. The evoked EMG responses were larger when the muscles were preactivated by a small voluntary contraction compared to when they were completely relaxed. The latency of these responses in preactivated muscles was approximately midway between that produced by electrical stimulation over the motor cortex, and by electrical stimulation over the cervical enlargements. With horizontally spaced electrodes, the latency difference between cortical and brainstem stimulation was 1.8 milliseconds in all muscles tested. The latency difference between cervical and brainstem stimulation was 3.9 milliseconds for the first dorsal interosseous and 2.6 milliseconds for tibialis anterior muscles. These values suggest that brainstem stimulation occurs at the level of the cervicomedullary junction. With vertically spaced electrodes in the midline, stimulation often occurs at a higher level. The EMG responses from brainstem stimulation differed from those following cortical stimulation in two ways: (1) They were simpler in form, and (2) their onset latency was the same in active as it was in relaxed muscles. This suggests that brainstem stimulation evoked a large descending motor volley in comparison with the multiple volleys that cortical stimulation can produce. Collision experiments between cortical and brainstem volleys indicated that the major part of the responses evoked by brainstem stimulation were conducted via the large‐diameter component of the corticospinal tract.
Immunocytochemical and virological characteristics of hiv‐associated inflammatory myopathies: Similarities with seronegative polymyositis
Authors: Illa Isabel , Nath Avindra , Dalakas Marinos
Published: January 2005

We performed an immunoperoxidase study on muscle biopsy specimens from 19 patients with polymyositis who were seropositive for human immunodeficiency virus (HIV) (21 specimens) and 5 HIV‐seronegative patients with polymyositis and compared the findings. A quantitative analysis of T cells and T‐cell subsets, B cells, natural killer cells, interleukin‐2 receptor–positive cells, and macrophages was performed on serial sections from all the specimens. Localization of major histocompatibility complex (MHC)‐I and ‐II antigens, alpha and gamma interferon, and HIV antigens (p24, gp120, and gp41) was performed using specific antisera. In specimens from HIV‐positive and seronegative patients, the predominant cell population was CD8+s cells and macrophages invading or surrounding healthy muscle fibers that expressed MHC‐I antigen on their surface. The endomysial infiltrates in specimens from HIV‐positive patients differed from those seen in specimens from the seronegative patients only by a significant reduction of the CD4+ cells (12.6 ± 3.2% versus 21.1 ± 4.2%). HIV antigens were seen in occasional interstitial mononuclear cells (but not in muscle fibers) in 6 of the 21 specimens from HIV‐positive patients. Interferon was not localized. We conclude that the development of HIV‐associated polymyositis does not appear to be related to direct infection of the muscle fibers by HIV but rather is due to a T‐cell–mediated and MHC‐I–restricted cytotoxic process, perhaps triggered by HIV. Because this immunopathological mechanism is common in both HIV‐associated polymyositis and polymyositis alone, it is suggested that viruses may also be responsible in triggering polymyositis.
Fabry disease: Detection of 13‐bp deletion in α‐galactosidase a gene and its application to gene diagnosis of heterozygotes
Authors: Ishii Satoshi , Sakuraba Hitoshi , Shimmoto Michie , Minamikawa‐Tachino Reiko , Suzuki Tadashi , Suzuki Yoshiyuki
Published: January 2005

Polymerase chain reaction amplification of reversetranscribed messenger RNA from a patient with Fabry disease revealed a 13‐base pair deletion in the 5′ region (exon 1) of α‐galactosidase A complementary DNA. This gene rearrangement was not detected by Southern or Northern analysis. Short direct repeats were present around the breakpoints, and considered to be of pathogenetic significance. Gene diagnosis of the mother and a female cousin was successfully achieved by polymerase chain reaction amplification of genomic DNA; the former as a Fabry disease heterozygote and the latter as a normal homozygote.
Zidovudine myopathy: A distinctive disorder associated with mitochondrial dysfunction
Authors: Mhiri C. , Baudrimont M. , Bonne G. , Geny C. , Degoul F. , Marsac C. , Roullet E. , Gherardi R.
Published: January 2005

Muscle biopsy specimens were obtained from 48 human immunodeficiency virus–infected patients suffering from various neuromuscular symptoms. Microscopic examination by conventional and electron microscopy revealed a characteristic structural myopathy associated with mitochondrial changes in 13 patients, all of whom had received longterm zidovudine therapy. The mean cumulative dose they had received (498 ± 145 gm) was significantly higher than that of the other 14 zidovudine recipients of the study. They suffered from a progressive, usually painful, proximal myopathy with pronounced wasting, normal‐to‐moderately elevated creatine kinase levels, and a myopathic electromyographic pattern. The condition usually improved after withdrawal of the drug. Assay of mitochondrial enzymes, including succinate–cytochrome c reductase, cytochrome c oxidase, and citrate synthase, showed a decline in respiratory chain capacity. Southern blot analysis of mitochondrial DNA showed no abnormality. It is likely that mitochondrial dysfunction, probably resulting from drug‐induced inhibition of the mitochondrial DNA polymerase, is implicated in the pathogenesis of this complication of zidovudine therapy.
Double infarction in one cerebral hemisphere
Authors: Bogousslavsky Julien
Published: January 2005

Thirty‐two patients whose first stroke was due to double infarct in one cerebral hemisphere were identified among 1,911 consecutive patients from the Lausanne Stroke Registry. The double infarct involved territories of the superficial middle cerebral artery, superficial posterior cerebral artery, lenticulostriate, anterior choroidal artery, or borderzone. The most common combination involved territories of the anterior middle cerebral artery plus the posterior middle cerebral artery. In the patients with the double infarct, the prevalence of potential cardiac sources of embolism (19%) was similar to that found in the registry in general, but the double infarct was closely associated with tight (≥ 90% of the lumen diameter) stenosis or occlusion (75%) of the internal carotid artery. The most common neurological picture mimicked large infarction in the middle cerebral artery territory, but nearly half of the patients with double infarct in one cerebral hemisphere had a specific clinical syndrome, which was not found in the 1,879 remaining patients from the registry, including hemianopia‐hemiplegia (in 6), acute conduction aphasia‐hemiparesis (in 2), and acute transcortical mixed aphasia (in 6), in relation to characteristic combinations of infarcts. These unique clinical and etiological correlates warrant the recognition of double infarct in one cerebral hemisphere from other acute ischemic strokes.
Dopa‐responsive dystonia: [18F]dopa positron emission tomography
Authors: Sawle G. V. , Leenders K. L. , Brooks D. J. , Harwood G. , Lees A. J. , Frackowiak R. S. J. , Marsden C. D.
Published: January 2005

The syndrome of dopa‐responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L‐dopa therapy. Benefits from this treatment are lasting, and the problems associated with long‐term L‐dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L‐dopa. We have studied [18F]dopa uptake in 6 patients with classic doparesponsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia‐parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa‐responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that doparesponsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.
Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin
Authors: Cornblath David R. , Chaudhry Vinay , Griffin John W.
Published: January 2005

Chronic inflammatory demyelinating polyneuropathy is an immune‐mediated demyelinating peripheral neuropathy usually treated with immunosuppressants. We reviewed our experience treating 15 patients (9 men, 6 women) with intravenous immunoglobulin. Six patients were on other therapies at the time of intravenous immunoglobulin infusions (4, prednisone; 2, prednisone and azathioprine). The dose of intravenous immunoglobulin was either 0.3 or 0.4 gm/kg/day for 4 to 5 days. Transient fever occurred in 1 patient. Subjective improvement in sensory symptoms was reported by almost all patients. Objective improvements in strength or functional tasks occurred in only 3 patients, a man with human immunodeficiency virus infection, a 14‐year‐old girl, and a woman with an immunoglobulin G kappa paraprotein. Our results suggest that individual patients may respond to intravenous immunoglobulin therapy. A multicenter controlled trial is needed to assess properly the role of intravenous immunoglobulin therapy in patients with chronic inflammatory demyelinating polyneuropathy.
Use of computed tomography, magnetic resonance imaging, and localized 1H magnetic resonance spectroscopy in canavan's disease: A case Report
Authors: Marks Harold G. , Caro Pilar A. , Wang Zhiyue , Detre John A. , Bogdan Andrew R. , Gusnard Debra A. , Zimmerman Robert A.
Published: January 2005

The neuroradiological evaluation of Canavan's disease in a 38‐month‐old girl is discussed. Computed tomography showed diffuse symmetrical low attenuation values of the subcortical and deep cerebral white matter. Magnetic resonance imaging demonstrated symmetrical diffuse low signal intensity of T1‐weighted images and high signal intensity on T2‐weighted images. With the use of 1H magnetic resonance spectroscopy, we were able to show elevated levels of N‐acetylaspartic acid in the occipital lobe of our patient. The in vivo measurement of N‐acetylaspartic acid in the brain by 1H magnetic resonance spectroscopy offers an additional noninvasive diagnostic test for establishing the diagnosis of Canavan's disease. With the increasing availability of magnetic resonance spectroscopy, clinicians may be able to confirm the diagnosis of Canavan's disease immediately after magnetic resonance imaging reveals the typical abnormalities of the white matter.
Does tremor pace repetitive voluntary motor behavior in parkinson's disease?
Authors: Logigian Eric , Hefter Harald , Reiners Karlheinz , Freund Hans‐Joachim
Published: January 2005

In patients with Parkinson's disease and in normal subjects, the influence of tremor on repetitive voluntary movement was investigated in the index figer by comparing frequency of isometric force tremor with frequency of voluntary alternating isometric contractions. Tremor frequency, measured over the range from 0 to 70% maximum voluntary force, usually increased with force. The tremor frequency bands was lower and more often overlapped with the upper voluntary frequency range in patients than in normal subjects. Normal subjects could accurately produce voluntary contractions at all cue frequencies from 1 to 5 Hz. Patients could produce auditory‐paced frequencies of 1 and 2 Hz, but at higher cue frequencies, their voluntary contractions were often faster or slower than the cue. The faster or “hastened” voluntary frequencies were within the tremor frequency band, whereas the slowed voluntary frequencies were below t. Maximal voluntary frequency was often greater than the lowest but always less than the highest tremor frequency. It is concluded that parkinsonian tremor may pace voluntary repetitive movements to go faster than intended with the highest tremor frequency being an upper limit for voluntary frequency. Similar mechanisms may underlie the hastened repetitive vocal responses that wee also observed in the parkinsonian patients.
Lyme neuroborreliosis: A new sensitive diagnostic assay for intrathecal synthesis of borrelia burgdorferi–specific immunoglobulin G, A, and M
Authors: Hansen Klaus , Lebech Anne‐Mette
Published: January 2005

An antibody capture enzyme‐linked immunosorbent assay was developed to measure directly intrathecal immunoglobulin (Ig) G, A, and M synthesis specific for Borrelia burgdorferi. Purified, biotin‐avidin‐peroxidase‐labeled B. burgdorferi flagella was used as test antigen. Paired cerebrospinal fluid and serum specimens from 100 patients with clinically definite neuroborreliosis and 35 control subjects with neurological diseases were examined. Significant B. burgdorferi‐specific intrathecal IgG, A, and M production was found in 89%, 65%, and 67% of patients with neuroborreliosis. Local synthesis of specific IgA was only seen in patients with significant local IgG synthesis. Antibody production in cerebrospinal fluid began by 2 weeks after onset of neurological symptoms. At the end of the second week specific IgM, IgG, or both, was detected in 88% of the patients. Specific IgG synthesis was present in all patients by 6 weeks after onset. Specific local IgM synthesis usually disappeared by 3 to 6 months after therapy, whereas specific IgG synthesis persisted after recovery. Even in patients with a severely altered blood‐brain barrier, the assay discriminated between intrathecal antibody synthesis and antibody leakage from serum. The assay makes diagnostic measurement of B. burgdorferi–specific intrathecal antibody synthesis reliable, rapid, and accessible as a routine serological test.