bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of genetic risk for alzheimer's disease among first‐degree relatives
Authors: Farrer Lindsay A. , O'Sullivan Dianne M. , Cupples L. Adrienne , Growdon John H. , Myers Richard H.
Published: January 2005

Life table methods were used to determine the relative risk of Alzheimer's disease (AD) in relatives of index cases with AD. Risk of AD was assessed in 967 first‐degree relatives of 128 probands with clinically diagnosed AD and 572 first‐degree relatives of a control group consisting of 84 subjects with Parkinson's disease (PD). Using a method that weights likelihood of correct diagnosis of AD, cumulative risk among AD relatives by age 93 was 24%, whereas relatives of the PD probands had a weighted risk of 16% by age 90. Overall, the total lifetime risk of developing dementia was similar among first‐degree relatives of patients with AD and those of patients with PD. The age‐specific risks were much different, however; from the age of 65 years to the age of 80 years, relatives of patients with AD had a twofold to fourfold increased risk of dementia. Equal risks were found for parents and siblings and for male and female relatives after adjustment for sex‐specific patterns of survivorship. Relatives of probanwith early‐onset (> 67 years) and late‐onset (> 67 years) AD had equivalent risks of developing illness. Because onset age was found to cluster in families, the apparent increase in cumulative incidence for dementia in relatives of early‐onset cases was likely due to relatives of the late‐onset cases dying before developing illness. Our interpretation of these data is that a proportion of AD cases is caused by a fully penetrant gene transmitted as an autosomal dominant with age‐dependent penetrance, whereas other cases, including some with multiple affected members, are clinically indistinguishable and of nongenetic cause.
Decrease of suppressor inducer (cd4+ 2h4+) t cells in multiple sclerosis cerebrospinal fluid
Authors: Chofflon Michel , Weiner Howard L. , Morimoto Chikao , Hafler David A.
Published: January 2005

T‐lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis are predominantly CD4+ (inducer) as opposed to CD8+ (suppressor/cytotoxic) T cells. The CD4+ lymphocytes can be subdivided into populations that express high densities of the CDw29 (4B4) determinant and have helper inducer function or express high densities of CD45R (2H4) determinant and have suppressor inducer function. In the present study, we characterized the nature of these CD4+ T cells in the cerebrospinal fluid of patients with multiple sclerosis by performing flow cytometric analysis on paired samples of blood and cerebrospinal fluid. There were significantly lower percentages of CD4+ 2H4+ T cells in the cerebrospinal fluid than in the peripheral blood (p = 0.001, paired t test). In contrast, there were increased percentages of helper inducer (CD4+ 4B4+) T cells in the cerebrospinal fluid (p = 0.001, paired t test), compared with the peripheral blood. Analysis of subjects with other inflammatory disorders of the central nervous system did not show significant decreases in CD4+ 2H4+ T cells in cerebrospinal fluid, though in some, decreases were also observed. These results indicate that the CD4+ T cells in the cerebrospinal fluid of patients with multiple sclerosis are predominantly helper inducer, as opposed to suppressor inducer T cells, and that the relative decrease of suppressor inducer cells in the peripheral blood of multiple sclerosis patients is not due to their migration to the cerebrospinal fluid. Furthermore, the increased numbers of helper inducer cells in the cerebrospinal fluid may contribute to local autoimmune processes in the central nervous system compartment of multiple sclerosis patients.
The effect of carbamazepine on cerebral glucose metabolism
Authors: Theodore William H. , Bromfield Edward , Onorati Linda
Published: January 2005

We used positron emission tomography with 18F‐2‐deoxy‐D‐glucose to study the effect of carbamazepine on local cerebral metabolic rate for glucose (lCMRGlc) in 9 patients with complex partial seizures. Twenty regions of interest were evaluated. Seven control patients had serial scans without a drug change. Metabolic rates were significantly (p ± 0.05) lower in patients on carbamazepine in 6 of 20 regions of interest (3 left cerebral hemisphere, 3 right). Mean lCMRGlc was 7.4 ± 2.0 mg/min/100 in patients on carbamazepine and 8.8 ± 2.5 in patients off carbamazepine (p < 0.00005; cutoff level for 180 comparisons: 0.00027). The mean (± SEM) difference in 1CMRGlc between scans was 12 ± 2%. No significant changes in lCMRGlc on serial scans were detected in any of the 20 regions for the control group. The mean (± SEM) variation for control regions of interest was 1 ± 1%. This study showed that carbamazepine depresses cerebral glucose metabolism as much as phenytoin does, but much less than phenobarbital does. The difference in effect on lCMRGlc may be related to drug mechanisms of action, as well as to effects on memory, learning, mood, and behavior.
Apraxia of eyelid opening secondary to right hemisphere infarction
Authors: Johnston James C. , Rosenbaum Daniel M. , Picone Carmela M. , Grotta James C.
Published: January 2005

A variety of eyelid movement abnormalities have been attributed to lesions of the central nervous system. Apraxia of lid movements, and especially of lid opening, has received the least attention. We present 2 cases of lid opening apraxia and propose that this abnormality may be due to right hemisphere dysfunction.
Parkinsonism and amiodarone therapy
Authors: Werner Elke G. , Olanow C. Warren
Published: January 2005

We report a case of reversible, dose‐related parkinsonian tremor in a patient taking amiodarone. In previous writings by others, basal ganglia dysfunction associated with amiodarone was dose related and reversibility was inversely related to duration of therapy. Patients receiving amiodarone are at risk for the development of basal ganglia dysfunction which may persist if the drug is not discontinued or the dosage reduced.
Amaurosis fugax and ocular infarction in adolescents and young adults
Authors: Tippin Jon , Corbett James J. , Kerber Richard E. , Schroeder Erwin , Thompson H. Stanley
Published: January 2005

Because the cause and natural history of amaurosis fugax and ocular infarction are unknown in most younger patients, we reviewed the records of 83 patients who had become symptomatic before the age of 45. Cerebral transient ischemic attacks had occurred in 9 of these patients but no case of stroke was found. A striking feature of these patients was that 41° had headache or orbital pain accompanying their amaurotic spells and an additional 25.3° had severe headaches independent of the visual loss. Results of laboratory studies were rarely abnormal and echocardiography disclosed that only 1 patient had previously unknown heart disease. Mitral valve prolapse was detected in 6.5°, a figure similar to that expected for the general population. Of the original 83 patients, 42 were reexamined after a mean period of 5.8 years. None of the patients in this group had had a stroke, and the clinical status at follow‐up was not found to correlate with the duration of the visual loss (amaurosis fugax versus ocular infarction), frequency (single versus recurrent episodes), sex, presence of headache or heart disease, cigarette smoking, use of oral contraceptives, or abnormal findings on echocardiograms or laboratory studies. We conclude that amaurosis fugax and ocular infarction occurring in the younger patient are probably associated with a more benign clinical course than that seen in older persons and that migraine is a likely cause for the episodes of visual loss in a majority of this group. Because of this, we believe that a conservative approach to the evaluation of such patients seems warranted.
Linkage to the Huntington's disease locus in a family with unusual clinical and pathological features
Authors: Zweig Richard M. , Koven Suzanne J. , Hedreen John C. , Maestri Nancy E. , Kazazian Haig H. , Folstein Susan E.
Published: January 2005

We used the anonymous DNA probe, D4S10 (G8), Known to be linked to the Huntington's disease (HD) locus, to confirm inheritance at that locus in a family in whom most affected individuals had atypical clinical and pathological features. Their clinical features were similar to the Westphal variant (usually seen in juvenile‐onset HD) but they had onset in adult life, and in contrast to juvenile‐onset HD, their course of illness was prolonged. Most family members had been repeatedly misdiagnosed during life because of the absence of chorea and prominence of long‐tract signs. In 2 patients who died, neuropathological examination at autopsy revealed prominent involvement of brainstem and spinal cord structures, and in 1, mild neostriatal atrophy relative to duration of the disease. The study demonstrates the usefulness of genetic linkage analysis as a diagnostic tool in families with atypical forms of HD. This method allows study of phenotypic variations that can be inherited at or near the HD locus and implies either multiple alleles at the locus gene, modifies of a single allele, or another locus in the same region causing a dominantly inherited neurodegenerative disease.
Molecular biology of duchenne and Becker's muscular dystrophy: Clinical applications
Authors: Gutmann David H. , Fischbeck Kenneth H.
Published: January 2005

Recent advances in molecular genetics have led to the isolation of the gene defective in patients with Duchenne and Becker's muscular dystrophy and the characterization of its protein product, dystrophin. In this communication, the developments culminating in the identification of the Duchenne muscular dystrophy locus are reviewed. The practical applications of this research and pitfalls that limit prenatal diagnosis and carrier detection are discussed.
Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome
Authors: Hayes Melvyn P. , Rubinow David , Lane Clifford , Markey Sanford P.
Published: January 2005

Dementia and brain atrophy are established features of a large proportion of patients with acquired immune deficiency syndrome (AIDS). To investigate a potential mechanism for atrophy in AIDS, we measured the concentration of the endogenous neurotoxin quinolinic acid in the cerebrospinal fluid of 10 patients with AIDS and found that they had 3‐fold higher quinolinic acid concentrations than 9 age‐matched control subjects: 53.8 10.7 pmol/ml versus 18.4 3.4 pmol/ml, respectively (p 0.005). It remains to be determined whether increased brain quinolinic acid concentrations are involved in the pathogenesis of the neuropathology of AIDS.
Tau in situ hybridization in normal and alzheimer brain: Localization in the somatodendritic compartment
Authors: Kosik Kenneth S. , Crandall James E. , Mufson Elliott J. , Neve Rachael L.
Published: January 2005

Tau messenger RNA in situ hybridization in human postmortem brain revealed that neurons are the predominant cell type labeled. The probe used includes the nucleotide sequence coding for the amino acids recognized by the well‐characterized tau monoclonal antibodies 5E2 and tau 1. The distribution of the tau RNA is abundant throughout the neuronal somata and into the proximal parts of dendrites of pyramidal cells in the cerebral cortex and the hippocamps. The distal extent to which silver grains cold be visualized in the pyramidal cell dendrite was comparable to that seen with a probe to ribosomal RNA. In contrast to the tau probe the ribosomal probe also labeled glial cells. Sections hybridized with the tau probe and then double‐labeled with thioflavine S revealed that neurons containing neurofibrillary tangles tangles continue to synthesize tau protein.
Low‐titer antibodies reactive with HTLV‐I gag P19 in patients with chronic myeloneuropathy
Authors: Kawanishi Taketo , Akiguchi Ichiro , Fujita Masashi , Kameyama Masakuni , Hatanaka Masakazu
Published: January 2005

To elucidate the possible association of human T‐lymphotropic virus type I (HTLV‐I) and chronic neurological diseases, 156 serum samples from patients with various neurological diseases, including multiple sclerosis, chronic progressive myelopathy, chronic inflammatory polyradiculoneuropathy, myasthenia gravis, polymyositis, motor neuron disease, and tension headache, and healthy control subjects were examined for IgG antibodies to HTLV‐I by three independent techniques–gelatin particle agglutination test, enzyme‐linked immunosorbent assay, and Western blot assay. Specificity of antibodies was assessed by homologous competitive inhibition on Western blot assay. Six patients (3 with chronic progressive myelopathy, 1 with chronic inflammatory polyradiculoneropathy, 1 with motor neuron disease, and 1 with tension headache) had high‐titer HTLV‐I antibodies. Twelve patients (5 with multiple sclerosis, 1 with chronic progressive myelopathy, 2 with chronic inflammatory polyradiculoneuropathy, 2 with myasthenia gravis, and 2 with motor neuron disease) had low‐titer HTLV‐I antibodies that reached with a single gag protein, p19, or p24, on Western blot assay. In 4 (2 with multiple sclerosis, 1 with chronic progressive myelopathy, and 1 with chronic inflammatory polyradiculoneuropathy) of these 12, the antibodies that were all directed to p19 were determined to be specific by homologous competitive inhibition. In the remaining 8 patients (3 with multiple sclerosis, 1 with chronic inflammatory polyradiculoneuropathy, 2 with myasthenia gravis, 2 with motor neuron disease), restricted reactions against p19 or p24 were considered to be nonspecific because they were not inhibited by homologous competitive inhibition. The results suggest that in some patients chronic myeloneuropathy diagnosed as chronic progressive multiple sclerosis, chronic progressive myelopathy, and chronic inflammatory polyradiculoneuropathy may be associated with HTLV‐I or related retroviruses.
Nigrostriatal function in humans studied with positron emission tomography
Authors: Martin W. R. W. , Palmer M. R. , Patlak C. S. , Calne D. B.
Published: January 2005

The dopamine depletion that is characteristic of Parkinson's disease has been hypothesized to result from the combination of environmentally induced subclinical damage to the substantia nigra and the age‐related loss of additional nigral neurons. Essential to this hypothesis is the existence of deteriorating function in the nigrostriatal pathway with advancing age. The present study was undertaken with [18F]6‐fluoro‐L‐dopa and positron emission tomography to determine in vivo the effects of age on the nigrostriatal pathway in a series of 10 asymptomatic subjects (age range, 22–80 years; mean, 49.8 years). A graphical approach was used in the analysis of multiple‐time tracer‐uptake data to establish the presence of a compartment with unidirectional uptake and to calculate the rate constant, K, for uptake of [18F]6‐fluoro‐L‐dopa from blood to striatum during steady‐state, an index of the functional integrity of nigrostriatal nerve endings. There was a significant linear relationship between K and age (r = 0.80, p < 0.005) with a decrease of 53.3% over the age range studied. These results demonstrate the application of a unidirectional transfer model to the analysis of [18F]6‐fluoro‐L‐dopa and positron emission tomography data and provide in vivo confirmation of an age‐related impairment of nigrostriatal function.
Axonal regeneration on mature human brain tissue sections in culture
Authors: Crutcher Keith A. , Privitera Michael
Published: January 2005

Fresh frozen sections of the temporal lobe from patients undergoing surgical resection for the control of epilepsy were used as a substrate in tissue culture to test for neurite growth‐promoting activity. Robust neurite growth from ganglia of embryonic chicks was observed on gray matter regions of the sections and little growth was observed on white matter regions. These results indicate that the dichotomy between gray and white matter regions of the mature central nervous system in supporting neurite growth is present in human brain tissue and supports the general hypothesis that white matter in the mature central nervous system inhibits neurite regeneration but that gray matter will support neurite growth.
Idiopathic dystonia among ashkenazi jews: Evidence for autosomal dominant inheritance
Authors: Bressman Susan B. , De Leon Deborah , Brin Mitchell F. , Risch Neil , Burke Robert E. , Greene Paul E. , Shale Heidi , Fahn Stanley
Published: January 2005

We studied families to clarify the mode of inheritance of idiopathic torsion dystonia among the Ashkenazim. Probands had symptoms before 28 years of age, had at least one Ashkenazi grandparent, and were ascertained independently of family history and not referred by another relative. All available first‐ and second‐degree relatives were examined, and videotapes were made. Examination notes and blinded review of videotapes led to rating of dystonia as definite, probable, possible, or absent. We determined rates to illness for first‐and second‐degree relatives and calculated age‐adjusted lifetime risks. The methods of maximun likelihood and likelihood ratio goodness‐of‐fit tests were used to estimate parameters and to test dominant and recessive models of inheritance. We studied 43 probands, 146 (90.1%) of 162 living first‐degree relatives, and 96 (40.2%) of 239 living second‐degree relatives. Nineteen relatives had definite dystonia, and 2 had probable dystonia. Using definite cases only, the age‐adjusted risk for all first‐degree relatives was 15.5percnt; and for all second‐degree relatives 6.5percnt;, with no significant sex differences; parent, offspring, and sibling risks did not differ significantly. The risks were consistent with autosomal dominant inheritance with a penetrance estimated at 29.4% using definite cases only or 32.2percnt; using definite and probable cases. Assuming a disease frequency of 1/15,000, the gene frequency was estimated to be 1/9000.
Bimodal treatment with nimodipine and low‐molecular‐weight dextran for focal cerebral ischemia in the rat
Authors: Salgado Antonio V. , Jones Stephen C. , Furlan Anthony J. , Korfali Ender , Marshall Sam A. , Little John R.
Published: January 2005

We compared the effects of intravenous treatment with combined low‐molecular‐weight dextran and nimodipine (n = 9), or placebo (n = 10), on local cerebral blood flow after occlusion of the left middle cerebral and common carotid artery in the rat. Treatment for a total of 4 hours with low‐molecular‐weight dextran (5 mg/kg/min) and nimodipine (0.25 μg/kg/min) produced a decrease in hematocrit from 46 ± 1 to 33 ± 1% at the end of the study and a statistically significant increase in local cerebral blood flow, when compared to the control group, in 6 regions of interest: the territories of the right middle (p = 0.01), right anterior (p = 0.007), and left anterior cerebral arteries (p = 0.001) the superior (p = 0.03) and inferior border zone (p = 0.003); and white matter in the right hemisphere (p = 0.04). The ischemic volume, defined as brain volume with a cerebral blood flow of less than the critical level of 25 ml/min/100 gm was determined as a percentage of total brain volume for the control and treatment groups. The group treated with lowmolecular‐weight dextran and nimodipine showed a 31% decrease in ischemic volume (p = 0.03). These results indicate that a bimodal approach with low‐molecular‐weight dextran and nimodipine can be safely used in a model of acute stroke and has a beneficial effect on local cerebral blood flow and ischemic volume when compared with control subjects. After 4 hours, the potential exists that this treatment is therapeutic, assuming that the ischemic volume progresses to infarction.
The early risk of multiple sclerosis following isolated acute syndromes of the brainstem and spinal cord
Authors: Miller D. H. , Ormerod I. E. C. , Rudge P. , Kendall B. E. , Moseley I. F. , McDonald W. I.
Published: January 2005

A combined clinical and magnetic resonance imaging follow‐up study was undertaken to determine the risk of early progression to multiple sclerosis in patients who present with clinically isolated lesions of the brainstem or spinal cord. Progression to multiple sclerosis was seen in 13 patients (57%) who had a brainstem syndrome and in 14 patients (42%) who had a spinal cord syndrome after mean intervals of 15 and 16 months, respectively. The risk of progression was increased by the presence of oligoclonal bands in the cerebrospinal fluid of patients with either syndrome and by the presence of disseminated brain lesions, as detected by magnetic resonance imaging, in those with a spinal cord syndrome. Follow‐up revealed evidence of multiphasic disease in 24 (69%) of 35 patients who had disseminated lesions on magnetic resonance imaging scans at presentation, suggesting that multiple sclerosis is the usual cause of such lesions.
Localization of epileptic foci with postictal single photon emission computed tomography
Authors: Rowe Christopher C. , Berkovic Samuel F. , Sia S. T. Benjamin , Austin Mark , McKay W. John , Kalnins Renate M. , Bladin Peter F.
Published: January 2005

Effective surgical treatment of patients with intractable complex partial seizures depends on accurate preoperative seizure focus localization. We evaluated seizure localization with interictal and immediate postictal single photon emission computed tomographic images of cerebral perfusion using technetium‐99m–hexamethyl‐propyleneamineoxime (99mTc‐HMPAO) in comparison with conventional ictal electroencephalographic (EEG) localization. Thirty‐two patients with intractable complex partial seizures were studied. The mean delay from seizure onset to injection was 6.3 ± 5.3 (SD) minutes. Independent blinded observers assessed the scans for interictal hypoperfusion and postictal focal hyperperfusion. Interictal scans alone were unreliable, indicating the correct localization in 17 patients (53percnt;) and an incorrect site in 3 (9%). When interictal and postictal scans were interpreted together, the focus was correctly localized in 23 patients (72%). There was 1 false‐positive study, and 8 patients had inconclusive changes, including 2 with inconclusive depth EEG studies. Postictal hyperperfusion was predominantly mesial temporal and frequently associated with hypoperfusion of lateral temporal cortex. Secondarily generalized seizures tended to show focal hyperperfusion less often than complex partial seizures did (Fisher's exact test p = 0.09). Combined interictal and immediate postictal single photon emission computed tomography with 99mTc‐HMPAO is a useful noninvasive technique for independent confirmation of electrographic seizure localization. It may provide a suitable alternative to the use of depth electrode studies for confirmation of surface EEG findings in many patients with complex partial seizures.
Adenosine receptors in brain: Neuromodulation and role in epilepsy
Authors: Chin Jerome H.
Published: January 2005

Adenosine is now recognized as an important endogenous modulator of neuronal excitability in the mammalian central nervous system. Adenosine is produced and released in the brain, where it exerts potent depressant effects on neuronal firing and synaptic transmission. Multiple adenosine receptor subtypes have been characterized using biochemical, electrophysiological, and radioligand binding techniques. Adenosine analogues have potent anticonvulsant actions in vitro and antagonize seizures in animals induced by a variety of mechanisms, including kindling. The future development of selective adenosine receptor agonists may provide new and more effective treatment for epilepsy.
PET Imaging of human gliomas with ligands for the peripheral benzodiazepine binding site
Authors: Junck Larry , Olson James M. M. , Ciliax Brian J. , Koeppe Robert A. , Watkins G. Leonard , Jewett Douglas M. , McKeever Paul E. , Wieland Donald M. , Kilbourn Michael R. , Starosta‐Rubinstein Simon , Mancini William R. , Kuhl David E. , Greenberg Harry S. , Young Anne B.
Published: January 2005

Human gliomas were imaged in vivo using ligands for the peripheral‐type benzodiazepine site (or ω3 binding site) and positron emission tomography (PET). Although gliomas have a high density of the peripheral‐type benzodiazepine binding site, PET scans with a selective ligand for this site, [11C]Ro5‐4864, failed to demonstrate higher radioactivity levels in human gliomas than in brain. In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5‐4864 but high levels of binding of another selective ligand, PK 11195. Scans with [11C]PK 11195 demonstrated increased radioactivity in glioma compared to brain in 8 of 10 patients. Radioactivity in tumor and the ratios of radioactivity in tumor to that in remote gray and in white matter correlated significantly with the specific activity of [11C]PK 11195, suggesting that accumulation represents saturable high‐affinity binding. We conclude that the PK 11195 manifests greater binding than Ro5‐4864 to the peripheral‐type benzodiazepine binding site on human gliomas and that human gliomas can be successfully imaged using [11C]PK 11195 and PET.
Computed tomographic patterns of proven embolic brain infarctions
Authors: Ringelstein E. Bernd , Koschorke Susanne , Holling Andreas , Thron Armin , Lambertz Heinz , Minale Carmine
Published: January 2005

To define patterns of infarction on computed tomography that are characteristic of embolism, as opposed to hemodynamically or microangiopathically induced brain lesions, a consecutive series of 60 patients with acute brain embolism were studied. Strokes were embolic in origin; that is, hemodynamic and in situ thrombotic stroke mechanisms had been excluded. Embolically active, cardiac disease was proved in 42 and was clinically evident in 13 patients. Five patients had suffered a stroke due to catheter‐related embolism. Computed tomography revealed pial artery territorial infarction in 55 patients (92%). In 5, the infarction had the size or location (or both) characteristic of lacunes, although shape and lack of multiplicity raised questions about this interpretation. No patient showed a low‐flow type of infarction pattern. These findings strongly support the view that (1) except for in situ thrombosis, pial artery territorial infarctions are indicative of an embolic mechanism, and (2) that the mechanism underlying lacunes is hardly, if ever, embolic.
The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition
Authors: Tabaton Massimo , Mandybur Thaddeus I. , Perry George , Onorato Michelle , Autilio‐Gambetti Lucila , Gambetti Pierluigi
Published: January 2005

The structural changes of Alzheimer's disease (AD) include a widespread alteration of neuronal cell processes in addition to senile plaques and neurofibrillary tangles. Since the antigenic characteristics of these abnormal neurites are similar to those of the abnormal neurites associated with the senile plaques, the question has been raised as to whether the widespread neuritic alteration is secondary to the deposition of amyloid. To answer this question, we examined brains from 2 subjects with a longer‐lasting form of subacute sclerosing panencephalitis (SSPE) characterized by the presence of numerous neurofibrillary tangles but no senile plaques, 3 subjects with AD, and 2 age‐matched controls. Light and electron immunocytochemical analyses revealed that abnormal neurites are present diffusely in SSPE cerebral cortex in the absence of amyloid deposits. These abnormal neurites were qualitatively identical to the widespread abnormal neurites of AD. The abnormal neurites, in contrast to the neurites of control brains, immunoreacted with antibodies to tau and ubiquitin. These distinctive antigenic features were due to the presence in these abnormal neurites of straight filaments, 14 to 16 nm in diameter, mixed with a few paired helical filaments. The spatial distribution of the widespread neuritic alteration correlated with that of neurofibrillary tangles in both conditions, but not with that senile plaques in AD. The present findings demonstrate that a diffuse alteration of neurites similar to that present in AD takes place independently of the deposition of amyloid in SSPE, and they are consistent with the hypothesis that in AD, also, this alteration is not secondary to the deposition of amyloid. It is suggested that the diffuse abnormality of neurites and the formation of neurofibrillary tangles in AD and SSPE, as well as in other conditions, are the expression of a widespread alteration of the neuronal cytoskeleton that involves the ubiquitin system and is likely to be caused by sustained stress conditions.
Naltrexone therapy of apnea in children with elevated cerebrospinal fluid β‐endorphin
Authors: Myer Edwin C. , Morris Dale L. , Brase David A. , Dewey William L. , Zimmerman Andrew W.
Published: January 2005

Previous studies have indicated increased immunoreactivity of the endogenous opioid peptide β‐endorphin in the cerebrospinal fluid (CSF) of infants under 2 years of age with apnea. To assess the role of endogeneous opioids in the pathogenesis of apnea in children, the effect of oral treatment with the opioid antagonist naltrexone was studied in apneic infants, as well as in older apneic children, with demonstrated increases in CSF immunoreactive β‐endorphin (i‐BE). In the 8 apneic infants with elevated i‐BE in lumbar CSF (range, 55–155 pg/ml normal, 17–52 pg/ml), no further apnea occurred during natltrexone therapy (1 mg/kg/day, by mouth). Five children (2–8 years old) with apnea of unknown cause had elevated CSF i‐BE (range, 74–276 pg/ml) compared to 6 age‐matched nonapneic children (range, 15–48 pg/ml). No apneic events occurred during natlrexone therapy, except in 1 child during stressful events, but apnea recurred in some patients after attempts to discontinue natlrexone treatment. Adverse effects of natlrexone included complaints of headaches in 2 children and symptoms of a narcotic withdrawal syndrome during the first 3 days of treatment in 1 child. Three children with Leigh's syndrome had elevated CSF i‐BE (range, 104–291 pg/ml) and their apnea also responded to naltrexone. We conclude that elevated endogenous opioids contribute to the pathogenesis of apnea in children and may even result in physical dependence.
Quantitative morphological analysis of striatal cholinergic neurons in perinatal asphyxia
Authors: Burke Robert E. , Karanas Andrew L.
Published: January 2005

Although the static encaphalopathies of childhood are common, little is known of the underlying alterations in the neurochemical anatomy of the brain. Using quantitative morphological techniques, we examined the effect of perinatal hypoxia‐ischemia on the number and distribution of cholinergic (ACh) neurons in a unilateral experimental striatal lesion in rats. The striatal pathology simulates status marmoratus, a recognized correlate of human dystonic cerebral palsy. We found that striatal injury results in a mean 22% decrease in the number of ACh neurons at the age of 3 to 4 weeks. The loss of neurons was relatively less than the volume loss, resulting in a mean 16% increase in neuron density. This effect was not uniform throughout the striatum; it was more pronounced caudally, resulting in a mean 52% increase in density in the most caudal striatal plane. These changes in immature rats were also seen in adult rats, indicating that there were lasting alterations in striatal cholinergic morphology. Hypoxic‐ischemic injury to the striatum also resulted in a persistent decrease in the mean area of ACh neurons. The increased density of these neurons may imply that they are relatively resistant to hypoxic‐ischemic injury. These findings may be relevant to the observation that anticholinergic drugs are among the most effective for treating dystonias, including those observed in staticencephalopathies.
Regional cerebral blood flow during focal seizures of temporal and frontocentral onset
Authors: Stefan H. , Bauer J. , Feistel H. , Schulemann H. , Neubauer U. , Wenzel B. , Wolf F. , Neundörfer B. , Huk W.‐J.
Published: January 2005

Ictal single photon emission computed tomography recordings were performed in 9 patients in the course of 11 seizures. Injections of radionuclide were made an average of 72 seconds after the onset of the seizure as indicated by electroencephalography. All patients also underwent interictal recordings. In 6 patients, the localization of the electroencephalographic focus and the morphological lesions corresponded with the ictal hyperperfusion. This could be seen in single photon emission computed tomography. Seizures triggered by hyperventilation, and seizures of patients with anatomical brain lesions (e.g., cysts, surgical defects, and recent injections of technetium‐hexamethylene‐propyleneamine‐oxime) showed an absent or noncorresponding localization of the ictal recording. The ictal and interictal recording seems suitable as a confirmatory noninvasive method for the localization of the epileptogenic focus, particularly in the preoperative evaluation of epilepsy.
Orally administered 4‐aminopyridine improves clinical signs in multiple sclerosis
Authors: Davis Floyd A. , Stefoski Dusan , Rush Jean
Published: January 2005

4‐Aminopyridine (4‐AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4‐AP on both visual and motor signs in MS. Twenty temperature‐sensitive male MS patients were given either 10 to 25 mg of 4‐AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker‐fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4‐AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4‐AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.
Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment
Authors: Chugani Harry T. , Shields W. Donald , Shewmon D. Alan , Olson Donald M. , Phelps Michael E. , Peacock Warwick J.
Published: January 2005

Positron emission tomography (PET) of local cerebral glucose metabolism in 13 children with infantile spasms of undetermined cause (cryptogenic spasms) revealed unilateral hypometabolism involving the parieto‐occipito‐temporal region in 5 female infants. Cranial computed tomography showed normal findings in all infants. Magnetic resonance imaging (MRI) demonstrated a normal appearance in 4 of the 5 infants; in 1 infant, MRI revealed a subtle abnormality consisting of poor demarcation between occipital gray and white matter. Surface electroencephalography (EEG) in 4 showed hypsarrythmia at some time in the patients' courses, but at other times showed localized or lateralized abnormalities corresponding to areas of PET‐detected hypometabolism. Because of poor seizure control, 4 infants underwent surgical removal of the cortical focus guided by intraoperative electrocorticography and were seizure free postoperatively. Neuropathological examination of resected tissue in each showed microscopic cortical dysplasia. Our findings indicate that in infants with cryptogenic spasms, PET can effectively identify those due to unsuspected focal cortical dysplasia, for which resective surgery offers improved prognosis.
Tourette's syndrome: A neurochemical analysis of postmortem cortical brain tissue
Authors: Singer Harvey S. , Hahn In‐Hei , Krowiak Edward , Nelson Eric , Moran Timothy
Published: January 2005

Postmortem frontal, temporal, and occipital regions of the brain from adult patients who had a diagnosis of Tourette's syndrome were analyzed for neurochemical alterations. In 3 of 4 TS‐affected brains, the concentration of adenosine 3′,5′ ‐monophosphate (cyclic AMP) was reduced in all brain regions evaluated. This diminution in cyclic AMP was not associated with a significant change in the activity of the synthesizing enzyme, adenylate cyclase. No significant differences were identified for the neurotransmitter‐synthesizing enzymes choline acetltransferase and glutamate decarboxylase. Concentrations of dopamine, norepinephrine, and the serotonin metabolite 5‐hydroxyindoleacetic acid were not altered. Postsynaptic receptor‐binding activity for muscarinic cholinergic ([3H] quinuclidiny1 benzilate) and beta receptors ([125I]iodocyanopindolol) showed no generalized impairment. It is suggested that symptoms of Tourette's syndrome might be related to an abnormality within a second messenger system.
Instability of gaze during locomotion in patients with deficient vestibular function
Authors: Grossman Gerald E. , Leigh R. John
Published: January 2005

We measured the stability of gaze in the horizontal and vertical planes, in 2 patients with bilaterally deficient vestibular function while they sat, stood still, walked in place, and made active horizontal and vertical head rotations. During sitting and standing, gaze was equally as stable as that in normal subjects. During walking in place, however, gaze velocity was double that of normal subjects. Thus, our patients' complaints of impaired vision and oscillopsia during walking could be ascribed to excessive motion of images on their retinas. Eye movements compensated for head rotations more effectively (higher gain) during active head rotations than during locomotion; this difference may be due to the predictable nature of active head movements. We conclude that testing of patients with vestibular symptoms should include stimuli corresponding to the rotational head perturbations that occur during locomotion; such head rotations have nonpredictable characteristics and a frequency range of 0.5 to 5.0 Hz.
An unusual variant of Becker muscular dystrophy
Authors: De Visser Marianne , Bakker Egbert , Defesche Joep C. , Bolhuis Piet A. , Van Ommen Gert Jan
Published: January 2005

We report on 5 brothers with slowly progressive limbgirdle weakness. Calf hypertrophy was absent. The levels of creatine kinase, electromyography, and findings from a muscle biopsy specimen were compatible with muscular dystrophy. The propositus's biopsy specimen also showed numerous rimmed vacuoles. DNA analysis revealed a deletion in the dystrophin gene, establishing a diagnosis of Becker muscular dystrophy. Both the absence of calf hypertrophy and the presence of rimmed vacuoles are unusual features in this disorder.
CGS‐19755, A competitive NMDA receptor antagonist, reduces calcium‐calmodulin binding and improves outcome after global cerebral ischemia
Authors: Grotta J. C. , Picone C. M. , Ostrow P. T. , Strong R. A. , Earls R. M. , Yao L. P. , Rhoades H. M. , Dedman J. R.
Published: January 2005

We evaluated several doses of cis‐4‐(phosphonomethyl)‐2‐piperidine‐carboxylic acid (CGS‐19755), a potent competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight‐arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium‐calmodulin binding. High‐dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS‐19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium‐calmodulin binding. We conclude that CGS‐19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.
Phosphorus magnetic resonance spectroscopy of patients with mitochondrial cytopathies demonstrates decreased levels of brain phosphocreatine
Authors: Eleff S. M. , Barker P. B. , Blackband S. J. , Chatham J. C. , Lutz N. W. , Johns D. R. , Bryan R. N. , Hurko O.
Published: January 2005

The hypothesis that brain mitochondria are directly affected in several phenotypes associated with disordered oxidative phosphorylation was tested using phosphorus 31 (31P) magnetic resonance spectroscopy. Abnormal phosphorylation potentials in skeletal muscle have been demonstrated by 31P magnetic resonance spectroscopy in patients with mitochondrial cytopathies (heritable disorders of oxidative phosphorylation), but abnormalities of phosphorylation potentials in other organs have not been documented. Several lines of evidence suggest that these mutations may affect mitochondria in nonmuscle tissue. In this study we found that phosphocreatine‐to‐ATP ratios in brain were significantly reduced and that calculated brain ADP concentrations, phosphorylation potentials, and percentage of maximal rate of ATP synthesis were significantly altered in the 5 patients examined. This study indicates a primary abnormality of mitochondrial function in the brain, even in the absence of clinically evident cerebral dysfunction.
The short‐duration response to apomorphine: Implications for the mechanism of dopaminergic effects in parkinsonism
Authors: Gancher Stephen T. , Woodward William R. , Gliessman Perry , Boucher Brian , Nutt John G.
Published: January 2005

The pharmacological basis of the short‐duration response to dopaminergic stimulation in parkinsonism is not completely understood. Whereas it is generally assumed that the response reflects concurrent dopamine receptor occupancy, it is also possible that receptor activation triggers events that outlast the time that receptors are occupied by agonist. To distinguish between these two possibilities, we administered apomorphine, a mixed D1‐D2 agonist with rapid equilibration between plasma and brain, to patients with parkinsonism. The clinical response to apomorphine injections lagged behind peak plasma concentrations and persisted beyond the time plasma apomorphine concentrations fell below threshold levels, which were estimated from peak plasma apomorphine concentrations following ineffective doses. We conclude that dopaminergic stimulation triggers effects that outlast the period of receptor occupancy by agonist. Understanding these steps may offer new pharmacological therapies for parkinsonism.
Soluble interleukin‐2 receptors in cerebrospinal fluid from individuals with various neurological disorders
Authors: Kittur Smita D. , Kittur Dilip S. , Soncrant Timothy T. , Rapoport Stanley I. , Tourtellotte Wallace W. , Nagel James E. , Adler William H.
Published: January 2005

Soluble interleukin‐2 receptor (IL‐2R) levels in the cerebrospinal fluid (CSF) were studied in infectious, inflammatory, degenerative, and neoplastic disorders to evaluate their usefulness as a marker for the presence of activated T cells, thus indicating an inflammatory process. CSF from control subjects and patients with stationary, progressive, and treated multiple sclerosis (MS); aseptic meningitis; lymphoid and nonlymphoid central nervous system (CNS) tumors; Alzheimer's disease, as well as serum from MS patients and control subjects were studied for levels of soluble IL‐2R. A significant increase in CSF IL‐2R levels was observed in patients with MS, meningitis, and lymphoid CNS tumors; the MS group showed the highest values. CSF from individuals with Alzheimer's disease and from patients with nonlymphoid tumors did not show significantly elevated values. Serum IL‐2R levels were significantly higher in MS patients than in control subjects, but there was no significant correlation between individual serum and CSF IL‐2R levels. This study suggests the presence of activated T‐lymphocytes in the CNS of patients with MS.
Anoxic injury of mammalian central white matter: Decreased susceptibility in myelin‐deficient optic nerve
Authors: Waxman Stephen G. , Davis Peter K. , Black Joel A. , Ransom Bruce R.
Published: January 2005

The rat optic nerve, a typical central nervous system white matter tract, rapidly loses excitability when it is exposed to anoxia and is irreversibly damaged by prolonged anoxia. Neonatal optic nerve is extremely resistant to anoxia‐induced dysfunction and injury; the adult pattern of response to anoxia appears between 10 and 20 days postnatal, that is, during the period of oligodendroglial proliferation and myelination. To test the hypothesis that myelination, or associated events, confer anoxic susceptibility on developing white matter, we analyzed the effects of anoxia on the myelin‐deficient (md) strain of rat. Acutely isolated optic nerves from 19‐ to 21‐day‐old md rats and control optic nerves from unaffected male littermates were maintained in vitro at 37T, and exposed to a standard 60‐minute period of anoxia. The supramaximal compound action potential was recorded and amplitude of the compound action poten‐ tial, expressed as % of amplitude before anoxic exposure, was determined. The compound action potential was nearly abolished within 3 to 6 minutes after onset of anoxia in control optic nerves, while optic nerves from md rats displayed a slower decrease in compound action potential amplitude during anoxia, with a distinct action potential present even after 60 minutes of anoxia. Optic nerves from md rats showed significantly greater recovery of compound action potential (71 ± 25%) than did control optic nerves (33 ± 21%; p < 0.02) after 60 minutes of anoxia. These findings support the hypothesis that myelination, or changes associated with it, may be important in the development of anoxic susceptibility in central white matter.
IgM deposits at nodes of ranvier in a patient with amyotrophic lateral sclerosis, anti‐GM1 antibodies, and multifocal motor conduction block
Authors: Santoro Maria , Thomas Florian P. , Fink Matthew E. , Lange Dale J. , Uncini Antonino , Wadia Noshir H. , Latov Norman , Hays Arthur P.
Published: January 2005

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti‐GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti‐GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.