bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities of somatosensory evoked potentials in the quinolinic acid model of Huntington's disease: Evidence that basal ganglia modulate sensory cortical input
Authors: Schwarz Michael , Block Frank , Töpper Rudolf , Sontag Karl‐Heinz , Noth Johannes
Published: January 2005

Intrastriatal injection of quinolinic acid (QA) in rats provides an animal model that mimics some of the neuropathological and neurochemical alterations observed in the striatum of patients with Huntington's disease (HD). One of the very early neurophysiological signs in HD is a diminution of amplitude of early somatosensory evoked potentials (SEPs) recorded over the parietal cortex. The present study investigated whether the QA model exhibits similar neurophysiological abnormalities. Two weeks after unilateral intrastriatal injection of QA (240 nmol) or of the solvent, early SEPs were recorded with chronically implanted electrodes from the somatosensory cortex or from the ventrobasal nucleus of the thalamus of lightly pentobarbital‐anesthetized rats, in response to single‐shock electrical stimulation of the contralateral forepaw. Whereas intrastriatal injection of solvent did not influence SEPs, the striatal QA lesion significantly reduced the amplitude of early cortical SEPs by about 40% without affecting the latency. SEPs recorded from the ventrobasal nucleus were unchanged after QA lesion. Histological examination and glial fibrillary acid protein staining after intrastriatal injection of QA revealed no evidence for damage in the somatosensory system. It is concluded that (1) the QA animal model of HD mimics some of the SEP abnormalities of patients, and (2) a striatal lesion modulates somatosensory transmission to the cortex in rats.
Absence of measles, mumps, and rubella viral genomic sequences from multiple sclerosis brain tissue by polymerase chain reaction
Authors: Godec Mark S. , Asher David M. , Murray Ronald S. , Shin Moon L. , Greenham Leighton W. , Gibbs Clarence J. , Gajdusek D. Carleton
Published: January 2005

We tested for measles, mumps, and rubella viruses in multiple sclerosis by polymerase chain reaction (PCR). Using RNA extracted from 19 multiple sclerosis and 8 control brain specimens, nested PCR was performed after reverse transcription (RT) of the RNA to cDNA using primer pairs directed against two regions in the genomes of measles and mumps viruses and one region in the rubella virus genome. Despite enhanced sensitivity of nested RT PCR, measles, mumps, and rubella viral genomic sequences were not found in any brain specimen.
Werdnig‐Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance
Authors: Boylan Kevin B. , Cornblath David R.
Published: January 2005

We report on a family in which both Werdnig‐Hoff‐mann disease (severe infantile‐onset spinal muscular atrophy) and chronic distal spinal muscular atrophy ocurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig‐Hoffmann disease and died at 10 months. In their second decade of life, the proband's father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the proband's condition was influenced by a maternally derived allelic or modifying trait.
Hemifacial spasm: Evaluation by magnetic resonance imaging and magnetic resonance tomographic angiography
Authors: Adler Charles H. , Zimmerman Robert A. , Savino Peter J. , Bernardi Bruno , Bosley Thomas M. , Sergott Robert C.
Published: January 2005

We evaluated 37 patients with hemifacial spasm and 16 age‐matched control patients with other neurological disorders using magnetic resonance (MR) imaging, MR angiography, and MR tomographic angiography. MR tomographic angiography is a new technique using computer reconstruction of MR angiographic images to create coronal angiotomes that display tissue and arterial structures on the same image. Twenty‐four of 37 (64.9%) patients with hemifacial spasm had ipsilateral vascular compression of cranial nerve VII or the pons noted by this technique, whereas only 1 of 16 (6.3%) control patients had compression. MR imaging and MR angiography were less sensitive and less specific in evaluating for vascular compression. This study supports vascular compression of cranial nerve VII or the pons as a cause of hemifacial spasm, and demonstrates MR tomographic angiography's value as an excellent, noninvasive technique to demonstrate the compression.
Magnetic resonance: A noninvasive approach to metabolism, circulation, and morphology in human brain death
Authors: Aichner F. , Felber S. , Birbamer G. , Luz G. , Judmaier W. , Schmutzhard E.
Published: January 2005

Phosphorus (31P) magnetic resonance spectroscopy and magnetic resonance imaging were used to study the intracellular metabolism, circulation, and morphology in the brains of 3 patients with clinical brain death syndrome due to traumatic brain damage, subarachnoid hemorrhage, and acute occlusive hydrocephalus caused by a colloid cyst. Magnetic resonance spectra were characterized by a complete absence of ATP and were dominated by an intense inorganic phosphate signal. Magnetic resonance imaging revealed a uniform pattern of diffuse brain swelling and tentorial and foraminal herniation. Intracranial blood flow was absent on the magnetic resonance angiography projections. These preliminary findings suggest an important impact of magnetic resonance in the determination of human brain death.
Paternal uniparental disomy of chromosome 15 in a child with angelman syndrome
Authors: Nicholls Robert D. , Pai G. Shashidhar , Gottlieb Wayne , Cantú Eduardo S.
Published: January 2005

Angelman and Prader‐Willi syndromes are clinically distinct neurobehavioral disorders most commonly resulting from large deletions of chromosome 15q11‐q13. The deletions arise differentially during maternal or paternal gametogenesis, respectively. A subgroup of patients with either syndrome have no apparent deletion, and because many such patients with Prader‐Willi syndrome display inheritance of two copies of chromosome 15 from the mother only (uniparental disomy; UPD), we suggested that paternal UPD might be found in patients with Angelman syndrome. We report here clinical, cytogenetic, and molecular evidence on the 1 patient with paternal UPD for chromosome 15 who was found in our study population. This represents, to our knowledge, the first patient with paternal UPD to be studied with DNA probes from the chromosome 15q11‐q13 critical region. In contrast to our findings for patients with Prader‐Willi syndrome, in which maternal UPD was common, our data demonstrate that paternal UPD is infrequent in patients with Angelman syndrome.
Three‐ and four‐year cognitive outcome in children with noncortical brain tumors treated with whole‐brain radiotherapy
Authors: Radcliffe Jerilynn , Packer Roger J. , Atkins Thomas E. , Bunin Greta R. , Schut Luis , Goldwein Joel W. , Sutton Leslie N.
Published: January 2005

Cognitive function and school achievement were studied prospectively over 3 to 4 years in 19 children treated for brain tumors with whole‐brain radiotherapy; 14 of 19 also received adjuvant chemotherapy. For the group as a whole, mean IQ fell from a baseline of 104 to 92 at follow‐up(p < 0.01). Age was inversely correlated with change in IQ over time (r = 0.71;p < 0.001). Children younger than 7 years at diagnosis had a mean IQ loss 27 points, while children over 7 years at diagnosis showed no significant decrease in IQ. Decline in IQ occured between baseline and year 2 of follow‐up; none could be documented between years 2 and 4. All children younger than 7 years at diagnosis were receiveing special education at follow‐up; 50% of the children over 7 years at diagnosis were receiving supplemental educational services.
Neurological intensive care
Authors: Ropper Allan H.
Published: January 2005

Neurological intensive care has evolved from the principles of respiratory care established during the poliomyelitis epidemics into a broad field encompassing all of the acute and serious aspects of neurological disease. The economic and political complexities of modern intensive care play a major role in organizing a unit and building a program. Central themes of practice in modern neurological intensive care units include the clinical physiology of intracranial pressure, verebral blood flow, and brain electrical activity; the systemic abnormalities and medical complications of nervous system, disease; postoperative care; and management of neuromuscular respiratory failure. Treatment of severe stroke andcerebral hemorrhage, brain death, ethical dilemmas of severe neurological illnesses, and neurological features of critically ill medical patients are also becoming neurological intensive care pursuits. The “neuro intensivist” is trained to defragment medical care by combining knowledge of neurological diseases with the techniques of intensive care. Future directions include the clinical implementation of brain resuscitation and brain‐sparing therapies, sophisticated monitoring of electrophysiological and intracranial physiological indices, and further understanding of the dysfunction of other organs that follows brain and nerve failure.
Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma
Authors: Mygland Åse , Tysnes Ole‐Bjørn , Aarli Johan A. , Gilhus Nils Erik , Matre Roald , Volpe Pompeo
Published: January 2005

Sera from patients with myasthenia gravis were examined by Western blot for the presence of antibodies to proteins of the sarcoplasmic reticulum from rabbit skeletal muscle. Fourteen of 30 patients with myasthenia gravis and a thymoma had IgG autoantibodies to the calcium release channel of the sarcoplasmic reticulum (the ryanodine receptor), which plays a crucial role in the mechanism of excitation‐contraction coupling in striated muscle. Ryanodine receptor autoantibodies were not detected in any of the 45 sera from patients with myasthenia gravis without a thymoma. Ryanodine receptor autoantibodies may have pathogenetic relevance in thymoma‐associated myasthenia gravis.
α‐tocopherol levels in brain are not altered in Parkinson's disease
Authors: Dexter D. T. , Jenner P. , Ward R. J. , Peter T. J. , Wells F. R. , Daniel S. E. , Lees A. J. , Marsden C. D.
Published: January 2005

α‐Tocopherol (vitamin E) levels in normal brain were lower in the cerebellum than in the cerebral cortex or basal ganglia. There was no difference in α‐tocopherol levels in the cerebellum, basal ganglia, or cerebral cortex between control subjects and patients with Parkinson's disease.
The identification of presymptomatic parkinsonism: Clinical and {18F}dopa positron emission tomography studies in an irish kindred
Authors: Sawle G. V. , Wroe S. J. , Lees A. J. , Brooks D. J. , Frackowiak R. S. J.
Published: January 2005

An Irish kindred is described in which 5 of 10 siblings in the fourth or fifth decade of life developed an akinetic‐rigid syndrome clinically indistinguishable from idiopathic Lewy body Parkinson's disease. Four of these patients were scanned by positron emission tomography (PET) with {18F}dopa after clinical diagnosis and in all, a profound impairment of tracer uptake into the striatum was recorded. The fifth patient was initially scanned at a time when he was asymptomatic and normal by clinical examination. His scan showed impaired tracer uptake, indicating a subclinical defect in the presynaptic nigrostriatal system. Within months of his scan, he too developed subtle symptoms and signs of parkinsonism although there was little further clinical piogression or change in his PET scan over the following year. A clinically normal sibling was also scanned and found to have subclinical impairment of [18F}dopa uptake in the putamen. The 19‐year‐old daughter of an affected sibling had a mild postural tremor but no other symptoms or signs. The {18F}dopa uptake in her putamen fell at the borderline between normal and parkinsonian values. This study confirms that PET can identify preclinical parkinsonism in at‐risk subjects. The finding of abnormalities in several clinically unaffected family members suggests that family studies based on clinical assessment alone may miss a significant number of subclinically affected individuals, leading to an underestimate of any genetic component to Parkinson's disease.
Neurological rehabilitation
Authors: Selzer Michael E.
Published: January 2005

Increasingly, neurologists are participating in the rehabilitation of disorders of the nervous system. Compelling reasons why neurologists, especially those with academic interests, should become involved in rehabilitation include the opportunity to observe patients in the recovery phases of their illnesses and to study issues relating to functional recovery, exposure to patients (such as those with spinal cord injury) who are often not seen by neurologists in the acute phase, and the opportunity to help establish a scientific base for rehabilitation medicine. Many areas of investigation can contribute to the scientific basis of neurological rehabilitation. Among the most promising are regeneration in the central (CNS) and peripheral nervous systems, adaptive mechanisms following CNS injury, computational neuroscience, neuromuscular physiology of chronic denervating conditions (e.g., the post‐polio syndrome), and outcome studies of both physical and pharmacological therapeutic modalities. While there may be financial advantages to involvement in neurological rehabilitation, these are probably overestimated and interest in this field would continue to grow without them. There is a need for enhanced training in this subspecialty, including the development of dual certification programs in neurology and rehabilitation medicine.
Increased levels of neuronal thread protein in cerebrospinal fluid of patients with Alzheimer's disease
Authors: de la Monte Suzanne M. , Volicer Ladislav , Hauser Stephen L , Wands Jack R.
Published: January 2005

Neuronal thread protein is a recently characterized, ∼20‐kd protein that accumulates in brains with Alzheimer's disease (AD) lesions. This study examined whether concentrations of neuronal thread protein (NTP) were also increased in the cerebrospinal fluid (CSF) of individuals with probable (clinically diagnosed) and definite (histopathologically proved) AD. Using a highly sensitive three‐site monoclonal antibody–based immunoradiometric assay, we measured NTP concentrations in CSF from 84 patients with probable AD and mild dementia (duration, 4.05 ± 0.36 years), 45 with Parkinson's disease and minimal or no dementia (duration, 4.73 ± 0.78 years), 73 with multiple sclerosis, and 73 nondemented control subjects. NTP concentrations were also measured in postmortem ventricular fluid and temporal lobe neocortex extracts from 31 subjects with histopathologically proved AD and 14 age‐matched control subjects. The mean concentration of NTP in the CSF was higher in AD (4.15 ± 0.25 ng/ml; 95% confidence interval [CI] limits, 3.65–4.65) than in Parkinson's disease (1.96 ± 0.16 ng/ml; 95% CI, 1.65–2.27), multiple sclerosis (1.6 0.14 ng/ml; 95% CI limits, 1.33–1.88), or control subjects (1.27 ± 0.06 ng/ml; 95% CI limits, 1.15–1.40) (p < 0.001). In addition, 70% of the patients with probable AD had concentrations of NTP in CSF that were higher than 2.5 ng/ml (> upper 99% CI limit in the control group), compared with 23%of Parkinson's disease patients, 11% of multiple sclerosis patients, and 40% of control subjects. The mean concentrations of NTP in the ventricular fluid and brain tissue from individuals with documented AD and end‐stage dementia were threefold higher than the levels detected in the CSF from the remaining patients with probable AD and mild dementia. Moreover, of 9 patients with AD, postmortem brain and CSF manifested 5‐ to 50‐fold higher levels of NTP compared with the CSF samples obtained an average of 6 years earlier. These findings demonstrate that NTP levels are elevated in the CSF of individuals with AD and that NTP levels in the CSF increase strikingly with progression of dementia and neuronal degeneration.
Continuous lisuride effects on central dopaminergic mechanisms in Parkinson's disease
Authors: Baronti Fabio , Mouradian M. Maral , Davis Thomas L , Giuffra Marianne , Brughitta Giorgio , Conant Kathy E. , Chase Thomas N.
Published: January 2005

Effects of the long term, continuous administration of a dopamine agonist on motor response complications attending levodopa therapy were studied in 7 patients with advanced Parkinson's disease under controlled conditions. After a 3‐month round‐the‐clock infusion of lisuride, the duration of antiparkinsonian action of levodopa increased by approximately 90%, and the therapeutic window for the acutely administered dopamine precursor widened by >300%. These benefits were more than three times greater than those produced by 9 days of continuous levodopa administration. In contrast to the effects on levodopa pharmacodynamics, the continuous infusion of lisuride did not prolong its action, suggesting a lisuride effect on presynaptic as well as postsynaptic dopaminergic mechanisms. These results lend further support to the view that continuous dopamine replacement ameliorates motor fluctuations and peak‐dose dyskinesias that complicate standard levodopa regimens. Our findings further suggest that alterations at both presynaptic and postsynaptic levels contributing to these motor complications tend to normalize with the more physiological stimulation afforded by continuous replacement strategies, especially when given chronically.
Laser microprobe analysis of brain aluminum in Alzheimer' disease
Authors: Lovell Mark A. , Ehmann William D. , Markesbery William R.
Published: January 2005

Aluminum (Al) levels were measured in the cytoplasm and nucleus of 241 neurofibrillary tangle (NFT)‐bearing neurons, in 217 NFT‐free neurons and adjacent neuropil from 7 autopsy‐confirmed Alzheimer's disease (AD) patients, and in 316 normal neurons from 5 control subjects, by laser micriprobe mass spectrometry. Grand mean Al levels (dry weight basis) in AD samples were 2.93 ± 1.24 μg/gm for NFT‐bearing neuron cytoplasm, 3.54 ± 1.39 μg/gm for NFT‐bearing neuron nuclei, 2.31 ± 1.09 μg/gm for NFT‐free neuron cytoplasm, and 3.23 ± 1.09μg/gm for NFT‐free neuron nuclei. Control values were 1.85 ± 0.78 μg/gm for cytoplasm and 2.01 ± 0.93 μg/gm for nuclei. The differences between corresponding regions of AD NFT‐bearing, AD NFT‐free, and control neurons were not significant (p > 0.05, analysis of variance). Al levels in neuropil were identical for AD and control samples at 2.16 ± 0.93 μg/gm. In contrast to some literature reports, we found very few (<2.5%) extremely high Al values (>20μg/gm, dry weight) on a cellular basis in AD samples. AD neurons did exhibit a higher number of Al values (9.6−14.3%) that were >sgrave; above the corresponding control means, than did control neurons (1.3–1.6%), indicating that small elevations of Al may exist in patients with AD. Our data suggest that any Al accumulation in patients with AD is small and generalized in both NFT‐free and NFT‐bearing neurons and that analyses of large bulk brain samples are likely to have AD/control differences masked by the large amount of unaffected neuropil sampled.
Alternating hemiplegia of childhood: Studies of regional cerebral blood flow using 99mTc‐hexamethylpropylene amine oxime single‐photon emission computed tomography
Authors: Aminian Abdolkarim , Strashun Arnold , Rose Arthur
Published: January 2005

Alternating hemiplegia of childhood is a rare disorder of unknown cause associated with progressive neurological deterioration. We report the results of regional cerebral blood flow studies using 99mTc‐hexamethylpropylene amine oxime single‐photon emission computed tomography in 3 patients. These studies were performed during the hemiplegic attacks (n = 6) and during the symptom‐free periods (n = 2). Six single‐photon emission computed tomographic studies performed during hemiplegic attacks consistently showed relative hyperperfusion of the contralateral cerebral hemisphere. Two single‐photon emission computed tomographic studies performed during the asymptomatic phase showed normal and symmetrical cerebral perfusion. This is the first definite demonstration of unilateral increase of cerebral blood flow in alternating hemiplegia. These findings support the possibility of a relationship between the cause of alternating hemiplegia and migraine.
Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices
Authors: Harris K. A. , Oyler G. A. , Doolittle G. M. , Vincent I. , Lehman R. A. W. , Kincaid R. L. , Billingsley M. L.
Published: January 2005

Hyperphosphorylated forms of the microtubule‐associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz‐50, 5E2, and Tau‐1. The results indicate that tau phosphorylation was altered in a dose‐dependent manner by the phosphatase inhibitor okadaic acid, but not by N‐methyl‐D‐aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed “PHF‐like tau,” produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF‐like tau peptides was blocked by KN‐62, 1{N,O‐bis(1,5‐isoquinolinesulfonyl)‐N‐methyl‐L‐tyrosyl}‐4‐phenylpiperazine, an inhibitor of Ca2+/calmodulin‐dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF‐like tau. These data suggest that phosphorylation of tau is regulated by Ca2+‐dependent protein kinases and okadaic acid–sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer' disease.
Molecular dissection of the myelinated axon
Authors: Waxman Stephen G. , Ritchie J. Murdoch
Published: January 2005

The membrane of the myelinated axon expresses a rich repertoire of physiologically active molecules: (1) Voltagesensitive NA+ channels are clustered at high density (∼1,000/μm2) in the nodal axon membrane and are present at lower density(<25/μm2) in the internodal axon membrane under the myelin. Na+ channels are also present within Schwann cell processes (in peripheral nerve) and perinodal astrocyte processes (in the central nervous system) which contact the Na+ channel–rich axon membrane at the node. In some demyelinated fibers, the bared (formerly internodal) axon membrane reorganizes and expresses a higher‐than‐normal Na+ channel density, providing a basis for restoration of conduction. The presence of glial cell processes, adjacent to foci of Na+ channels in immature and demyelinated axons, suggests that glial cells participate in the clustering of Na+ channels in the axon membrane. (2) “Fast” K+ channels, sensitive to 4‐aminopyridine, are present in the paranodal of internodal axon membrane under the myelin; these channels may function to prevent reexcitation following action potentials, or participate in the generation of an internodal resting potential. (3) “Slow” K+ channels, sensitive to tetraethylammonium, are present in the nodal axon membrane and, in lower densities, in the internodal axon membrane; their activation produces a hyperpolarizing afterpotential which modulates repetitive firing. (4) The “inward rectifier” is activated by hyperpolarization. This channel is permeable to both Na+ and K+ ions and may modulate axonal excitability or participate in ionic reuptake following activity. (5) Na+/K+‐ATPase and (6) Ca2+‐ATPase are also present in the axon membrane and function to maintain transmembrane gradients of Na+, K+, and Ca2+. (7) A specialized antiporter molecule, the Na+/Ca2+ exchanger, is present in myelinated axons within central nervous system white matter. Following anoxia, the Na+/Ca2+ exchanger mediates an influx of Ca2+ which damages the axon. The molecular organization of the myelinated axon has important pathophysiological implications. Blockade of fast K+ channels and Na+/K+‐ATPase improves action potential conduction in some demyelinated axons, and block of the Na+/Ca2+ exchanger protects white matter axons from anoxic injury. Modification of ion channels, pumps, and exchangers in myelinated fibers may thus provide an important therapeutic approach for a number of neurological disorders.
Pathological findings at the site of conduction block in multifocal motor neuropathy
Authors: Kaji Ryuji , Oka Nobuyuki , Tsuji Teruyuki , Mezaki Takahiro , Nishio Takeshi , Akiguchi Ichiro , Kimura Jun
Published: January 2005

We report on 2 patients with multifocal motor neuropathy with focal conduction block involving motor but not sensory fibers at the site of nerve swelling. A nerve biopsy specimen from adjacent to the enlargement in 1 patient showed a perivascular area containing scattered demyelinated axons surrounded by small onion bulbs. The observed pathological findings are consistent with the conduction block considered characteristic of this neuropathy, although the underlying immunological mechanisms for selectivity and persistence remain undetermined.
Pathophysiology of massive infantile spasms: Perpective on the putative role of the brain adrenal axis
Authors: Baram Tallie A.
Published: January 2005

Massive infantile spasms are an age‐specific seizure syndrome of infancy. Uniquely, the spasms respond to hormonal manipulation using adrenocorticotropic hormone(ACTH) or glucocorticoids. A hypothesis explaining the efficacy of hormonal therapy, age ‐specificity, multiple causative factors, and spontaneous resolution of infantile spasms is presented. Corticotropin‐releasing hormone(CRH), an excitant neuropeptide supressed by ACTH/Steroids, is implicated. Evidence for the age‐specific vonvulsant properties of CRH is presented, and a putative secenario in which a stressinduced enhancement of endogenous CRH‐mediated seizures is discussed. Clinical resting of the CRH‐Excess theory and its therapeutic implication are suggested.
Dopamine agonist treatment of antegrade amnesia from a mediobasal forebrain injury
Authors: Dobkin Bruce H. , Hanlon Robert
Published: January 2005

We studied the persistent antegrade memory impairment in a woman whose brain had been surgically impaled, leaving a 1‐cm‐wide mediobasal tract of encephalomalacia that entended just enterior to the septal, nuclei and medial to the nucleus accumbens. In a blinded, controlled, alternating repeated‐measures protocol, bromocriptine signigicantly improved her verbal learning, functional memory, and dailyrecall, perhaps by acting on neurons that had been disconnected fron the ventral tegmental tract's dopaminergic inputs.
Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease)
Authors: Bronson Roderick T. , Lake Brian D. , Cook Susan , Taylor Susanne , Davisson Muriel T.
Published: January 2005

Pathological studies of mice homozygous for the motor neuron degeneration (Mnd) mutation show abnormalities similar to those of the human neuronal ceroid lipofuscinoses: sudanophilic, autofluorescent intraneuronal inclusions that are immunoreactive with antibodies to subunit c of mitochondrial ATP synthase. Ultrastructurally, the inclusions have the pentalaminar structure characteristic of some forms of human neuronal ceroid lipofuscinosis and of canine and ovine models of neuronal ceroid lipofuscinosis. Similar inclusions are observed in many somatic organs and in the retina, which develops photoreceptor degeneration. This mutation, previously considered a model of amyotrophic lateral sclerosis, may be a useful model for molecular and genetic studies of human neuronal ceroid lipofuscinosis because mice have been well characterized genetically. Since they are inexpensive to breed and maintain, they can also be used to test therapeutic interventions.
Successful outcome of progressive multifocal leukoencephalopathy with cytarabine and interferon
Authors: Steiger M. J. , Tarnesby G. , Gabe S. , McLaughlin J. , Schapira A. H. V.
Published: January 2005

The prognosis of patients with progressive multifocal leukoencephalopathy is poor, with few patients showing remission or surviving. We describe a 37‐year‐old man who developed progressive multifocal leukoencephalopathy in association with sarcoidosis. Despite treatment with cytarabine and acyclovir, he continued to deteriorate. Shortly following the addition of interferon alfa, he made a dramatic improvement, regaining full functional independence. The use of interferon alfa in addition to cytarabine in such patients offers a new therapeutic approach worthy of further trial.
Oscillopsia and horizontal nystagmus with accelerating slow phases following lumbar puncture in the Arnold‐chiari malformation
Authors: Barton Jason J. S. , Sharpe James A.
Published: January 2005

Oscillopsia and nystagmus began in a woman 2 weeks after an inadvertent lumbar puncture during anesthesia for childbirth. Examination showed horizontal‐torsional jerk nystagmus in all positions of gaze. Magnetic‐search‐coil oculography revealed accelerating slow phases, with an increase in nystagmus amplitude in darkness. Magnetic resonance images showed type 1 Arnold‐Chiari malformation. Three months after occipital decompressive surgery, nystagmus had almost disappeared. Accelerating slow phases should not be considered diagnostic of congenital nystagmus, especially with an onset of oscillopsia in adult life; imaging should be considered to exclude treatable hindbrain anomalies. Lumbar puncture in patients with the Arnold‐Chiari malformation may accentuate craniospinal pressure dissociation and precipitate neurological signs.
Neuroleptic medications inhibit complex I of the electron transport chain
Authors: Burkhardt Carolyn , Kelly James P. , Lim Young‐Hwa , Filley Christopher M. , Parker W. Davis
Published: January 2005

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetra‐hydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol chlorpromazine, and thiothixine inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.
Clinical and virological analyses of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications
Authors: Suga Sadao , Yoshikawa Tetsushi , Asano Yoshizo , Kozawa Toru , Nakashima Toshihiko , Kobayashi Ikuko , Yazaki Takehiko , Yamamoto Hiroko , Kajita Yaji , Ozaki Takao , Nishimura Yataka , Yamanaka Tarsuhiro , Yamada Akira , Imanishi Jiro
Published: January 2005

Twenty‐one infants who had virologically confirmed exanthem subitum and central nervous system (CNS) complications were studied to elucidate the clinical fearures, laboratory and virological findings, and outcome. The primary infection with human herpesvirus 6 was confirmed by isolation of the virus from blood, a significant rise in the antibody titeres to the virus, or both. All convulsive seizures (15 generalized and 6 focal) occurred during the pre‐eruptive stage of exanthem subitum. Four infants with encephalities/encephalopathy had more severe clinical features with abnormalities demonstrated on electroencephalograms and cerebral computed tomograms. All infants except those with encephalities/encephalopathy recovered without any sequelae. One infant with encephalities/encephalopathy developed epilepsy and another one died. Human herpesvirus 6 DNA amplified by the nested polymerase chain reaction method was detected in the cerebrospinal fluid of 6 infants, including 3 with encephalities/encephalopathy, of 11 parients examined by the fifthy day of the illness. These findings suggest thar CNS complications including encephalitis/encephalopathy occur at the pre‐eruptive stae of exanthem subitum, that human herpesvirus 6 invades the CNS in some patients, and that the outcome is not always benign.
Reduction of low‐molecular‐ weight acid phosphatase activity in Alzheimer brains
Authors: Shimohama Shun , Fujimoto Sadaki , Taniguchi Takashi , Kameyama Masakuni , Kimura Jun
Published: January 2005

Recent studies in Alzheimer brains have shown aberrant protein phosphorylation, suggesting an afteration in protein kinases and/or phosphoprotein phosphatases. In the present stydy, the activity of acid phospharase was investigated in samples repared from postmortem normal human and alzheimer barains. p‐Nitrophenyl phosphate, a nonprotein phosphoester, was used as a substrate for acid phosphatase. The separation profile on Sephadx G0‐100 gel filtration chromatography revealed that two major forms of high‐molecular‐weight and low‐molecular‐weight acid phosphatse were present in the crude extracts of both rat and human brains. Another class of zinc ion (Zn2+)– dependent acid p‐nitrophenyl phosphatase was also detected in rat and human brains. In Alzheimer brains, the low‐molecular‐weight acid phosphatase activity was significantly decreased compared to that in control brains; however, the high‐molecular weight and Zn2+ dependent acid phosphatase activity in control and alzheimer brains was not differnt. These results suggest that reduced activity of the low‐molecular‐weight acid phosphatase, which prossesses phosphotyrosine protein phosphatase activity, might be linkd to aberrant protein tyrosine phosphorylation found in Alzheimer brains.
Mitochondrial encephalomyopathy, lactic acidosis, stroke‐like episodes (MELAS): Clinical, radiological, pathological, and genetic observations
Authors: Koo Betty , Becker Laurence E. , Chuang Sylvester , Merante Frank , Robinson Brian H. , MacGregor Daune , Tein Ingrid , Ho Vincent B. , McGreal Douglas A. , Wherrett John R. , Logan William J.
Published: January 2005

We reviewed 10 patients (5 males, 5 females) with mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes. The age of symptom onset ranged from 3 months to 12 years. All had lactic acidosis, multiple stroke‐like events with secondary neurological deficits, radiological changes of progressive brain infarction, and muscle biopsy showing ragged‐red fibers. In patients with earlier onset of symptoms (<2 yr), involvement tended to be more diffuse, with failure to thrive and early onset of delayed development. Patients whose symptoms appeared later tended to have focal neurological deficits with migraine‐like headache, and a rate of cognitive regression reflecting the rapidity of disease progression. Radiological changes included multiple areas of infarction with initial predilection for parietal occipital areas, progressing to generalized atrophy. Pathological findings in muscle biopsies included type 1 fiber predominance, ragged‐red fibers, increased intermyofibrillar lipid deposition, and abnormal mitochondria. Four patients showed mitochondrial DNA tRNA mutation at position 3,243. No difference was noted in clinical, radiological, or pathological findings in patients with and without this mutation, suggesting that multiple sites of point mutation may give rise to mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes.
Diffuse microgliosis associated with cerebral atrophy in the acquired immunodeficiency syndrome
Authors: Gelman Benjamin B.
Published: January 2005

The cause of cerebral atrophy in patients with acquired immunodeficiency syndrome (AIDS) is obscure because human immunodeficiency virus type 1 (HIV‐1)‐related histopathological changes hardly correlate with cerebral atrophy. In this study, brain ventricular expansion was compared to the frontal lobe density of mononuclear and astroglial cells at autopsy. Twenty‐eight male patients with AIDS displaying varying degrees of atrophy were compared to 17 age‐matched male control subjects without AIDS or atrophy. An index of ventricular expansion was measured in uniformly sliced, formalin‐fixed brain specimens, and immunochemically marked cells in coronal sections of the left superior frontal gyrus (Brodmann area 8) were quantified by field counting and planimetry. In the cortex, diffuse ferritin‐stained microglia and glial fibrillary acidic protein‐positive astrocytes were about twice as numerous in the patients with AIDS. Sixty‐five percent (18/28) of the patients with AIDS had a microglial cell density greater than 2 standard deviations above the control mean. Microglial cell density was correlated positively with the severity of ventricular expansion (r = 0.71, p <0.0001), while hypertrophied astroglial cells were very weakly related. In white matter, Ham‐56–‐positive macrophages and glial fibrillary acidic protein‐positive astrocytes were not meaningfully correlated with the index of ventricular expansion. Brain ventricular expansion and diffuse cortical microgliosis are highly prevalent anomalies in patients with AIDS, and their interrelationship may be more important than previously recognized.
When does human brain development end? Evidence of corpus callosum growth up to adulthood
Authors: Pujol Jesús , Vendrell Pere , Junqué Carme , Martí‐Vilalta Josep L. , Capdevila Antoni
Published: January 2005

To locate structural changes in the brain accounting for the increasing effectiveness in cognition and skills that occurs at the final stage of behavioral development, we attempted to determine the age at which the corpus callosum completes its active growth period. We assessed the growth rate of the corpus callosum by measuring its area twice on midsagittal magnetic resonance imaging scans separated by a 2‐year interval, in a series of 90 subjects with a wide range of ages. We observed an increase in the size of the corpus callosum as long as human mentation expands, up to the middle 20s. Clinical and experimental data about the corpus callosum, together with the present findings, suggest that the corpus callosum is part of the highest order‐latest maturing neural network of the brain.
Quantitative cerebrospinal fluid cytology in patients receiving intracavitary chemotherapy
Authors: Russack Valentina , Kim Sinil , Chamberlain Marc C.
Published: January 2005

Cytological evaluation of cerebrospinal fluid (CSF) is an important means of following response to intracavitary chemotherapy for leptomeningeal malignancy. We studied the feasibility of quantitative cytological evaluation by retrospective analysis of serial CSF specimens from 7 patients receiving phase I intracavitary chemotherapy for leptomeningeal malignancy who had persistent malignant cytology. Three to 34 CSF specimens per patient obtained over a 3‐ to 48‐week period were reviewed. Significant (five‐ to 10‐fold or greater) reductions in numbers of malignant cells in CSF during treatment could be identified in specimens otherwise diagnosed as positive. Quantitative CSF cytological evaluation is neither overly time consuming nor tedious to perform and may provide useful clinical information.
Visual evoked potentials in adrenolukodystrophy: A trial with glycerol trioleate and Lorenzo oil
Authors: Kaplan Peter W. , Tusa Ronald J. , Shankroff Jan , Heller Joellen , Moser Hugo W.
Published: January 2005

Adrenoleukodystrophy is an X‐linked metabolic disorder with very‐long‐chain fatty acid (VLCFA) accumulation and multifocal nervous system demyelination, often with early involvement of visual pathways. Dietary therapy with glycerol trioleate and glycerol trieucate (Lorenzo oil) diminishes VLCFA levels. In a study of patients with the adrenomyeloneuropathy phenotype of adrenolukodystrophy, we used pattern‐reversal visual evoked potentials to evaluate visual pathways before and after treatment. Of 108 patients tested, all 26 women and 68 of the 82 men had normal potentials at baseline. Seventy patients were retested at 1 year, at which time VLCFA levels were markedly diminished. Of them, the responses in the 10 men who showed abnormalities at baseline remained abnormal; the latencies in 4 men with initially normal responses became abnormal. No patients improved. There were no correlations between disease duration prior to treatment, baseline P100 latencies, VLCFA levels, or the change in P100 latencies and VLCFA levels after dietary treatment for 1 year. Pattern‐reversal visual evoked potentials were abnormal in 17% of the men with adrenoleukodystrophy, and there was no evidence that reduction of VLCFA levels improved or retarded visual pathway demyelination.
Metachromatic leukodystrophy: Multiple nonfunctional and pseudodeficiency alleles in a pedigree: Problems with diagnosis and counseling
Authors: Francis Gordon S. , Bonni Azad , Shen Ning , Hechtman Peter , Yamut Bassem , Carpenter Stirling , Karpati George , Chang Patricia L.
Published: January 2005

Metachromatic leukodystrophy is due to deficiennt activity of arylsulfatse A, an enzyme important in myelin catabolism. The deficiency can be caused by different point mutations in the gene coding for arylsulfatase A (nonfunctional alleles). In addition, certain mutations result in low levels of enzyme activity detectable with artificial substrates in vitro but no clinical dysfunction (pseudodeficiency alleles). The described family has various combinations of normal, nonfunctional, and pseudodeficiency alleles that presented diagnostic and counseling dilemmas which were resolved at the genomic levle. We find no evidence that compound beterozygote individuals have subclinical involvement of the nervous system. We report the clinical, pathological, electrophysiological, imaging, biochemical, and genetic data of this family and discuss the difficulties in analyzing such pedigrees.
Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease
Authors: Scheff Stephen W. , Sparks D. Larry , Price Douglas A.
Published: January 2005

We quantified the synaptic density in the entorhinal cortex (Brodmann area 28) in autopsy material from 10 individuals with Alzheimer's disease and compared them to 11 age‐matched, postmortem‐matched control subjects without dementia, using standard electron microscopy. The statistical data showed no change in synaptic density between control and Alzheimer subjects, in either lamina III or V of the cortex. There were no correlations between synaptic density and synaptic apposition length or density of senile plaques. The entorhinal cortex stands in marked contrast to other cortical areas that show a significant decline in synaptic numbers with Alzheimer's disease. This preservation of synaptic numbers may be related to a plasticity response that is greater in the entorhinal area than in other areas of the cortex.
The transport of L‐6‐fluorodopa and its metabolites from blood to cerebrospinal fluid and brain
Authors: Hammerstad John P. , Pate Brian D. , Hewitt Kellie A. , Chan Grace L‐Y. , Ruth Thomas J. , Calne Donald B.
Published: January 2005

The transport of L‐6‐fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa‐pretreated cynomolgus monkeys. A bolus intravenous injection of 18F‐L‐6‐fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L‐6‐fluorodopa and its metabolites were determined in blood plasma and CSF by highperformance liquid chromatography. Raising the blood concentration of phenylanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L‐6‐fluorodopa and 3‐O‐methylfluorodopa, like native L‐dopa and its O‐methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier‐mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L‐6‐fluorodopa and 3‐O‐methylfluorodopa, in CSF. This suggests that the transport of L‐dopa and its derivatives at the blood‐CSF barrier differs from the transport at the blood‐brain barrier and also that measurement of CSF L‐dopa is not a good index of the transport and pharmacokinetics of L‐dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.
Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain
Authors: Mecocci Patrizia , MacGarvey Usha , Kaufman Allan E. , Koontz Deborah , Shoffner John M. , Wallace Douglas C. , Beal M. Flint
Published: January 2005

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age‐related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8‐hydroxy‐2′‐deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/μg of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10‐fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15‐fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age‐related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age‐dependent increases in incidence of neurodegenerative diseases.
Herpes simplex type 1 encephalitis in acquired immunodeficiency syndrome
Authors: Tan Stella V. , Guiloff Roberto J. , Scaravilli Francesco , Klapper Paul E. , Cleator Graham M. , Gazzard Brian G.
Published: January 2005

A severe acute necrotizing herpes simplex virus type 1 encephalitis, apparently mediated by macrophages or cytokines or both, was seen in a patient with acquired immunodeficiency syndrome. The necrosis had a distribution similar to that seen in immunocompetent subjects. Viral inclusions were abundant and meningeal reaction was minimal, as previously described in one anergic patient.
Cerebrospinal fluid inhibits Alzheimer β‐amyloid fibril formation in vitro
Authors: Wisniewski Thomas , Castano Eduardo , Ghiso Jorge , Frangione Blas
Published: January 2005

Alzheimer's disease is characterized by the deposition of β‐protein (Aβ) as amyloid. Recently, it was found that Aβ is a normal component of serum and cerebrospinal fluid. Synthetic peptides homologous to Aβ form amyloid‐like fibrils spontaneously in water or physiological solutions. Using a peptide homologous to Aβ1–40, we find that fibril formation is inhibited by the presence of cerebrospinal fluid.