bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain
Authors: Tuszynski Mark H. , Sang U Hoi , Yoshida Kazunari , Gage Fred H.
Published: January 2005

Atrophy of cholinergic neurons is a prominent component of Alzheimer's disease, and may explain in part the profound memory loss that is characteristic of patients with this disorder. Previous studies in animal models have shown that infusions of nerve growth factor into the adult brain can prevent both age‐related and lesion‐induced cholinergic neuronal atrophy. Recently, recombinant human nerve growth factor was found biologically active in nonprimate animal models. In the present experiment, recombinant human nerve growth factor infusions into the brains of adult primates prevented lesion‐induced cholinergic neuronal degeneration and promoted cholinergic neurite sprouting. These findings provide additional support for potential therapeutic trials of human nerve growth factor in patients with Alzheimer's disease.
Parametric in vivo imaging of benzodiazepine receptor distribution in human brain
Authors: Frey Kirk A. , Holthoff Vjera A. , Koeppe Robert A. , Jewett Douglas M. , Kilbourn Michael R. , Kuhl David E.
Published: January 2005

Emission computed tomographic methods for the in vivo quantification of radioligand‐binding sites in human brain have previously been limited either by a lack of correction for possible effects of altered ligand transport or by highly complicated physiological models that preclude display of binding data in a detailed anatomical format. We investigated the application of a simplified compartmental model to the kinetic analysis of in vivo ligand binding to central benzodiazepine receptors. The human brain distribution of {11C}flumazenil, as determined by dynamic positron emission tomography, combined with metabolite‐corrected arterial blood samples, permitted estimations of local cerebral ligand transport and of receptor binding. This approach allows calculation of transport and binding “maps” on a pixel‐by‐pixel basis, resulting in the display of binding data in a familiar tomographic format while maintaining much of the physiological accuracy inherent in more complex methods. The results obtained in a study of 6 normal volunteers revealed good interindividual precision, with coefficients of variation between 10 and 15% of mean regional values, suggesting the utility of this approach in future clinical studies of benzodiazepine receptor binding.
Anti—tumor necrosis factor therapy abrogates autoimmune demyelination
Authors: Selmaj K. , Raine C. S. , Cross A. H.
Published: January 2005

To define a role for the cytokine tumor necrosis factor (TNF) in immune‐mediated demyelination, the effect of anti‐TNF antibody was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein‐(MBP)‐sensitized T lymphocytes, an animal model of the human disease multiple sclerosis (MS). In three separate experiments, no mouse sensitized for EAE and then treated with anti‐TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease. Examination of CNS tissue from anti‐TNF‐treated animals showed no pathological changes. CNS tissue from control animals demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti‐TNF therapy was inhibitory to encephalitogenic cells, preincubation of MBP‐sensitized T lymphocytes with anti‐TNF in vitro prior to injection into recipient mice was performed, and resulted in no diminution of their ability to transfer EAE. In addition, spleen cells from anti‐TNF‐ treated mice were capable of serial transfer of EAE, similar to spleen cells from control animals. However, spleen cells from anti‐TNF‐treated mice did not produce TNF on stimulation with MBP or concanavalin A. This study showed that anti‐TNF antibody can inhibit effectively the development of EAE by interfering with the effector, rather than the induction, phase of the disease. Anticytokine therapy may have important applications in the development of new therapeutic strategies for MS.
The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine‐depleted rats and MPTP‐treated monkeys
Authors: Klockgether Thomas , Turski Lechoslaw , Honoré Tage , Zhang Zhiming , Gash Don M. , Kurlan Roger , Greenamyre J. Timothy
Published: January 2005

Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)subtype of glutamate receptor, AMPA receptor antagonists may posses antiparkinsonian properties. We report that in monoamine‐depleted rats, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(f)quinoxaline (NBQX) (Novo‐Nordisk, Copenhagen, Denmark)—a selective antagonist of the AMPA subtype of glutamate receptor—suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydrophyridine‐induced parkinsonism intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L‐3,4‐dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).
Brain amino acid reductions in one family with chromosome 6p—linked dominantly inherited olivopontocerebellar atrophy
Authors: Kish Stephen J. , Robitaille Yves , El‐Awar Munir , Gilbert Joseph , Deck John , Chang Li‐Jan , Schut Lawrence
Published: January 2005

We measured the levels if aspartate, glutamate, gamma‐aminobutyric acid (GABA), and other amino acids in autopsied brain of 6 patients from one family (Pedigree S) with dominantly inherited olivopontocerebellar atrophy. A previous demonstration of redeuced aspartate concentration in plasma of affected members of this family suggested the possibility of a generalized disorder of amino acid metabolism affecting the brain. As compared with the control levels, mean levels of aspartate and glutamate were markedly reduced by about 70 and 40°, respectively, in the degenerated cerebellar cortex from the patients. Since the cerebellar asparate reduction liekly exceeds the amount that could be explained by neuronal loss, other factors such as abnormal asparate metabolism, neurotransmitter turnover, or both are probably involved. Mean aspartate, glutamate, and GABA levels were also reduced by about 10 to 30° in most of the 16 examined extracerebellar brain areas in which no or, at most, mild neuronal cell loss was observed by semiquantitative estimation. Concentrations of taurine, glutamine, and o‐phosphoethanolamine were normal in all brain areas examined. Our biochemical data provide support to the presence of a generalized, but quantitatively mild, disturbance in amino acid metabolism in patients with olivopontocerebellar atrophy from Pedigree S. The regionally widespread amino acid reductions in the brain, of as yet unknown pathophysiological significance, could be due to a failure of one or more enzymes involved in aspartate and glutamate metabolism.
MK‐801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex
Authors: Sharp Frank R. , Jasper Pat , Hall John , Noble Linda , Sagar Stephen M.
Published: January 2005

MK‐801 and ketamine are noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK‐801 itself can damage neurons. Here we show that MK‐801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72‐immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0‐mg/kg doses of MK‐801 and disappears by 2 weeks. Based on these data, we propose: (1) MK‐801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK‐801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK‐801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults.
The prevalence of vascular dementia in europe: Facts and fragments from 1980–1990 studies
Authors: Rocca Walter A. , Hofman Albert , Brayne Carol , Breteler Monique M. B. , Clarke Michael , Copeland John R. M. , Dartiques Jeanm‐François , Engedal Knut , Hagnell Olle , Heeren Thea J. , Jonker Cees , Lindesay James , Lobo Antonio , Mann Anthony H. , Mölsä Pekka K. , Morgan Kevin , O'Connor Daniel W. , Droux Arnaldo da Silva , Sulkava Raimo , Kay David W. K. , Amaducci Luigi ,   EURODEM‐Prevalence Research Group
Published: January 2005

We selected, reanalyzed, and compared data from current prevalence studies of vascular dementia in Europe. Inclusion criteria were: dementia defined by the Diagnostic and Statistical Manual for Mental Disorders, edition 3, or equivalent criteria; case finding through direct individual examination; appropriate sample size; and inclusion of institutionalized persons. Mixed dementia was combined with vascular dementia. Of the 23 surveys of dementia considered, five fulfilled the inclusion criteria. Age‐specific prevalence varied more widely for men than for women; differences were greater in older ages. The prevalence increased steeply with advancing age in all countries, and was generally higher in men; it declined over 15 years in the age class of 80 to 89 years in one Swedish population. Within populations, Alzheimer's disease was generally more common than vascular dementia. Unfortunately, prevalence studies of vascular dementia are limited in Europe and worldwide, and their comparison is impeded by the lack of common diagnostic criteria.
Inter‐ and intra‐examiner reliability of nerve conduction measurements in normal subjects
Authors: Chaudhry Vinay , Cornblath David R. , Mellits E. David , Avila Orlando , Freimer Miriam L. , Glass Jonathan D. , Reim Johannes , Ronnett Gabriele V. , Quaskey Shirley A. , Kuncl Ralph W.
Published: January 2005

Nerve conduction studies are widely employed in evaluating patients with peripheral nerve disease and are often used serially to measure disease progression or to assess a therapeutic intervention. We determined the inter‐ and intra‐examiner reliability of electrophysiological data by performing serial nerve conduction studies on 7 normal subjects. A high degree of inter‐examiner reliability was present, but significant inter‐examiner differences were found. Our results suggest that if nerve conduction studies are to be used longitudinally, they should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.
Thrombotic microangiopathy isolated to the central nervous system
Authors: Dawson Ted M , Lavi Ehud , Raps Eric C. , Goldberg Herbert I.
Published: January 2005

A man with plasma cell dyscrasia and bone marrow infiltration presented with rapidly progressive encephalopathy. Magnetic resonance imaging revealed multiple small areas of abnormal signal that correlated with the autopsy findings of thrombotic microangiopathy isolated to the central nervous system.
Outcome after ischemia in the developing sheep brain: An electroencephalographic and histological study
Authors: Williams Chris E. , Gunn Alistair J. , Mallard Carina , Gluckman Peter D.
Published: January 2005

The role of seizures occurring with perinatal hypoxic‐ischemic encephalopathies is unclear. We examined the relationships between the time course of parasagittal electroencephalographic (EEG) activity and pathological outcome following transient cerebral ischemia, which was induced in 33 chronically instrumented fetal sheep by occluding the carotid arteries after ligation of the vertebral‐carotid anastomoses. The EEG was quantified with real‐time spectral analysis. Histological outcome was assessed 72 hours later. After 10 or 20 minutes of ischemia, EEG activity was depressed and then progressively recovered and mild selective neuronal loss was seen. The length of this depression correlated with the duration of ischemia (r = 0.88). After 30 or 40 miniutes of ischemia, EEG activity remained depressed for 8 ± 2 hours, followed by a rapid transition to low‐frequency epileptiform activity that reached maximum intensity at 10 ± 3 hours. By 72 hours, EEG intensity had fallen below control levels. This sequence of prolonged depression, epileptiform activity, and then loss of intensity was associated with the development of laminar necrosis of the underlying cortex. These electrophysiological sequelae may have prognostic value. The results indicate that after a severe hypoxicischemic insult, the parasagittal cortex becomes hyperexcitable before the final loss of activity. Secondary neuronal death may occur in this phase.
Transplantation of fetal dopamine neurons in Parkinson's disease: One‐year clinical and neurophysiological observations in two patients with putaminal implants
Authors: Lindvall Olle , Widner Håkan , Rehncrona Stig , Brundin Patrik , Odin Per , Gustavii Björn , Frackowiak Richard , Leenders Klaus L. , Sawle Guy , Rothwell John C. , Ourklund Anders Bj , Marsden C. David
Published: January 2005

Ventral mesencephalic tissue from aborted human fetuses (age, 6–7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1‐year follow‐up period. Clinical improvement was observed as a reduction of the time spent in the “off” phase and the number of daily “off” periods; a lessening of bradykinesia and rigidity during the “off” phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L‐dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine‐rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.
Multifocal inflammatory leukoencephalopathy with 5‐fluorouracil and levamisole
Authors: Hook C. Christopher , Kimmel David W. , Kvols Larry K. , Scheithauer Bernd W. , Forsyth Peter A. , Rubin Joseph , Moertel Charles G. , Rodriguez Moses
Published: January 2005

A cerebral demyelinating disease developed in 3 patients during adjuvant therapy with 5‐fluorouracil and levamisole for adenocarcinoma of the colon. None of the patietns had evidence of metastatic disease or prior neurological disease. The duration of chemotherapy before onset of neurological symptoms ranged from 15 to 19 weeks. The total dose of 5‐fluorouracil was 9.7 to 15.7 gm. The total dose of levamisole was 2.7 to 3.75 gm. Two patietns presented with a subacute (2–3 weeks) progressive decline in mental status and ataxia. The third patient had two unexplained episodes of loss of consciousness. In each, magnetic resonance imaging with gadolinium demostrated prominent multifocal enhancing white matter lesions. Cerebral biopsy was performed stereotaxically in 2 patietns. The morphological features were those of active demyelinating disease. The myelin loss was associated with numerous dispersed as well as vasocentric macrophages, sparing of axons, and pervisacular lymphocytic inflammation. Electron microscopy confirmed the light microscopic findings. All 3 patients improved after cessation of chemotherapy and a short course of corticosteroid therapy. Our patients represent the first reported examples of an inflammatory leukoencephalopathy associated with the administration of 5‐fluorouracil and levamisole. This syndrome may represent the pathological basis for 5‐fluorouracil neurotoxicity, although we cannot completely exclude the role of levamisole.
Phenotypic characteristics of familial Creutzfeldt‐Jakob disease assoicated with the codon 178AsnPRNP mutation
Authors: Brown Paul , Goldfarb Lev G. , Kovanen Jussi , Haltia Mattie , Cathala Françoise , Sulima Michael , Gibbs C. J. , Gajdusek D. Carleton
Published: January 2005

A group of 43 patietns from seven families affected by Creutzfeldt‐Jakob disease (CJD) with the codon 178Asn mutation of the PRNP amyloid precursor gene is compared to a group of 211 patients with the sporadic form of the disease. As a group, the patients with codon 178Asn mutation had an earlier age at onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic electroencephalographic activity. Transmission of disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings are interpreted and discussed in terms of possible differences in the temporospatial evolution of damage to the brain, and of accelerated induction of polymerized amyloid protein by its mutationally altered template precursor.
T cells from normal and myasthenic individuals recognize the human acetylcholine receptor: Heterogeneity of antigenic sites on the α‐subunit
Authors: Melms A. , Malcherek G. , Gern U. , Wiethölter H. , Müller C. A. , Schoepfer R. , Lindstrom J.
Published: January 2005

The α‐subunit of the nicotinic acetylcholine receptor is the major target of the autoimmune response in myasthenia gravis. We investigated the proligerative response of T cells from patients with myasthenia gravis and healthy volunteers to recombinant polypeptides of the human acetylcholine receptor including the full‐length α‐subunit (α1–437). T cells from 20 (71%) of 28 patients and 7 (37%) of 19 healthy volunteers responded in primary cultures. Subsequently, specific T‐cell lines were established: CD4+, CD8−, UCHL1+, and major histocompatibility complex (MHC) class II–restricted. Using a set of fragments of the α‐subunit, major antigenic sites could be localized on the extracellular, N‐terminal part of the molecule as well as close to the C‐terminus. The T‐cell response was heterogeneous, both among different individuals and among T‐cell lines from a single donor. These T cells did not cross‐react with Torpedo acetylcholine receptor, which was previously used as a substitute for human muscle acetylcholine receptor, suggesting that the T cells had a bias for unique human sequences. A single antigenic fragment could be presented in the context of different MHC class II molecules, and different fragrnents could be presented in the context of the same MHC molecule. This supports earlier observations of considerable heterogeneity in dealing with acetylcholine receptor as an autoantigen on the level of both T cells and antigen‐presenting cells. The data also demonstrate that acetylcholine receptor–specific T cells are present in the normal immune repertoire, and emphasize the role of immune regulation for maintaining a state of tolerance.
Human immunodeficiency virus infection in microglia: Correlation between cells infected in the brain and cells cultured from infectious brain tissue
Authors: Brinkmann R. , Schwinn A. , Narayan O. , Zink C. , Kreth H. W. , Roggendorf W. , Dörries R. , Schwender S. , Imrich H. , ter Meulen V.
Published: January 2005

In acquired immunodeficiency syndrome, the lesions of the central nervous system in association with the human immunodeficiency virus are thought to be related to an infection of microglia, although no studies are available in which cultured and physiological characteristics of microglia cells infected in vivo have been examined. In this report, we used brain tissue from a child dying of human immunodeficiency virus infection and show that microglia cells were the main cell population being infected. Moreover, isolated macrophage‐like cells from fresh brain material revealed a close resemblance to peripheral blood macrophages in their content of surface and intracellular antigens. No virus particles or viral antigens were produced by these cells during the first week of cultivation. Productive infection was readily apparent, however, by day 30. This finding illustrates the slow nature of the virus life cycle in these cells and the minimal cytopathology that accompanied the infection.
Bilateral striopallidodentate calcinosis: Cerebrospinal fluid, imaging, and cerebrospinal fluid, imaging, and electrophysiological studies
Authors: Manyam Bala V. , Bhatt Mohit H. , Moore William D. , Devleschoward Allen B. , Anderson Darrel R. , Calne Donald B.
Published: January 2005

We report the genetic, clinical, electrophysiological, and imaging studies in a family with bilateral striopallidodentate calcinosis (Fahr's disease). The intracerebral calcium deposits occurred before onset of the symptoms in the third decade of life. Progressive neurological deterioration occurred in the fifth decade of life in the proband. Cerebrospinal fluid homocarnosine, a central nervous system–specific peptide, was increased twofold in patients with autosomal dominant bilateral striopallidodentate calcinosis; in sporadic cases, there was no detectable homocarnosine and a decreased level of histidine. With advancing age, the amount of calcification increase, but it has not been determined if a critical amount must be reached before symptoms occur. Computerized tomography is superior to magnetic resonance imaging for radiological diagnosis. Despite diffuse striatal calcification, striatal 6‐[18F]fluoro‐L‐dopa uptake did not reveal any difference between patients and control subjects, from which we infer persisting integrity of the nigrostriatal dopaminergic pathway.
Idiopathic recurring stupor: A case with possible involvement of the gamma–aminobutyric acid (GABA)ergic system
Authors: Tinuper P. , Montagna P. , Cortelli P. , Avoni P. , Lugaresi A. , Schoch P. , Bonetti E. P. , Gallassi R. , Sforza E. , Lugaresi E.
Published: January 2005

A patient had recurrent spontaneous episodes of stupor or coma in the absence of toxic, metabolic, or structural brain damage. Ictal electroencephalography showed fast 14 Hz background activity; sleep studies excluded narcolepsy. Flumazenil (Anexate), a benzodiazepine antagonist, promptly resolved the episodes and normalized the electroencephalogram. Radioreceptor binding studies showed the presence of a ligand to the central benzodiazepine receptor in plasma and cerebrospinal fluid during the episodes, suggesting a gamma‐aminobutyric acid (GABA)ergic system involvement in the origin of the attacks.
Detection of coronavirus RNA and antigen in multiple sclerosis brain
Authors: Murray Ronald S. , Brown Bonnie , Brain David , Cabirac Gary F.
Published: January 2005

Epidemiological studies of patients with multiple sclerosis (MS) and animal model data support the hypothesis that viruses initiate the immunopathogenic events leading to demyelination in MS. There have been no reports, however, of consistent detection of viruses in MS central nervous system tissue. We probed MS and control brain with cDNA probes specific for human, murine, porcine, and bovine coronaviruses. We report the in situ hybridization detection of coronavirus RNA in 12 of 22 MS brain samples using cloned coronavirus cDNA probes. In addition, tissue was screened for coronavirus antigen by immunohistochemical methods; antigen was detected in two patients with rapidly progressive MS. Significant amounts of coronavirus antigen and RNA were observed in active demyelinating plaques from these two patients. These findings show that coronaviruses can infect the human central nervous system and raise the possibility that these viruses may contribute to the pathogenesis of MS in some patients.
Differences in sensitivity to hyperglycemic hypoxia of isolated rat sensory and motor nerve fibers
Authors: Schneider U. , Jund R. , Nees S. , Grafe P.
Published: January 2005

We explore whether the prevalence of sensory deficits in diabetic neuropathy can be explained by diffuse endoneurial hypoxia. Isolated ventral and dorsal rat spinal roots incubated in 2.5 or 25 mM extracellular glucose were transiently exposed to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials and extracellular direct current potentials were continuously recorded before, during, and after hypoxia. In both ventral and dorsal roots incubated in 2.5 mM glucose, sensitivity to hypoxia and posthypoxic recovery were similar. In contrast, hypoxia in 25 mM glucose preferentially induced electrophysiological damage in dorsal roots as indicated by a lack of posthypoxic recovery. This observation was not made in the presence of 25 mM bicarbonate, which suggests involvement of nerve acidosis. In conclusion, the different sensitivity of sensory and motor fibers to hyperglycemic hypoxia supports the hypothesis that hypoxia has an important role in the pathogenesis of diabetic neuropathy.
Quantitative magnetic resonance imaging in temporal lobe epilepsy: Relationship to neuropathology and neuropsychological function
Authors: Lencz Todd , McCarthy Gregory , Bronen Richard A. , Scott Tammy M. , Inserni Jaime A. , Sass Kimberlee J. , Novelly Robert A. , Kim Jung H. , Spencer Dennis D.
Published: January 2005

Magnetic resonance images (MRIs) were obtained from 25 patients with medically refractory epilepsy of temporal lobe origin (12 on the left, 13 on the right) and 14 right‐handed control subjects. The hippocampi and temporal lobes were traced by computer on successive coronal images and the resulting measurements of area were summed for each region. The left and right hippocampi were symmetrical in the control subjects; however, for patients the hippocampus was smaller on the side of the seizure focus. Moreover, the left‐right hippocampal ratio significantly differentiated the control subjects from each patient group. The left temporal lobe was significantly smaller than the right in control subjects. The epileptics' temporal lobes were smaller on the side of the seizure focus, compared to the temporal lobes in the control subjects. MRI hippocampal measurements were compared to hippocampal neuronal densities obtained postoperatively. Significant correlations were obtained between the ration (side ipsilateral to focus/side contralateral to focus) of MRI hippocampal measurements and neuronal densities in all hippocampal subfields except CA2. Prior to surgery, patients were administered the Wechsler Memory Scale and the verbal Selective Reminding Test. Significant correlations existed between MRI measurements of the left hippocampus and the Wechsler logical memory percent retention scores and between the left temporal lobe measurements and the verbal Selective Reminding Test scores for patients with seizure foci in the left temporal lobe.
Neurological complications following liver transplantation
Authors: Stein Daniel P. , Lederman Richard J. , Vogt David P. , Carey William D. , Broughan Thomas
Published: January 2005

Neurological complications occurred in 4 (19%) of 21 consecutive patients (Group II) undergoing orthotopic liver transplantation, compared with a 47% (9/19) incidence in our initial series (Group I). In Group II, the neurological problems included new recurrent headaches and delayed intracerebral hemorrhage (1 patient), partial third nerve palsy and brachial plexopathy (1 patient), and ataxic dysarthria with encephalopathy (2 patients). Seizures, noted in 8 of 9 neurologically affected Group I patients, were not encountered in Group II. Of the 4 patients in the entire series with the cerebrocerbellar syndrome, 2 had partial recovery after stopping treatment with cyclosporine, 1 stabilized when cyclosporine was discontinued but later worsened when rechallenged, and 1 had full recovery but died following a second transplantation. Brain magnetic resonance images appeared normal in 3 of the 4 patients. Complications affecting vision included cortical blindness in 2 patients and occipital lobe hemorrhage in 1. All completely recovered. Survival was comparable for patients with and those without neurological complications (69% and 63%, respectively). Immediate withdrawal of cyclosporine at the onset of a change in mental status or dysarthria and improvement in intra‐and postoperative management may have contributed to the decreased incidence of neurological complications.
Functional neuroimaging strategy in temporal lobe epilepsy: A comparative study of 18FDG‐PET and 99mTc‐HMPAO–SPECT
Authors: Ryvlin Philippe , Philippon Bernard , Cinotti Luc , Froment Jean C. , Le Bars Didier , Mauguière François
Published: January 2005

We performed 99mTc‐hexamethylpropyleneamineoxime–single‐photon emission computed tomography (SPECT) and 18F‐fluorodeoxyglucose‐positron emission tomography (PET) in 20 epileptic patients with well‐lateralized temporal electroencephalographic focus, normal computed tomographic scan, and brain magnetic resonance imaging (MRI) either normal (n = 10) or showing nonspecific changes in the epileptogenic temporal lobe (n = 10). In patients with a normal MRI, PET exhibited focal hypometabolism in 80%, whereas SPECT showed corresponding hypoperfusion in only 20%. In patients with an abnormal MRI, PET and SPECT yielded 100% and 90% sensitivity, respectively. The metabolic and regional cerbral blood flow disturbances were topographically concordant with electroencephalographic and MRI findings in all these patients. Only patients with a large and pronounced hypometabolism on PET images exhibited hypoperfusion on SPECT. Spatial resolution appeared to be the critical factor responsible for the higher sensitivity of PET. However, this superiority of PET did not prove clinically useful in patients whose SPECT was abnormal, particularly when brain MRI showed nonspecific changes in the epileptogenic temporal lobe.
The twentieth century
Authors: Asbury Arthur K. , Aring Charles D.
Published: January 2005

Neurology in the twentieth century has undergone extraordinary change, particularly in the past 40 years. We trace the major trends, including the growth of the field, the technological advances, the revolution in neuroscience, the emergence of neurology as a free‐standing specialty, the rise of child neurology, and the development of neurological subspecialization. Subsequent articles in this series will expand on these subjects.
A novel point mutation in the mitochondrial tRNALeu(UUR) gene in a family with mitochondrial myopathy
Authors: Goto Yu‐ichi , Tojo Megumu , Tohyama Jun , Horai Satoshi , Nonaka Ikuya
Published: January 2005

A T‐to‐C transition mutation at nucleotide position 3,250 in the mitochondrial tRNALeu(UUR) gene was present in a family with mitochondrial myopathy. Two of three muscle biopsies examined had complex I (NADH‐ubiquinone oxidoreductase) deficiency. Heteroplasmy of wild and mutant mitochondrial DNA was detected by Nae I digestion of the polymerase chain reaction products with a modified primer. This was found in blood or muscle samples or both from all seven members examined. Similar to the 3,243 mutation in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes), the new mutation site was located in the dihydrouridine loop and embedded in the binding region of mitochondrial transcription termination factor. Elucidation of the effects of this mutation may help clarify the role of mitochondrial tRNAs and transcription termination.
Quantitation of T‐cell receptor Vβ chain expression on lymphocytes from blood, brain, and spinal fluid in patients with multiple sclerosis and other neurological diseases
Authors: Birnbaum Gary , Van Ness Brian
Published: January 2005

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system in which large numbers of T cells enter the brain and cerebrospinal fluid (CSF). To determine whether these cells represent restricted populations, we studied expression of T‐cell receptor Vβ chains on paired samples from the central nervous system and blood of patients with MS or other neurological diseases (OND) using a quantitative polymerase chain reaction. The distribution of Vβ chain expression in blood was skewed, with a significant preponderance of message from Vβ genes 1 through 8 (p = 0.0001). Such skewing was not present in samples from the CSF and brain. Patterns of Vβ gene expression were different among paired samples from spinal fluid and blood and were relatively heterogeneous. Blood and CSF samples from a patient with acute meningitis were studied on two separate occasions. The patterns of Vβ expression changed over 72 hours in both the blood and the CSF. With one exception, no oligoclonal populations of T cells were observed nor were there disease‐specific patterns of Vβ gene expression in the blood or CSF. Samples from 2 MS brains and 1 OND brain expressed patterns of Vβ genes that were different and less heterogeneous than those in paired blood. In addition, expression of Vβ 12 was remarkably increased in the 2 MS brains, suggesting a selective recruitment or expansion of T cells expressing this gene. These data demonstrate that populations of T cells from blood, spinal fluid, and brain differ from one another and can fluctuate during periods of acute inflammation. In addition, studies of brain T cells may be more informative in terms of defining oligoclonal populations of potentially pathogenic T cells than will studies of nonselected CSF T cells.
Lack of major olfactory dysfunction in MPTP‐induced parkinsonism
Authors: Doty Richard L. , Singh Anu , Tetrud James , Langston J. William
Published: January 2005

The olfactory function of 6 patients whose parkinsonism was the result of intravenous administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) was compared to that of 12 age‐matched patients with idiopathic Parkinson's disease (PD) and 10 age‐matched normal control subjects. Unlike their PD counterparts, the olfactory test scores of patients with MPTP‐induced parkinsonism, did not differ significantly from those of control subjects. These findings suggest that MPTP induced parkinsonism, unlike idiopathic PD, is unaccompanied, on average, by major alterations in the ability to smell.
Juvenile fire setting and the photoparoxysmal response
Authors: Milrod Lewis M. , Urion David K.
Published: January 2005

We report on 3 boys with fire setting, photoparoxysmal responses to intermittent photic stimulation, and temporal lobe electroencephalographic abnormalities. Fire setting resolved and behavior improved with administration of anticonvulsants.
Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia
Authors: Allen Andrew M. , MacGregor Duncan P. , Chai Siew Y. , Donnan Geoffrey A. , Kaczmarczyk Stanislav , Richardson Karen , Kalnins Renata , Ireton John , Mendelsohn Frederick A. O.
Published: January 2005

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine‐containing cell bodies. In contrast, angiotensin‐converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin‐converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin‐converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.
Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease
Authors: Stern Yaakov , Alexander Gene E. , Prohovnik Isak , Mayeux Richard
Published: January 2005

A higher prevalence of dementia in individuals with fewer years of education has suggested that education may protect against Alzheimer's disease (AD). We tested whether individuals with more years of education have a more advanced AD before it is clinically evident. As a measure of pathophysiological severity, we quantified regional cerebral blood flow (rCBF), by the 133Xenon inhalation technique; a specific pattern of flow reduction in the parietotemporal cortex corresponds to AD pathology. In 3 groups of patients with probable AD, matched for clinical measures of dementia severity but with varying levels of education, whole‐cortex mean flows were comparable. However, the parietotemporal perfusion deficit was significantly greater in the group with the highest level of education, indicating that AD was more advanced in this group. We conclude that education or its covariates or both may provide a reserve that compensates for the neuropathological changes of AD and delays the onset of its clinical manifestations.
Amygdala cell loss and atrophy in Alzheimer's disease
Authors: Scott Samuel A. , Sparks D. Larry , Scheff Stephen W. , Dekosky Steven T. , Knox Craig A.
Published: January 2005

The amygdala and its subnuclei undergo severe volumetric atrophy in Alzheimer's disease (AD). To determine whether this atrophy is due to loss of neuropil, specific neuronal populations, or both, we evaluated the number, size, and packing density of neurons and glia in the cortical and magnocellular basal amygdaloid subregions. The neuropil fraction did not change with AD in either region. Despite a mean 35% increase in cell packing density in the AD amygdala, total numbers of neurons and glia within tissue sections were reduced significantly; medium and large neurons were preferentially affected. The total number of small neurons was stable in the AD sample despite sharp reductions in nuclear size, suggesting that AD also results in pronounced amygdaloid neuronal shrinkage. Differences in the degree of cell loss between the two nuclei as well as changes in glial cell numbers are discussed in relation to characteristic AD neuropathology and relevant anatomical connectivity.
Severity of X‐linked recessive bulbospinal neuronopathy correlates with size of the tandem cag repeat in androgen receptor gene
Authors: Doyu Manabu , Sobue Gen , Mukai Eiichiro , Kachi Teruhiko , Yasuda Takeshi , Mitsuma Terunori , Takahashi Akira
Published: January 2005

The genetic mutation of X‐linked recessive bulbospinal neuronopathy is amplification of a polymorphic tandem CAG repeat in the androgen receptor gene. We studied this CAG repeat in 26 Japanese patients from 21 families with X‐linked recessive bulbospinal neuronopathy. The number of CAG repeats was significantly correlated with the age at onset of limb muscular weakness (r = −0.596, p < 0.001) and age‐adjusted scored disability (r = 0.446, p < 0.03). The length of the CAG repeat therefore seems to be a determinant factor of clinical severity.
The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats
Authors: Goadsby Peter J. , Edvinsson Lars
Published: January 2005

Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted on cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency‐dependent increase in cerebral blood flow, with a mean maximum of 43 ± 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene–related peptide (CGRP), with the level rising from 67 ± 3 to 82 ± 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 ± 8 pmol/liter) were normalized, with the headache being relieved (40 ± 8 pmol/liter). These data characterize some aspects of the cerebrovascular physiology of the trigeminovascular system and demonstrate important interactions between this system and the effective antimigraine agents sumatriptan and dihydroergotamine and that such interactions can be represented in animal models.
Glycogen branching enzyme deficiency in adult polyglucosan body disease
Authors: Bruno Claudio , Servidei Serenella , Shanske Sara , Karpati George , Carpenter Stirling , McKee David , Barohn Richard J. , Hirano Michio , Rifai Ziad , Dimauro Salvatore
Published: January 2005

Branching enzyme activity was assayed in muscle, peripheral nerve, and leukocytes from 2 Ashkenazi‐Jewish patients with adult polyglucosan body disease and 1 African‐American and 3 Caucasian patients with the same clinical and pathological features. Branching enzyme activity was normal in the muscle specimens from both Jewish and non‐Jewish patients. However, the activity was markedly decreased not only in the leukocytes from the 2 Jewish patients (confirming previous findings), but also in peripheral nerve specimens, whereas it was normal in nerve tissue and leukocytes from all non‐Jewish patients. These data confirm a branching enzyme deficiency in a subgroup of patients with adult polyglucosan body disease, and show that the defect is tissue‐specific, suggesting that adult polyglucosan body disease has more than one biochemical basis.
The neurological complications of sepsis
Authors: Bolton Charles F. , Bryan G. Young , Zochodne Douglas W.
Published: January 2005

Encephalopathy and polyneuropathy occur in 70% of septic patients. The encephalopathy is diffuse, appears early, is often severe, but reverses quickly with successful treatment of the sepsis. The electroencephalogram is a sensitive indicator of the incidence and severity of the encephalopathy, but computed tomograms of the brain and cerebrospinal fluid findings are unremarkable. Critical‐illness polyneuropathy develops later and in association with multiple‐organ failure. Recovery is more gradual. Difficulty in weaning from the ventilator is an important early manifestation. Electromyography should be routinely performed to establish the diagnosis. The polyneuropathy is a primary axonal degeneration, predominantly of distal motor fibers. A persistent deficit may eventuate in severe cases. Whether muscle is affected as consistently as brain and peripheral nerve, and by the same process, has not been determined. Medications used in critical care units, notably sedatives and neuromuscular blocking agents, often confuse the clinical picture. The neurological pathophysiology is unknown but current evidence suggests that nervous system dysfunction arises through the same mechanisms as for systemic organs in the septic syndrome.
Assessment of reliability and biological significance of glutamate levels in cerebrospinal fluid
Authors: Ferrarese Carlo , Pecora Nicoletta , Frigo Maura , Appollobnio Ildebrando , Frattola Lodovico
Published: January 2005

The published information on glutamate levels in cerebrospinal fluid (CSF) and modifications in neurological disorders is controversial. In the present study, we demonstrated a metabolic instability of glutamare in untreated CSF and a spurious elevation of its levels by the current methods of CSF acidification. These findings may explain the discrepancies observed with different methods of CSF processing and analysis. We suggest a method of inactivating CSF enzymes that yields stable glutamate levels under different storage conditions. Use of such a method may be necessary for clinical studies.
Can neurologists survive or thrive with health care reform?
Authors: Ringel Steven P.
Published: January 2005

The economics of present‐day health care and the politics of recent elections will forever change the practice of neurology. Managed care, outcomes research, limits on price and volume of services, diagnostic and treatment restraint, divestiture of ownership in health facilities, malpractice reform, increased use of preventive services, and administrative simplifications will all be part of the new practice of medicine, and hence neurology. The challenge for neurologists will be to define cost‐effective neurological services, put greater emphasis on the most prevalent and costly diseases of the nervous system, and convince primary care providers and patients of their value. Health care reform is an opportunity and challenge for neurologists to improve patient access while achieving acceptable financing mechanisms.