bluuebunny/crossref_metadata_2025 huggingface dataset:
Polysomnographic sleep measures in Parkinson's disease patients with treatment‐induced hallucinations
Authors: Comella Cynthia L. , Tanner Caroline M. , Ristanovic Ruzica K.
Published: January 2005

Prior studies of sleep in Parkinson's disease (PD) have been compromised by inadequate comparison groups, mixed medication regimens, and absence of quantitative data collection. This is the first study to compare polysomnographic sleep measures in PD patients on only dopaminergic medications with and without hallucinations. We performed two consecutive nights of polysomnography in 10 nondepresed, nondemented PD patients, 5 with and 5 without hallucinations. All patients were being treated with carbidopa/levodopa and a dopaminergic agonist only. Hallucinators and nonhallucinators were group‐matched for age, PD duration, severity, and medication doses. Both groups had abnormal sleep records. In particular, there was a reduction in K‐complexes and spindle formation, and the frequent occurrence of motor activation during rapid eye movement (REM) sleep consistent with REM behavior disorder. The hallucinator group had a significantly lower sleep efficiency (0.25 in hallucinators vs 0.61 in nonhallucinators, p = 0.006), a reduced total REM sleep time (mean total REM sleep time, 3 minutes in hallucinators vs 50 in nonhallucinators; p = 0.005), and a reduced REM percentage (mean, 5% in hallucinators vs 20% in nonhallucinators; p = 0.011). This study demonstrates that advanced PD patients treated with dopaminergic agents have abnormal sleep patterns and that those with dopaminergic‐induced hallucinations have significantly greater REM aberrations than nonhallucinating PD patients.
Unverricht‐Lundborg disease: Absence of nonallelic genetic heterogeneity
Authors: Cochius J. I. , Figlewicz D. A. , Kälviäinen R. , Nousiainen U. , Farrell K. , Patry G. , Söderfeldt B. , Frydman M. , Lerman P. , Andermann F. , Andermann E. , Rouleau G. A.
Published: January 2005

Unverricht‐Lundborg disease is a clinically recognizable form of progressive myoclonus epilepsy. Recently, in several families of both Finnish and Mediterranean extraction segregating Unverricht‐Lundborg disease, the gene for this disease was linked to the same region of the long arm of chromosome 21. We performed linkage analysis in eight families, including four of neither Baltic nor Mediterranean origin, using a polymorphic (CA)n repeat marker for the human liver‐type 6 phosphofructokinase (PFKL) gene, previously mapped to 21q22.3. No recombinations were observed between the disease phenotype and the PFKL marker and a maximum lod score of 5.63 was obtained. These findings confirm tight linkage between PFKL and the gene for Unverricht‐Lundborg disease and strongly suggest a lack of nonallelic genetic heterogeneity of the disease.
Significance of reactive lyme serology in multiple sclerosis
Authors: Coyle P. K. , Krupp Lauren B. , Doscher Carol
Published: January 2005

Nineteen of 283 consecutive patients evaluated in the Multiple Sclerosis (MS) Comprehensive Care Center had a borderline or positive B. burgdorferi serology. In 8 patients a repeat serology was nonconfirmatory. Cerebrospinal fluid was examined in 10 seropositive patients and showed anti‐B. burgdorferi antibodies without intrathecal production in 5 patients. Antibiotic treatment did not prevent subsequent neurological relapses. The finding of reactive Lyme serology in an MS patient with no suggestive features of the infection is unlikely to indicate neurological Lyme disease.
Neuron loss localizes human temporal lobe epilepsy by in vivo proton magnetic resonance spectroscopic imaging
Authors: Hugg James W. , Laxer Kenneth D. , Matson Gerald B. , Maudsley Andrew A. , Weiner Michael W.
Published: January 2005

Temporal lobe epileptogenic foci were blindly localized in 8 patients with medically refractory unilateral complex partial seizures using noninvasive in vivo proton magnetic resonance spectroscopic imaging (1H‐MRSI) with 4‐ml effective voxel size. The brain proton metabolite signals in 8 matched normal controls were bilaterally symmetrical within ± 10%. The hippocampal seizure foci had 21 ± 5% less N‐acetyl aspartate signal than the contralateral hippocampal formations (p < 0.01). The focal N‐acetyl aspartate reductions were consistent with pathology findings of mesial temporal sclerosis with selective neuron loss and gliosis in the surgically resected epileptogenic foci. Proton MRSI correctly localized the seizure focus in all 8 cases. By comparison, MR imaging correctly localized 7 of 8 cases and single photon emission computed tomography correctly localized 2 of 5 cases. No lactate was detected in these interictal studies. No significant changes in choline or creatine were observed. In conclusion, 1H‐MRSI is a useful tool for the noninvasive clinical assessment of intractable focal epilepsy. These preliminary results suggest that 1H‐MRSI can accurately localize temporal lobe epileptogenic foci.
Site of autonomic deficit in Harlequin syndrome: Local autonomic failure affecting the arm and the face
Authors: Drummond Peter D. , Lance James W.
Published: January 2005

The site of autonomic deficit was investigated in 4 patients with loss of thermoregulatory flushing and sweating on one side of the face but no associated miosis (harlequin syndrome). In 2 patients the sudomotor deficit included the hand. Signs of postganglionic sympathetic deficit included pathological lacrimal sweating (2 patients) and supersensitivity to 1% phenylephrine eyedrops (3 patients). One or both pupils constricted excessively to 0.0625% pilocarpine eyedrops (3 patients), consistent with ocular parasympathetic deficit. These findings suggest that pre‐ or postganglionic cervical sympathetic fibers, and parasympathetic neurons in the ciliary ganglia, are compromised in harlequin syndrome. The finding of cholinergic supersensitivity in the iris muscles of patients with harlequin syndrome indicates a relationship with Holmes‐Adie syndrome, Ross's syndrome, and the persistent autonomic deficit occasionally associated with Guillain‐Barré syndrome.
Expression of immunologically relevant endothelial cell activation antigens on isolated central neurvous system microvessels from patients with multiple sclerosis
Authors: Washington Ruth , Burton Jeffrey , Todd Robert F. , Newman Walter , Dragovic Ljubisa , Dore‐Duffy Paula
Published: January 2005

Activation of the vascular endothelium is thought to be an important facet of inflammation, thrombosis, and vasculitis. Activated endothelial cells express a number of immunologically relevant surface markers not expressed by normal endothelial cells. Many of these surface antigens are thought to augment adhesion reactions and migration. Our results show that endothelial activation may play a centrla role in the pathogenesis of multiple sclerosis (MS). Normal human central nervous system microvessels isolated from autopsy material do not express endothelial cell activation markers, including the adhesion proteins vascular cell adhesion molecule‐1 (VCAM‐1) and endothelial cell leukocyte adhesion molecule‐1 (E‐selectin/ELAM‐1). They exhibit little to no constitutive expression of immunoreactive intercellular adhesion molecule‐1 (ICAM‐1) or the urokinase plasminogen activator receptor. Control microvessels exhibit no major histocompatibility complex (MHC) class II antigen. MS microvessels express significant levels of MHC class II antigens, ICAM‐1, VCAM‐1, and urokinase plasminogen activator receptor. E‐selectin was expressed by 3 of 5 MS brains tested. Histologically unaffected areas of MS brain expressed less VCAM‐1, ICAM‐1, and E‐selectin than did microvessels from periplaque zones. However, MHC class II antigens and urokinase plasminogen activator receptor were increased in areas exhibiting little to no evidence of leukocyte infiltration. When microvessels were examined for dual expression of activation markers, we found that in periplaque areas, 50% of microvessels coexpressed HLA‐Dr. and VCAM‐1, 28% of microvessels coexpressed HLA‐Dr. and urokinase plasminogen activator receptor, and 43% of microvessels coexpressed HLA‐Dr. and ICAM‐1.
Distal vacuolar myopathy in nephropathic cystinosis
Authors: Charnas Lawrence R. , Luciano Carlos A. , Dalakas Marinos , Gilliatt Roger W. , Bernardini Isa , Ishak Kamal , Cwik Valerie A. , Fraker Douglas , Brushart Thomas A. , Gahl William A.
Published: January 2005

Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long‐term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post–renal‐transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase–positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.
Myotonic dystrophy with no trinucleotide repeat expansion
Authors: Thornton Charles A. , Griggs Robert C. , Moxley Richard T.
Published: January 2005

We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.
Anti‐myelin basic protein and anti‐proteolipid protein specific forms of multiple sclerosis
Authors: Warren Kenneth G. , Catz Ingrid , Johnson Edward , Mielke Bruce
Published: January 2005

Human myelin basic protein (hMBP) and proteolipid protein (PLP) were used as antigens in a solid‐phase radioimmunoassay to determine relative frequencies of anti‐MBP and anti‐PLP in cerebrospinal fluid (CSF) of optic neuritis and multiple sclerosis (MS) patients. Forty‐nine of 55 patients with optic neuritis had increased CSF anti‐MBP and the remaining 6 had increased anti‐PLP. Of 385 MS patients, MS relapse: 173 of 180 patients had increased anti‐MBP, 5 of the remaining 7 patients had elevated anti‐PLP, and 2 had neither of these autoantibodies. Progressive MS: 111 of 116 patients had increased anti‐MBP in either free and/or bound form, of the remaining 5 patients 4 had increased anti‐PLP, and 1 had neither anti‐MBP nor anti‐PLP. MS remission: 15 of 87 patients had somewhat increased anti‐MBP, none had anti‐PLP. IgG was purified by affinity chromatography from necropsy central nervous system (CNS) tissue samples of 4 individual patients with clinically definite and neuropathologically confirmed MS. Three of these 4 patients who had increased levels of CSF anti‐MBP also had increased anti‐MBP titers in CNS tissue‐extracted IgG. The fourth patient who had anti‐PLP in CSF also had anti‐PLP in brain tissue IgG. These autoantibodies were not detected simultaneously in any patient. These results suggest that there are at least two immunologically distinct forms of MS, i.e., a common form highly associated with anti‐MBP and more frequent prominent inflammatory characteristics in CSF and CNS, and an infrequent form associated with anti‐PLP in CSF and tissue, and less abundant inflammation. Anti‐MBP purified from CNS tissue IgG by antigen‐specific affinity chromatography was reacted with synthetic peptides of hMBP. The anti‐MBP epitope on the hMBP molecule was restricted between residues 75 and 106. The PLP epitope for anti‐PLP has not as yet been determined. These observations have theoretical implications for anticipated future specific immunotherapy of MS.
Peripheral neuropathy from taxol and cisplatin combination chemotherapy: Clinical and electrophysiological studies
Authors: Chaudhry Vinay , Rowinsky Eric K. , Sartorius Susan E. , Donehower Ross C. , Cornblath David R.
Published: January 2005

Taxol is a novel antineoplastic agent that has demonstrated impressive clinical activity in breast, ovarian, lung, and head and neck cancers. This broad antitumor activity of taxol in cisplatin‐sensitive tumors suggests that the combination of taxol and cisplatin may become one of the most commonly used taxol‐based chemotherapeutic regimen in the treatment of solid tumors. Both taxol and cisplatin, however, are neurotoxic. To study the neurotoxic effects of these two agents when used in combination, we prospectively evaluated neurological function at baseline, during, and following treatment, in 21 cancer patients treated with taxol (135–350 mg/m2), cisplatin (75–100 mg/m2), and granulocyte‐colony stimulating factor (5μ/kg). Twenty of the 21 patients (95%) developed a sensory–motor neuropathy 1 to 21 weeks after the initiation of therapy, that was progressive with each additional course of chemotherapy. The neuropathy was symmetrical, length dependent, axonal in nature by physiological studies, and more pronounced in those patients who received higher doses of taxol. The neuropathy appeared earlier and at lower taxol doses in those patients with preexisting neuropathies. We conclude that sensory–motor neuropathy is a frequent dose‐dependent toxicity of combined cisplatin and taxol use. Peripheral neuropathy is likely to become the major dose‐limiting toxicity of taxol–cisplatin combination chemotherapy when higher doses of these agents are administered with granulocyte‐colony stimulating factor.
Vestibular cortex lesions affect the perception of verticality
Authors: Brandt Th. , Dieterich M. , Danek A.
Published: January 2005

Seventy‐one patients with unilateral supratentorial infarctions were evaluated with respect to static vestibular function in the roll plane, including determinations of the subjective visual vertical, skew deviation, and ocular torsion. Since animal studies have revealed at least four different areas of the parietal and temporal cortex involved in vestibular function, we tried to identify cortical areas in humans responsible for vestibular function in the roll plane. Infarcted areas, as demonstrated in magnetic resonance and computed tomography scans, were projected onto the appropriate sections of an atlas of the human brain. Infarctions in the territories of the posterior and anterior cerebral arteries did not affect static vestibular function in roll. Twenty‐three of 52 patients with infarctions in the middle cerebral artery territory showed significant (p < 0.0005), mostly contraversive, pathological subjective visual vertical tilts. The overlapping area of these infarctions centered on the posterior insula, probably homologous to the parieto‐insular vestibular cortex in the monkey. Although electrophysiological and cytoarchitectonic data in animals demonstrate several multisensory areas rather than a single primary vestibular cortex, the parieto‐insular vestibular cortex seems to represent the integration center of the multisensory vestibular cortex areas within the parietal lobe.
Zidovudine‐induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage
Authors: Dalakas Marinos C. , Leon‐Monzon Marta E. , Bernardini Isa , Gahl William A. , Jay Cheryl A.
Published: January 2005

The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA‐depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibers with “ragged‐red”–llike features, red‐rimmed or empty cracks, granular degeneration, and rods (AZT fibers). Because dysfunctioning muscle mitochondria may lead to defects of β‐oxidation of fatty acids, we examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT‐induced myopathic symptoms of varying severity. Six patients with no AZT fibers had normal endomyofibrillar lipid deposits and muscle carnitine levels; 7 patients with fewer than 5 AZT fibers per field had a mild (+) to moderate (++) increase in lipid droplets, and reduced muscle carnitine levels (3 patients); and 8 patients with more than 5 AZT fibers had severe muscle changes, a ++ to marked (+++) increase in lipid droplets, and reduced muscle carnitine levels (6 patients). Serial sections showed lipid globules often within “cracks” or vacuoles of the abnormal muscle fibers. We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibers owing to poor utilization of long‐chain fatty acids, (2) reduction of muscle carnitine levels probably due to decreased carnitine uptake by the muscle, and (3) depletion of energy stores within the muscle fibers. The findings may have potential therapeutic implications in the treatment of AZT‐induced myopathic symptoms using oral carnitine supplementation.
Sequences of memory‐guided saccades in Parkinson's disease
Authors: Vermersch Anne‐Isabelle , Rivaud Sophie , Vidailhet Marie , Bonnet Anne‐Marie , Gaymard Bertrand , Agid Yves , Pierrot‐Deseilligny Charles
Published: January 2005

Sequences of ocular saccades were studied in 8 patients with Parkinson's disease, with (i.e., “on”) and without (i.e., “off”) levodopa treatment. The amplitude of single saccades was decreased and not improved by treatment. The chronology of saccades during sequences was impaired in patients in the “off” state, but significantly improved during the “on” period. These results are compatible with a decreased activation of the supplementary motor area, which can be reversed by levodopa.
Dopamine transporter messenger RNA in Parkinson's disease and control substantia nigra neurons
Authors: Uhl George R. , Walther Donna , Mash Deborah , Faucheux Baptiste , Javoy‐Agid France
Published: January 2005

Dopamine transporter messenger RNA (mRNA) expression was assessed by in situ hybridization over individual pigmented neurons from the substantia nigra pars compacta in midbrain sections from 7 parkinsonian and 7 age‐matched, neurologically normal patients. In the normal control brains, high levels of expression of dopamine transporter mRNA were noted over pigmented neurons in the substantia nigra pars compacta; neurons in the adjacent nucleus paranigralis of the ventral tegmental area displayed less hybridization. Nigra compacta neurons surviving in brains of patients with Parkinson's disease displayed only 57% of the dopamine transporter mRNA hybridization intensity displayed by nigral neurons in normal control brains. The disease‐related decrease in the apparent level of dopamine transporter mRNA expression in remaining neurons could reflect neuronal dysfunction. Conceivably, it might also reflect differential vulnerability of those neurons that initially expressed higher levels of this transporter to the insult of parkinsonism.
Early weight loss and high serum tumor necrosis factor‐α levels in polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes syndrome
Authors: Gherardi R. K. , Chouaïb S. , Malapert D. , Bélec L. , Intrator L. , Degos J.‐D.
Published: January 2005

We studied tumor necrosis factor‐α (TNF‐α) levels in serial serum samples from 3 consecutive patients who had a complete form of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome and early weight loss. Serum TNF‐α levels were compared with those of 10 patients with multiple my eloma (5) or Waldenström's macroglobulinemia (5). Elevated serum levels of TNF‐α were found in the patients with POEMS syndrome (two‐ to eightfold increase in 10 of 11 samples) and not in those with other malignant plasma cell dyscrasias. These results are in keeping with the hypothesis of a role for nonimmunoglobulinic mediators in the pathogenesis of the POEMS syndrome, and are consistent with previous reports of TNF‐α overproduction in inflammatory demyelinating neuropathies and cachectic states.
Discontinuing antiepileptic drugs in children with epilepsy: A prospective study
Authors: Shinnar Shlomo , Berg Anne T. , Moshé Solomon L. , Kang Harriet , O'Dell Christine , Alemany Marta , Goldensohn Eli S. , Allen Hauser W.
Published: January 2005

In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure‐free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RR] = 1.81). On multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3.1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children.
Astasia and gait failure with damage of the pontomesencephalic locomotor region
Authors: Masdeu Joseph C. , Alampur Uma , Cavaliere Rossella , Tavoulareas George
Published: January 2005

Although there is evidence in experimental animals of the importance of the pedunculopontine area in locomotion, clinical lesion reports are lacking. An 83‐year‐old woman became unable to stand and to generate stepping movements after a hemorrhage at the pontomesencephalic junction involving the right pedunculopontine area. Her deficit resembled the gait failure present in some elderly individuals.
The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy
Authors: Sloviter Robert S.
Published: January 2005

Temporal lobe seizures are frequently associated with a characteristic pattern of hippocampal pathology (hippocampal sclerosis), as well as pathology in other temporal lobe structures. Despite more than a century of study, the relationship between pathology and epileptogenesis remains unclear. Endfolium sclerosis, which is characterized by the loss of dentate hilar neurons that are presumed to govern dentate granule cell excitability, is evident whenever hippocampal sclerosis exists and is the only temporal lobe pathology in some patients. Because prolonged seizures or head trauma produce endfolium sclerosis and granule cell hyperexictability in experimental animals, hilar neuron loss may be the common pathological denominator and primary network defect underlying development of a hippocampal seizure “focus.” Physiological studies suggest that vulnerable hilar mossy cells normally excite neurons that mediate granule cell inhibition. Recent anatomical studies indicate that the axons of mossy cells project longitudinally, out of the lamellar plane in which their cell bodies lie. If mossy cells in one lamella excite inhibitory neurons in surrounding lamellae, neocortical excitation of one segment of the granule cell layer may produce lateral inhibition and limit neocortical excitation to the targeted lamella. In patients who have had status epilepticus, prolonged febrile seizures, head trauma, or encephalitis, loss of dentate mossy cells may deafferent inhibitory neurons, render them “dormant,” and thereby disinhibit an encephalitis, loss of dentate mossy cells may deafferent inhibitory neurons, render them “dormant,” and thereby disinhibit an enlarged expanse of the granule cell layer. The selective loss of neurons that normally govern lateral inhibition in the dentate gyrus may cause functional delamination of the granule cell layer and result in synchronous, multilamellar discharges in response to cortical stimuli. Repetitive seizures may ultimately produce the full pattern of hippocampal and mesial temporal sclerosis by destroying cells within the seizure circuit that were not injured irreversibly by the initial insult. Thus, hippocampal pathology may be both the cause and effect of seizures that originate in the temporal lobe.
The prevalence of narcolepsy: An epidemiological study of the Finnish Twin Cohort
Authors: Hublin Christer , Kaprio Jaakko , Partinen Markku , Koskenvuo Markku , Heikkila Kauko , Koskimies Saija , Guilleminault Christian
Published: January 2005

We investigated the prevalence of narcolepsy using a well‐defined white population previously used for epidemiological investigations: the Finnish Twin Cohort. The Cohort consists of 13,888 monozygotic and dizygotic twin pairs born before 1958. There were 16,179 individuals who participated in the study, with a 77.3% response rate. The study methodolgy included a questionnaire covering sleep and alertness, the Ullanlinna Narcolepsy Scale (UNS), a scale specifically developed and tested for the study, telephone interviews, and finally, clinical evaluation, polygraphic recording, and HLA blood typing. Seventy‐five subjects were selected for telephone interviews and laboratory evaluations based on data from both questionnaires. Five of them were strongly suspected of narcolepsy, but laboratory data identified only 3. All were dizygotic (fraternal) twins discordant for the disease with a negative family history and presence of DR2 DQw1 (i.e., DRw15 DQw6, new World Health Organization classification). The prevalence of narcolepsy in the Finnish population is 0.026% (95% confidence interval, 0.0–0.06). This prevalence is lower than that reported in studies performed without polygraphic recording and is close to that reported in 1945 in the black U.S. population. The tools developed to perform this study, the largest population study of its kind yet performed, can now be used for other population investigations.
Interical spiking increases 2‐deoxy[14C]glucose uptake and c‐fos—like reacitivity
Authors: Handforth Adrian , Finch David M. , Peters Richard , Tan Aiko M. , Treiman David M.
Published: January 2005

Although interical spikes are thought to share pathophysiological mechanisms with partial‐onset seizure discharges, positron emission tomographic studies of the interictal stare have paradoxically shown focal hypometabolism whereas seizures produce hypermetabolism. To address this question, we performed functional mapping studies in an interictal spiking model in the rat. Recording screw electrodes were inserted through the skull bone so as to depress underlying cortex. Interictal spiking was subsequently induced by systemic administration of bicuculline methiodide. 2‐deoxy[14C]glucose studies revealed increased glucose utilization in superficial and middle cortical layers at spiking screw sites. Nonspiking screw sites in the same animals and in controls did not show increased uptake. Convulsive seizures caused additional 2‐deoxy[14C]glucose uptake at screw sites and in widespread forebrain areas. c‐fos immunoreactivity occurred in superficial cortex at interictal spiking, but not nonspiking, sites. Convulsive seizures induced widespread forebrain c‐fos immunoreactivity. These data suggest interictal epileptiform activity occurs in cells adjacent to cortical injury; these activate deeper layers via local connections. Interictal and ictal epileptiform states share common mechanisms, as both induce glucose hypermetabolism and immediate‐early gene product activation. Possible reasons for failure to detect hypermetabolism in interictal human subjects are discussed.
Neuropeptides in the sympathetic system: Presence, plasticity, modulation, and implications
Authors: Benarroch Eduardo E.
Published: January 2005

Neuropeptides are ubiquitous in the sympathetic system and modulate transmission at the levels of the intermediolateral cell column, sympathetic ganglia, and neuroeffector junctions. Several neuropeptide‐containing pathways from the hypothalamus and medulla modulate excitability of preganglionic neurons. Neuropeptides coexist with norepinephrine or acetylcholine in subpopulations of chemically coded, target‐specific sympathetic ganglion neurons. Neuropeptide Y is colocalized in adrenergic vasconstrictor neurons, whereas vasoactive intestinal polypeptide is colocalized in cholinergic sudomotor neurons. Neuropeptide expression is plastic; during development, neurons that switch from a noradrenergic to a cholinergic phenotype increase expression of vasoactive intestinal polypeptide, somatostatin, and substance P. Preganglionic inputs increase neuropeptide Y and inhibit substance P expression. Sympathetic denervation produces sprouting of sensory fibers containing substance P and calcitonin gene–related peptide in target tissues. Neuropeptides from preganglionic fibers (e.g., enkephalin) and primary afferents (e.g., substance P, vasoactive intestinal polypeptide) modulate transmission in sympathetic ganglia. Neuropeptide Y produces vasoconstrction, prejunctional inhibition of norepinephrine release, and postjunctional potentiation of norepinephrine effects. Plasma neuropeptide Y increase during intense sympathoexcitation, hypertension, and pheochromocytoma. Dystrophic neurites containing neuropeptide Y occur in human sympathetic ganglia during aging, diabetes, and dysautonomia. Sympathetic neuropeptides may thus have important clinical implications.
Treatment of abnormal eye movements that impair vision: Strategies based on current concepts of physiology and pharmacology
Authors: Leigh R. John , Averbuch‐Heller Lea , Tomsak Robert L. , Remler Bernd F. , Yaniglos Stacy S. , Dell'Osso Louis F.
Published: January 2005

Certain abnormal eye movements, especially pathological nystagmus, degrade vision and cause illusory motion of the seen environment. These symptoms are due to excessive movement of images of stationary objects on the retina. Recently, the pathophysiology underlying several types of nystagmus and saccadic oscillations was better defined by the development of animal models and by experimental pharmacological studies. Despite this, few reliable therapies are currently available for these abnormal eye movements. In clinical studies, a number of drugs reportedly helped individual patients, but few drugs have been subjected to double‐blind trials. An alternative approach to pharmacological suppression of abnormal eye movements is optical stabilization of images on the retina, which is helpful in selected patients. Weakening of the extraocular muscles, using botulinum toxin or surgery, is prone to cause diplopia and may induce plastic‐adaptive changes that render the effect temporary. In some patients, treatment of an underlying condition, such as the Arnold‐Chiari malformation, reduces nystagmus and improves vision. There is a need for multicenter trials to evaluate systematically potential treatments of abnormal eye movements that impair vision.
Biochemical alterations in multiple sclerosis lesions and normal‐appearing white matter detected by in vivo 31P and 1H spectroscopic imaging
Authors: Husted C. A. , Goodin D. S. , Hugg J. W. , Maudsley A. A. , Tsuruda J. S. , de Bie S. H. , Fein G. , Matson G. B. , Weiner M. W.
Published: January 2005

The goals of the current study were threefold: first, to confirm previous single volume proton (1H) magnetic resonance spectroscopy results of reduced N‐acetyl aspartate (NAA, a putative marker of neurons) in multiple sclerosis (MS) white matter lesions using multiple volume 1H magnetic resonance spectroscopic imaging (MRSI); second, to measure the phospholipid metabolites phosphomonoesters and phosphodiesters in such lesions using phosphorus (31P) MRSI; and third, to test the hypothesis that biochemical changes occur in the normal‐appearing (on spin echo T2‐weighted magnetic resonance images) white matter in patients with MS. Thirteen subjects with clinically definite MS were studied with both 1H and 31P MRSI, and 19 controls were studied with either 1H MRSI, 31P MRSI, or both. MS lesion, MS normal‐appearing white matter, and region‐matched control spectra from the centrum semiovale were analyzed. The major findings of this study were that in both white matter lesions and normal‐appearing white matter in patients with MS, the metabolite ratio NAA/creatine and the total 31P peak integrals were significantly reduced compared with controls. In addition, in MS lesions NAA/choline and phosphodiesters/total 31P were significantly reduced compared with controls, and in MS normal‐appearing white matter there was a trend for NAA/choline to be reduced compared with controls. In normal‐appearing white matter in patients with MS, total creatine and phosphocreatine were significantly increased compared to controls, as detected with both 1H (total creatine peak integrals) and 31P (phosphocreatine/total 31P) MRSI techniques. These results suggest reduced neuronal density and altered phospholipid metabolites in white matter lesions in patients with MS. Furthermore, the results suggest the presence of biochemical abnormalities not detected by standard spin echo magnetic resonance imaging in normal‐appearing white matter in MS.
Role of nerve growth factor in suramin neurotoxicity studied in vitro
Authors: Russell James W. , Windebank Anthony J. , Podratz Jewel L.
Published: January 2005

We determined whether suramin neurotoxicity can be prevented by nerve growth factor (NGF) and if this interaction occurs at the level of the NGF receptor. Neurite outgrowth from rat dorsal root ganglia in vitro was measured serially in the presence of suramin (100–600 μM) alone or with β‐NGF (50–1,000 ng/ml). Competitive NGF receptor–binding studies were done with 125I‐labeled NGF in the presence or absence of suramin. Neurite growth was inhibited in a dose‐dependent manner, but at usual neurotoxic levels this inhibition could be overcome completely by increasing the concentration of NGF. Receptor‐binding assays showed similar dose‐dependent inhibition of 125I‐labeled NGF binding. In the presence of suramin, the dissociation constant for high‐affinity binding was decreased from 1.2 × 10−11 to 3.9 × 10−10 and low‐affinity binding from 2.7 × 10−9 to 1.2 × 10−8. Increasing doses of suramin inhibited 125I‐labeled NGF specific binding in a dose‐dependent fashion, and doses of suramin ± 1,000 μM were able to completely inhibit 125I‐labeled NGF specific binding. Suramin‐induced dorsal root ganglia damage can be ameliorated by high‐dose NGF. This effect is most likely due to competition between suramin and NGF at the high‐affinity NGF receptor.
Phenobarbital modifies seizure‐related brain injury in the developing brain
Authors: Mikati Mohamad A. , Holmes Gregory L. , Chronopoulos Antonia , Hyde Pamela , Thurber Samuel , Gatt Arkadi , Liu Zhao , Werner Suzanne , Stafstrom Carl E.
Published: January 2005

To investigate the potential role of drug therapy in preventing or exacerbating seizure‐related brain injury in the prepubescent brain, we administered kainic acid to rats at postnatal day 35. Therapy with daily phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats receiving phenobarbital had therapeutic concentrations during most of the 24‐hour dosing period, but also experienced supratherapeutic peak concentrations. The animals were subsequently tested using the water maze (a measure of visuospatial memory), open field (a measure of activity level), and handling tests (a measure of emotionality). The frequency of spontaneous recurrent seizures was monitored during and after phenobarbital therapy. Kainic acid resulted in status epilepticus on postnatal day 35 in all the rats that received it but those receiving phenobarbital first manifested a shorter and less severe status epilepticus as compared to the rats given kainic acid alone. Rats starting phenobarbital immediately before kainic acid was administered did not differ from control rats on behavioral testing and had no subsequent spontaneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, and manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiveness and histological lesions, similar frequency of spontaneous recurrent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate that kainic acid–related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.
Trinucleotide repeat expansion in neurological disease
Authors: La Spada Albert R. , Paulson Henry L. , Fischbeck Kenneth H.
Published: January 2005

Expansion of trincleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X‐linked spinal and bulbar muscular atrophy (SBMA), two fragile×syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral‐pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile×and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lenghthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.
Predictive value of apolipoprotein E genotyping in Alzheimer's disease: Results of an autopsy series and an analysis of several combined studies
Authors: Nalbantoglu Josephine , Gilfix Brian M. , Bertrand Philippe , Robitaille Yves , Gauthier Serge , Rosenblatt David S. , Poirier Judes
Published: January 2005

Apoliprotein E (apoE) is associated with Alzheimer's neurofibrillary tangles and β‐amyloid protein in senile plaques. Recent studies have shown an increased frequency of the ϵ4 allele of the apoE gene in familial and sporadic cases of Alzheimer's disease (AD). In the present case control study, we have determined the apoE genotype by allele‐specific extension of 113 postmortem cases of sporadic AD and 77 control brains shown to be free of AD neuropathological features and then calculated the frequency of the various allelic forms of apoE (ϵ2, ϵ3,ϵ4). The odds ratio associating ϵ4 with AD was 15.5 (95% confidence interval {CI} 6.2–38.5), and the population attributable risk was 0.53. We have also combined the results of our study and several others to calculate these same parameters in a larger population (570 controls and 961 AD subjects); the odds ratio for this larger group was 6.2 (95% CI 4.9–7.8) and the population attributable risk was 0.57. These results further substantiate and strengthen the association between the ϵ4 allele of apoE gene and AD. We have also used these results to investigate the usefulness of the determination of ϵ4 carrier status in the diagnosis of AD.
Low‐dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis
Authors: Goodkin Donald E. , Rudick Richard A. , Medendorp Sharon Vanderbrug , Daughtry Michele M. , Schwetz Kathleen M. , Fischer Jill , van Dyke Carolyn
Published: January 2005

A randomized, double‐blinded, placebo‐controlled, clinical trial of low‐dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral‐based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low‐dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9‐Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper‐extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low‐dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.
Neuroprotective effects of gangliosides may involve inhibition of nitric oxide synthase
Authors: Dawson Ted M. , Hung Kenneth , Dawson Valina L. , Steiner Joseph P. , Snyder Solomon H.
Published: January 2005

Gangliosides are polar, sugar‐containing lipids that are major constituents of neuronal membranes. Gangliosides are neuroprotective in animal models of neurotoxicity and may also be useful in patients with clinical conditions such as spinal cord injury. We show that a series of gangliosides inhibit nitric oxide synthase activity by binding calmodulin. The prevention of glutamate neurotoxicity in cortical cultures by gangliosides closely parallels their potencies in binding calmodulin and inhibiting nitric oxide synthase. Neuroprotective effects of gangliosides may arise from blockade of nitric oxide formation.
Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans
Authors: Hendrie H. C. , Hall K. S. , Hui S. , Unverzagt F. W. , Yu C. E. , Lahiri D. K. , Sahota A. , Farlow M. , Musick B. , Brashear A. , Burdine V. E. , Osuntokun B. O. , Ogunniyi A. O. , Gureje O. , Baiyewu O. , Schellenberg G. D.
Published: January 2005

As part of a community‐based study of Alzheimer's disease (AD) in the African‐American population age 65 and over, we have determined apolipoprotein E (Apo E) genotypes in 85 subjects (31 AD patients and 54 controls). The €4 allele of Apo E was strongly associated with AD in this population sample. The € allele frequency in AD patients was 40.3% compared with 13.9% in the control group, and 22.6% of the AD patients were homozygous for this allele compared with 3.7% of the control subjects (p = 0.01). This study extends the association of Apo E‐∈4 and AD to nonwhite populations and provides further evidence that the observed allelic association is biologically relevant.
Changes in excitability of motor cortical circuitry in patients with parkinson's disease
Authors: Ridding M. C. , Rothwell J. C. , Inzelberg R.
Published: January 2005

Using the technique of transcranial magnetic stimulation over the motor areas of cortex and recording electromyographic (EMG) responses from the first dorsal interosseous muscle, we measured the excitability of corticocortical inhibitory circuits at rest using a double pulse paradigm, in 11 patients with Parkinson's disease (PD) studied both on (ON) and off (OFF) (after overnight withdrawal) their normal medication and in 10 age‐matched control subjects. There was a significant decrease in the amount of corticocortical inhibition at short (1–5 msec) interstimulus intervals in patients relative to their controls, which improved after L‐dopa intake. For comparison with previous reports using transcranial magnetic stimulation we also measured the duration of the EMG silent period when stimuli were given to voluntarily active muscle, and the threshold for evoking an EMG response in both the active and relaxed states. There was no change in the threshold for evoking EMG responses whether muscles were active or relaxed. However, the silent period was significantly prolonged when ON compared with OFF, although in neither state was the duration significantly different from that seen in normals. We suggest that there may be abnormalities of motor cortical inhibitory mechanisms in patients with Parkinson's disease that are not readily detected using threshold or silent period measurements alone.
A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four european families
Authors: Warner T. T. , Williams L. D. , Walker R. W. H. , Flinter F. , Robb S. A. , Bundey S. E. , Honavar M. , Harding A. E.
Published: January 2005

Dentatorubropallidoluysian atrophy is a neurodegenerative disorder with characteristic pathology, chiefly described in reports from Japan, and is associated with an unstable CAG trinucleotide repeat in a gene on chromosome 12. We describe four European families, three British and one Maltese, with this mutation. All exhibited autosomal dominant inheritance, and there was evidence for anticipation associated with an increase of the expansion with paternal transmission in two families. Affected chromosomes from patients with dentatorubropallidoluysian atrophy had CAG expansions of 58 to 74 repeats, compared to 7 to 26 in control chromosomes, and the size of repeat was significantly inversely correlated with age of onset. The clinical features were diverse, even within individual families, and comprised a combination of a movement disorder (chorea, myoclonus, dystonia, or parkinsonism), cerebellar ataxia, epilepsy, psychosis, and dementia. A clinical diagnosis of Huntington's disease had been made in affected individuals from all families. Neuropathological examination of 2 patients showed no specific abnormality in one and degenerative changes predominantly affecting the spinal cord in the other. Investigation of 55 patients who might represent sporadic examples of dentatorubropallidoluysian atrophy did not detect any expanded alleles. Dentatorubropallidoluysian atrophy is likely to be more common than previously recognized in non‐Japanese populations, and should be considered in any patient with a dominantly inherited neurodegenerative disorder with the above‐mentioned clinical features.