bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of a monoamine oxidase B allele with Parkinson's disease
Authors: Kurth Janice H. , Kurth Matthias C. , Poduslo Shirley E. , Schwankhaus John D.
Published: January 2005

Monoamine oxidase B(MAO‐B) is implicated in the cause of Parkinson's disease(PD) because of its role in metabolizing the neurotoxin 1‐methyl–4‐phenyl–1,2,3,6‐tetrahydropyridine, and forming H2O2 during dopamine metabolism. Altered MAO‐B activity has been observed in PD platelets. Polymerase chain reaction was used to amplify a portion of the MAO‐B gene. Polymerase chain reaction products were screened with restriction enzymes to identify fragments useful for single‐stranded conformational polymorphism analysis. A single‐stranded conformational polymorphism was identified in an MAO‐B polymerase chain reaction product after Hae III digestion. One hundred twenty‐one control individuals were allelotyped with frequencies of 0.45 and 0.55 for alleles 1 and 2, respectively. Frequencies of 0.62 and 0.38 (1 and 2, respectively) were observed in a population of 46 patients with PD. The presence of MAO‐B allele 1 is associated with a relative risk for PD of 2.03‐fold (confidence interval, 1.44–2.61; p < 0.02). For comparison, a monoamine oxidase A polymorphism was used to determine allelic frequencies in these same populations and no statistically significant differences were found. These results suggest that an inherited variant of MAO‐B may be involved in a genetic predisposition for PD.
Maple syrup urine disease: Metabolic decompensation monitored by proton magnetic resonance imaging and spectroscopy
Authors: Felber S. R. , Sperl W. , Chemelli A. , Murr Ch. , Wendel U.
Published: January 2005

Metabolic decompensation of maple syrup urine disease in a 3.5‐year‐old boy was monitored by means of proton magnetic resonance imaging and spectroscopy. In the acute stage, imaging showed diffuse cerebral edema. Proton spectra showed an elevation of lactate and a previously unassigned resonance at 1 ppm. This peak disappeared with normalization of branched‐chain amino acids and oxoacids in the plasma and cerebrospinal fluid. In vitro spectroscopy of these metabolites at 1.5 T confirmed the chemical shift position of their methyl resonances at 1 ppm. The duration of lactate elevation correlated with the presence of brain edema and coma. These results demonstrate that magnetic resonance imaging can monitor therapeutic effects, and suggest that proton spectroscopy can detect cerebral accumulation of branched‐chain amino acids and oxoacids in maple syrup urine disease.
X‐linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course
Authors: Arts W. F. M. , Loonen M. C. B. , Sengers R. C. A. , Slooff J. L.
Published: January 2005

An X‐linked recessive disease with, in almost all patients, a fatal course in early childhood, occurring in a five‐generation family is described. The 12 affected boys had early‐onset floppiness, ataxia, liability to infections especially of the upper respiratory tract, deafness, and later, a flaccid tetraplegia and areflexia. Eleven boys died before the age of 5 years. One boy is still alive at the age of 12 years, but in addition to the above‐mentioned signs, he must be ventilated at night and is nearly blind due to optic atrophy. In the only patient whose central nervous system could be examined at the time of autopsy, an almost complete absence of myelin in the posterior columns of the spinal cord was found. This may be the main pathological substrate for the neurological findings. No biochemical or immunological defects were detected. The family also counted 16 healthy male siblings and 13 definite of 28 possible female carriers. Some carriers developed a hearing impairment in early adulthood. As far as is known now, this disease has not been described before.
Systemic histiocytosis presenting as multiple sclerosis
Authors: Smith M. E. , Katz D. A. , Harris J. O. , Frank J. A. , Kufta C. V. , McFarlin D. E.
Published: January 2005

A Patient resembling one with progressive multiple sclerosis in clinical presentation and by magnetic resonance imaging was studied in detail. Some features atypical for multiple sclerosis prompted a persistent search for an alternative cause. The diagnosis of a non‐Langerhans systemic histiocytosis involving brain and bone was established and showed a partial response to radiation therapy. This patient illustrates the continued importance of a broad approach to the evaluation of possible multiple sclerosis, with particular attention to atypical features.
Increases levels of circulating intercellular adhesion molecule‐1 in multiple sclerosis and human T‐lymphotropic virus type I‐associated myelopathy
Authors: Tsukada N. , Miyagi K. , Matsuda M. , Yanagisawa N.
Published: January 2005

We evaluated the presence of soluble intercellular adhesion molecule‐1(slCAM‐1)antigen in the sera of patients with multiple sclerosis and human T‐lymphotropic virus type I(HTLV‐I)‐associated myelopathy (HAM) using an enzyme‐linked immunosorbent assay. Patients with multiple sclerosis in the active phase had higher sICAM serum levels than did control subject (p < 0.01). In addition, a significantly increased serum level of sICAM‐1 was found in patients with HAM ( p < 0.001). Furthermore, we found a positive correlation with HAM sICAM‐1 and tumor necrosis factor‐α levels in the sera of patients with multiple sclerosis in the active phase (=0.88, p < 0.01) and in those with HAM (r=0.86, p < 0.01). These results suggest that serum sICAM‐1 may be related to clinical activity in patients with multiple sclerosis and the detection of sICAM‐1 could be useful as a marker of inflammatory disease.
Coexistence of hereditary motor and sensory neuropathy type IA and IGM paraproteinemic neuropathy
Authors: Gregory R. , Thomas P. K. , King R. H. M. , Hallam P. L. J. , Malcolm S. , Hughes R. A. C. , Harding A. E.
Published: January 2005

A patient with minimal motor dysfunction dating from early childhood developed more rapidly progressive distal weakness and positive sensory symptoms due to peripheral neuropathy in the fourth decade of life. DNA analysis showed the partial duplication of chromosome 17p associated with hereditary motor and sensory neuropathy type Ia. In addition, the patient had an IgM paraproteinemia and the typical morphological features of IgM paraproteinemic neuropathy on nerve biospsy.
Molecular genetic characterization of an X‐linked form of Leigh's syndrome
Authors: Matthews P. M. , Marchington D. R. , Squier M. , Land J. , Brown R. M. , Brown G. K.
Published: January 2005

We report a patient with necrotizing encephalomyelopathy (Leigh's syndrome) associated with a deficiency of pyruvate dehydrogenase complex activity. The underlying muration is an A to C transversion in the pyruvate dehydrogenase complex Elα subnit gene. As the Elα subunit is encoded on the X chromosome, this observation confirms that some patients with Leigh's syndrome may potentially exhibit X‐linked inheritance.
The pathophysiology and pharmacology of photic cortical reflex myoclonus
Authors: Artieda Julio , Obeso Jose A.
Published: January 2005

We studied 6 patients with myoclonus elicited by flash stimulation (1–15 Hz). Multichannel electromyographic recording showed a rostrocaudal recruitment order for the generalized myoclonic jerk. In all patients, each flash induced a large (36.9 ± 5.7 μV) frontal biphasic wave with an onset latency of 42 msec that preceded the earliest muscle response in the face by at least 4 msec (range, 4–7 msec), the activity in the biceps by 11 to 14 msec, and the activity in tibialis anterior by 26 to 34 msec. Occipital potentials evoked by the same flash stimulation had a latency of 33.7 msec and were of normal amplitude (2.1 ± 1.2 μV). Brain‐mapping analysis indicated that the frontal activity correlated with the myoclonus originated in the premotor and motor cortices. These findings provide evidence for a cortical origin of this form of stimulus‐sensitive myoclonus in humans. Administration of apomorphine and lisuride (intravenously) and levodopa‐carbidopa (orally) abolished the photic myoclonus. Intravenous 5‐hydroxytryptophan plus carbidopa (orally) and piracetam (orally) were also effective against photic myoclonus. The wide range of drugs active against photic cortical myoclonus suggests the participation of several biochemical mechanisms in its origin.
Differential neural activity in the human temporal lobe evoked by faces of family members and friends
Authors: Seeck M. , Mainwaring N. , Ives J. , Blume H. , Dubuisson D. , Cosgrove R. , Mesulam M.‐M. , Schomer D. L.
Published: January 2005

In 6 patients, depth electrodes revealed differential evoked responses to familiar versus novel faces. These differential responses were obtained in the amygdala, hippocampus, and temporal neocortex but not in the dorsolateral frontal or cingulate cortex. The limbic and temporal structures that differentiated novel from familiar faces did not respond differentially to variations in luminance. Limbic structures and temporal cortex thus appear to participate in face recognition and in encoding the familiarity of visual experiences.
Toward an understanding of the role of glutamate in experimental parkinsonism: Agonist‐sensitive sites in the basal ganglia
Authors: Klockgether Thomas , Turski Lechoslaw
Published: January 2005

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N‐methyl‐D‐asparate (NMDA), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA), kainate, and trans‐(±)‐1‐amino‐1,3‐cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non‐NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate‐induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.
Forearm 3‐methylhistidine efflux in myotonic dystrophy
Authors: Rifai Ziad , Kingston William J. , McCraith Brian , Moxley Richard T.
Published: January 2005

Myotonic dystrophy is associated with progressive muscular atrophy. To define the mechanism of muscle wasting in this disease, we studied myofibrillar proteolysis in vivo in 8 men moderately affected with myotonic dystrophy, and compared the results with those of 10 normal men. Myofibrillar proteolysis was estimated by measuring the 3‐methylhistidine arteriovenous difference (A – V) and efflux (Q) across the forearm in the postabsorptive state. Plasma 3‐methylhistidine concentrations were determined by high‐performance liquid chromatography with postcolumn o‐phthalaldehyde derivatization and fluorescence detection. Plasma flow to the forearm muscles (F) was estimated to represent 85% of total forearm plasma flow as determined by the indicator‐dilution technique. Forearm 3‐methylhistidine efflux was calculated as: Q = F(A – V). Mean muscle mass (24‐hour creatinine excretion), lean body mass, and forearm volume were decreased in the patients with myotonic dystrophy, confirming the presence of muscle atrophy. Mean forearm 3‐methylhistidine arteriovenous difference and efflux were not significantly different in the two groups. We conclude that myofibrillar protein degradation is not increased in myotonic dystrophy, even when measured in a muscle compartment selectively affected by wasting. Muscle atrophy in myotonic dystrophy is probably the result of defective anabolism rather than accelerated catabolism.
Developmental changes in human γ‐aminobutyric acida receptor subunit composition
Authors: Brooks‐Kayal A. R. , Pritchett D. B.
Published: January 2005

γ‐Aminobutyric acid (GABA) is the neurotransmitter at most inhibitory synapses in the human central nervous system. The GABAA receptor, a ligand‐gated ion channel, is the site of action of benzodiazepines, the most widely prescribed neuroactive drugs. It was recently demonstrated that there are multiple subtypes of GABAA receptors. Studies of rodents have shown that receptor subunits are developmentally controlled. The major α subunit of the adult receptor is expressed at low levels before birth. This study, using postmortem human tissue, shows that GABAA receptors are present in significant numbers in the human cerebellum at birth, and the numbers rise threefold by adulthood. Two subtypes of benzodiazepine receptors were detected by binding studies in the neonate, whereas only a single subtype of receptor was detected in the adult cerebellum. Comparison to recombinant human GABAA receptors shows that receptors containing α 1 constitute 50% of the receptors at birth and the percentage rises to over 95% by adulthood. In both cerebral cortex and cerebellum, a dramatic rise in α 1 messenger RNA was observed during development, suggesting that the complement of GABAA receptors differs in infants and adults. These findings have significant implications for normal neurodevelopment as well as for the understanding and treatment of pathophysiological states such as seizures.
Positron emission tomographic studies of dopa‐responsive dystonia and early‐onset idiopathic parkinsonism
Authors: Snow Barry J. , Nygaard Torbjoern G. , Takahashi Hirohide , Calne Donald B.
Published: January 2005

There are two major syndromes presenting in the early decades of life with dystonia and parkinsonism: dopa‐responsive dystonia (DRD) and early‐onset idiopathic parkinsonism (EOIP). DRD presents predominantly in childhood with prominent dystonia and lesser degrees of parkinsonism. EOIP presents before age 40 with parkinsonism (often with associated dystonia). Both disorders are exquisitely sensitive to levodopa, although the long‐term prognosis in each appears to be different. Some have suggested, however, that DRD is a form of EOIP. We performed positron emission tomography with 6‐fluorodopa in 10 patients with DRD and 18 patients with EOIP to study the integrity of their nigrostriatal dopaminergic systems. In DRD, we found normal striatal FD uptake. In contrast, patients with EOIP had reduced striatal FD uptake. We conclude that the pathophysiologies of DRD and EOIP are distinct. Although both disorders presumably represent a deficiency of striatal dopamine, the results suggest that in DRD dopa uptake, decarboxylation, and storage mechanisms are intact. This may explain the sustained response of DRD to low doses of levodopa. 6‐Fluorodopa positron emission tomography distinguishes DRD from EOIP.
Electroclinical signs of benign neonatal familial convulsions
Authors: Hirsch E. , Velez A. , Sellal F. , Maton B. , Grinspan A. , Malafosse A. , Marescaux C.
Published: January 2005

Benign neonatal familial convulsions comprise a distinct epileptic syndrome with a autosomal mode of transmission. The electroclinical signs of seizures in this syndrome are not yet well defined. In 3 children from two families presenting with benign neonatal familial convulsions, 14 seizures were recorded during electroencephalographic (EEG)‐video sessions. All seizures occurred during sleep, after a short arousal reaction. Seizures started with bilateral, symmetrical flattening of the EEG for 5 to 19 seconds; simulataneously there was apnea and tonic motor activity. The EEG flattening was followed by a long (1–2‐minute) bilateral discharge of spikes and sharp waves; simultaneously, there were vocalizations, chewing, and focal or generalized clonic activity. The prominence of EEG and motor abnormalities varied between the left and the right from one seizure to the next in any given child. The seizures stopped without EEG or clinical postictal depression. These electroclinical observations suggest that the convulsions of benign neonatal familial convulsions are a form of generalized tonic‐clonic seizure whose expression may be asymmetrical, probably because of the immaturity of the corpus callosum or other structures ensuring seizure synchronization.
Concentric sclerosis (Baló): Morphometric and in situ hybridization study of lesions in six patients
Authors: Yao Da‐Lin , Webster Henry deF. , Hudson Lynn D. , Brenner Michael , Liu Duo‐San , Escobar Alfonso I. , Komoly Samuel
Published: January 2005

Brain tissues from 6 patients with concentric sclerosis (Baló) were examined by in situ hybridization, immunocytochemistry, morphometry, and histological methods. The patients were 24 to 48 years old and had progressive cerebral symptoms and signs that lasted 15 to 100 days. Large demyelinative lesions, most frequent in the frontal white matter, contained alternating bands of demyelinated and partly myelinated white matter that were arranged in concentric or mosaic patterns. In the areas of demyelination, axons were relatively well preserved and there were perivascular inflammatory infiltrates. In 2 specimens, lesions contained regions with the characteristic appearance of actively demyelinating multiple sclerosis plaques. Oligodendroglial densities were highest in normal‐appearing white matter, lower in partially myelinated areas, and lowest in demyelinated areas, which also contained many hypertrophic astrocytes closely associated with oligodendroglia. Messenger RNA levels for myelin‐related proteins followed the same pattern; they were lowest in demyelinated areas, higher in partially myelinated areas, and highest in normal‐appearing white matter beyond lesion margins. Our findings suggest that concentric sclerosis is a variant of multiple sclerosis, that oligodendroglial loss is important in the pathogenesis of demyelination, and that partially myelinated areas probably represent stages of ongoing myelin breakdown rather than remyelination of previously demyelinated areas.
Localization of non–N‐methyl‐D‐aspartate glutamate receptors in normal and Alzheimer hippocampal formation
Authors: Hyman Bradley T. , Penney John B. , Blackstone Craig D. , Young Anne B.
Published: January 2005

The hippocampi and adjacent temporal cortices of 24 human brains were examined with antibodies to the GluR1, GluR2/3, and GluR4 subunits of the D,L‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid–preferring glutamate receptor. GluR1 immunoreactivity was most dense in the dentate gyrus, with lower densities in other hippocampal and cortical regions. GluR2/3 immunoreactivity was the most intense of the three antibodies, with high levels throughout most hippocampal subfields, where it was localized to cell bodies, proximal axons, and dendrites. GluR4 immunoreactivity was very sparse in all regions. In Alzheimer's disease brains, the general pattern of staining was similar to that seen in control brains. GluR1 and GluR4 immunoreactivity was seen in some but not all neuritic plaques. All three antibodies recognized some neurons undergoing neurofibrillary degeneration.
Aspartame has no effect on seizures or epileptiform discharges in epileptic children
Authors: Shaywitz B. A. , Anderson G. M. , Novotny E. J. , Ebersole J. S. , Sullivan C. M. , Gillespie S. M.
Published: January 2005

The effects of aspartame (L‐aspartyl‐L‐phenylalanine methyl ester; APM) on the neurological status of children with well‐documented seizures were examined in a randomized, double‐blind, placebo‐controlled, crossover study. We report on 10 children (5 boys, 5 girls, ages 5–13 yr) who were tested for 2 weeks each on APM and placebo (single morning dose, 34 mg/kg). Seven children had generalized convulsions with 4 also having absence episodes. One child had absence seizures and 2 had complex partial seizures only. On each arm of the study, children were admitted to the hospital for a standard 21‐lead electroencephalogram (EEG), continuous 24‐hour cassette EEG, and determination of biochemical variables in plasma and urine. Subjects completed the Subjects Treatment Emergent Symptoms Scale (STESS) and parents the Conners Behavior Rating Scale. There were no significant differences between APM and placebo in the standard EEG or 24‐hour EEG. No differences were noted for the STESS or the Conners ratings, and no differences were noted for any of the biochemical measures (except for expected increases in phenylalanine and tyrosine after APM). Our findings indicate that, in this group of vulnerable children, APM does not provoke seizures.
Evidence for long‐term survival and function of dopaminergic grafts in progressive Parkinson's disease
Authors: Lindvall Olle , Sawle Guy , Widner Håkan , Rothwell John C. , Björklund Anders , Brooks David , Brundin Patrik , Frackowiak Richard , Marsden C. David , Odin Per , Rehncrona Stig
Published: January 2005

Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine‐rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6‐L‐[18F]‐fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the “off” phase, and by a prolongation of the effect of a single dose of L‐dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L‐dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non‐grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.
Lateralization of temporal lobe epilepsy based on regional metabolic abnormalities in proton magnetic resonance spectroscopic images
Authors: Cendes Fernando , Andermann Frederick , Preul Mark C. , Arnold Douglas L.
Published: January 2005

Magnetic resonance spectroscopic imaging (MRSI) is capable of determining the spatial distribution in vivo of cerebral metabolites, including N‐acetylaspartate (NAA), a compound found only in neurons. We used this technique in 10 patients with temporal lobe epilepsy (TLE) to determine the location of maximal neuronal/axonal loss or damage and to evaluate the potential of MRSI for presurgical lateralization. Asymmetry of the relative resonance intensity of NAA to creatine was determined for mid and posterior regions of the temporal lobes defined anatomically and also for “metabolic lesions” defined as the regions of maximal abnormality on MRSI. MRSI revealed decreased relative signal intensity in at least one temporal lobe of all patients. Two patients had a widespread reduction in NAA in both temporal lobes. The region of maximal abnormality was usually in the posterior temporal lobe but sometimes in the mid temporal lobe. The side of lowest NAA was ipsilateral to the clinical electroencephalographic lateralization in all patients. Lateralization based on NAA to creatine correlated with the atrophy of amygdala and hippocampus in 8 patients who showed this on magnetic resonance imaging volumetric measurements. MRSI can demonstrate regional neuronal loss or damage that correlates with clinical electroencephalographic and structural lateralization in temporal lobe epilepsy. The ability to identify a region of maximal metabolic abnormality on spectroscopic images may confer greater sensitivity than that available from single voxel methods. The maximal metabolic abnormality may not be located in a voxel defined a priori, and based on anatomical considerations, without knowledge of the distribution of the metabolic abnormality.
Human prion diseases
Authors: Prusiner Stanley B. , Hsiao Karen K.
Published: January 2005

The prion diseases, sometimes referred to as the “transmissible spongiform encephalopathies,” include kuru, Creutzfeldt‐Jakob disease, and Gerstmann‐Sträussler‐Scheinker disease of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite intriguing evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve the aberrant metabolism of the prion protein (PrP). In many cases, the cellular prion protein is converted into the scrapie isoform by a posttranslational process that involves a conformational change. Often, the human prion diseases are transmissible to experimental animals and all of the inherited prion diseases segregate with PrP gene mutations.
Single muscle fiber analysis of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS)
Authors: Tokunaga Makoto , Mita Shuji , Murakami Tatsufumi , Kumamoto Toshihide , Uchino Makoto , Nonaka Ikuya , Ando Masayuki
Published: January 2005

We examined muscle sections from 3 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS), using single‐fiber polymerase chain reaction, histochemistry, and in situ hybridization. Most type 1 ragged‐red fibers showed positive cytochrome c oxidase activity at the subsarcolemmal region, while type 2 ragged‐red fibers had little cytochrome c oxidase activity. However, there was no difference in the amount of total (mutant and wild‐type) mitochondrial DNAs (mtDNAs) and the proportion of mutant mtDNA between type 1 and type 2 ragged‐red fibers. These observations suggest that mitochondrial proliferation and nuclear factors affect muscle pathology, including cytochrome c oxidase activity, in MELAS. Total mtDNAs were greatly increased in ragged‐red fibers (about 5–17 times over those in non–ragged‐red fibers). The proportion of mutant mtDNA was significantly higher in ragged‐red fibers (88.1 ± 5.5%) than in non–ragged‐red fibers (63.2 ± 21.6%). Thus, the amount of wild‐type mtDNA as well as mutant mtDNA was increased in ragged‐red fibers in MELAS, failing to support the contention of a replicative advantage of mutant mtDNA. The proportion of mutant mtDNA was significantly higher in the strongly succinate dehydrogenase–reactive blood vessels (83.2 + 4.2%) than in non–succinate dehydrogenase–reactive blood vessels (38.8 ± 16.2%). It seems likely that systemic vascular abnormalities involving cerebral vessels lead to the evolution of stroke‐like episodes in MELAS.
Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging
Authors: Meyrhoff D. J. , MacKay S. , Constans J.‐M. , Norman D. , Van Dyke C. , Fein G. , Weiner M. W.
Published: January 2005

We used spin‐echo magnetic resonance imaging and prton magnetic resonance spectroscopic imaging in 8 patients with probable Alzheimer's disease and in 10 age‐matched elderly control subjects to assess the effects of Alzheimer's disease on the brain. On magnetic resonance images the patients showed signficant ventricular enlargements relative to the control subjects. We measured the distribution and relative signal intensities of N‐acetylaspartate (a putative neuronal marker), of choline residues representing lipid metabolities, and of creatine‐containing metabolites in a large section of the centrum semiovale containing white and mesial gray matter. Throughout the white matter of the patients with Alzheimer's disease compared to elderly control subjects, N‐acetylaspartate was decreased relative to choline (N‐acetylaspartate–choline ration) and creatine‐containing metabolities (N‐acetylaspartate–creatine ratio) with no changes in the choline‐creatine ratio. The N‐acetylaspartate–choline ratio was lower and choline‐creatine higher in the mesial gray matter of AD patients relative to elderly controls. The posterior section of the centrum semiovale in the patients showed increased choline‐creatine and choline–N‐acetylaspartate ratios with the N‐acetylaspartate–creatine ratio unchanged between the patients and control subjects. These spectroscopic findings give suggestive evidence of diffuse axonal injury and membrane alterations in gray and white matter of the centrum semiovale in patients with Alzheimer's disease.
Repeated treatment with chimeric anti‐CD4 antibody in multiple sclerosis
Authors: Lindsey R. J. W. , Hodgkinson S. , Mehta R. , Mitchell D. , Enzmann D. , Steinman L.
Published: January 2005

We treated 21 multiple sclerosis patients with two to four doses of cM‐T412, a chimeric monoclonal antibody against the CD4 antigen found on helper/inducer T lymphocytes. The mean number (± standard error) of circulating CD4 lymphocytes decreased from 888 (± 81) cells/mm3 at baseline to 246 (± 18) after treatment. At 1 year after the last treatment, the CD4 count had recovered to only 335 (± 32). The antibody had no effect on CD8 lymphocytes, B lymphocytes, or other leukocytes. Side effects were minimal. Despite the prolonged depletion of CD4 lymphocytes, no opportunistic infections occurred. Only 1 patient had a possible allergic reaction. Most patients were clinically stable, but a few progressed. We conclude that repeated treatment with cM‐T412 is effective in reducing the number of circulating CD4 lymphocytes and has no limiting side effects.
Decreased levels of soluble amyloid β‐protein precursor are associated with Alzheimer's disease in concordant and discordant monozygous twin pairs
Authors: Wagner Steven L. , Peskind Elaine R. , Nochlin David , Provow Sally , Farrow Jeffrey S. , Pandian M. R. , Cleveland Michelle , Ito Ralph K. , Farlow Martin R.
Published: January 2005

We conducted immunochemical measurements of soluble amyloid β‐protein precursor (βPP) in cerebrospinal fluid (CSF) from three monozygous twin pairs. Two of the twin pairs are discordant for Alzheimer's disease and one pair showed concordance for Alzheimer's disease, which was confirmed neuropathologically. All affected individuals displayed substantially lower levels of soluble βPP in CSF compared with the unaffected individuals. There were no differences in total protein levels in CSF samples from the affected twins compared with those of the unaffected twins. These studies suggest that decreased soluble βPP in CSF may reflect neuropathological processes in Alzheimer's disease involving βPP.
The Denny‐brown collection: A research and teaching resource
Authors: Vilensky Joel A. , Gilman Sid , Dec Elaine M.
Published: January 2005

A large collection of potentially valuable materials compiled by the late Dr Derek Denny‐Brown is described. This consists of 2,200 films of monkeys with central nervous system lesions, associated behavior and neuropathological descriptions, and histological slides. There are also 500 films of patients with a wide assortment of diseases, including some not currently seen, like postencephalitic parkinsonism. This description will enable contemporary researchers to utilize this collection in their research and teaching programs.
Frequency and clinical correlates of anti–neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy
Authors: Nobile‐Orazio E. , Manfredini E. , Carpo M. , Meucci N. , Monaco S. , Ferrari S. , Bonetti B. , Cavaletti G. , Gemignani F. , Durelli L. , Barbieri S. , Allaria S. , Sgarzi M. , Scarlato G.
Published: January 2005

We studied the frequency and clinical correlates of different IgM specificities in 75 patients with neuropathy associated with IgM monoclonal gammopathy. Patients were tested for IgM reactivity with the myelin‐associated glycoprotein, PO, neurofilaments, and tubulin by immunoblot; with GM1, asialo‐GM1, GM2, GD1a, GD1b, sulfatide, and chondroitin sulfate C by enzyme‐linked immunosorbent assay; and with brain and nerve glycolipids by overlay highperformance thin‐layer chromatography. Forty‐two patients (56%) had high titers of IgM antibodies to MAG; 4 (5%), to sulfatide (1 also to myelin‐associated glycoprotein); 4 (5%), to the 200‐kd neurofilament (2 also to myelin‐associated protein); and 1 each, to GD1b and chondroitin sulfate C. No reactivity was found in 26 patients (35%). More patients with anti–myelin‐associated glycoprotein IgM (62%) than with unknown IgM reactivity (31%) had a predominantly sensory neuropathy (p < 0.025). Nerve conduction findings were consistent with a demyelinating neuropathy in 77% of patients reactive to myelin‐associated glycoprotein and 24% with unknown reactivity (p < 0.0001) and the mean conduction velocity of peroneal nerve was lower in the former group (22.9 m/sec) than in the latter group (39.6 m/sec) (p < 0.000001). Patients with anti–sulfatide IgM had a sensorimotor neuropathy with morphological evidence of demyelination while anti–neurofilament IgM was not associated with homogeneous findings. Patients with anti–GD1b or anti–chondroitin sulfate C IgM had a predominantly motor impairment. The frequent occurrence of anti–neural IgM antibodies in neuropathy associated with IgM gammopathy, and their frequent, though not constant association with similar neuropathy features, support their possible pathogenetic role in the neuropathy.
Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA
Authors: Liu Philip K. , Salminen Antero , He Ye Y. , Jiang Ming H. , Xue J. J. , Liu Jia S. , Hsu Chung Y.
Published: January 2005

Activation of c‐fos, an immediate early gene, and the subsequent expression of the Fos protein have been noted following focal cerebral ischemia. Fos and Jun form a heterodimer as activator protein 1 (AP‐1), which transregulates the expression of several genes. To study the postischemic events related to c‐fos expression, we suppressed the expression of c‐fos by intraventricular infusion of an antisense oligodeoxynucleotide (anti‐rncfosr115) of c‐fos mRNA. The effectiveness of anti‐rncfosr 115 was confirmed first by its capability to block in vitro c‐fos mRNA translation. In vivo, after intraventricular infusion of 32P‐labeled anti‐rncfosr115, the oligodeoxynucleotide was internalized iwthin 6 hours and detectable aslo in the nucleic acids fraction up to 41 hours. Treatment of the recovered nucleic acids with RNase H separated the labeled oligodeoxynucleotide from the nucleic acid fraction, indicating an association of the antisense oligodeoxynucleotide and cellular RNA after uptake. When focal cerebral ischemia was induced 16 hours after the infusion of anti‐rncfosr115, the postischemic increase in Fos expression and AP‐1 binding activity were suppressed. Specificity of the effect of anti‐rncfosr 115 was suggested by its failure to suppress the DNA binding activity of nuclear cyclic AMP response elements. These results support the hypothesis that increased AP‐1 binding activity following focal cerbral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c‐fos oligodeoxy‐nucleotides.
Selective vulnerability in Huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus
Authors: Richfield Eric K. , Herkenham Miles
Published: January 2005

Selective neuronal vulnerability is a key feature of the neuropathology of Huntington's disease. We used [3H]CP‐55,940, a synthetic cannabinoid, to label cannabinoid receptors in tissue sections from individuals dying with Huntington's disease and from normal control subjects. The density of cannabinoid receptors in striatum and pallidum was measured using quantitative autoradiography. There was a greater loss of cannabinoid receptors on striatal nerve terminals in the lateral pallidum compared to the medial pallidum, in Huntington's disease of all neuropathological grades. The disparity in binding density between the lateral and medial pallidum increased with higher grades of disease. There was also a greater loss of receptors in the lateral pallidum than in the putamen. The disproportionate loss of receptors in the lateral pallidum compared to the putamen increased in magnitude with severity of neuropathological grade. These data support the relative preferential loss or dysfunction of striatal neurons projecting to the lateral pallidum compared to neurons projecting to the medical pallidum. Terminals in the lateral pallidum containing cannabinoid receptors may be affected earlier or more severely than terminals in the medial pallidum, and both pallidal segments may be affected before or more severely than cell bodies or dendrites in the striatum. Terminal loss of markers may represent a response to perikaryal injury or dysfunction, or less likely, may indicate the primary site of neuronal damage in Huntington's disease.
Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy
Authors: Nemni R. , Braghi S. , Natali‐Sora M. G. , Lampasona V. , Bonifacio E. , Comi G. , Canal N.
Published: January 2005

We report the presence of serum autoantibodies directed aginst glutamic acid decarboxylase in a patient with epilepsy and palatal myoclonus not associated with brain lesions. Glutamic acid decarboxylase antibody reactivity was dependent on the presence of carboxy‐terminal amino acids, similar to that reported in patients with stiff‐man syndrome. Marked reduction in the frequency of epileptic attacks and improvement in palatal myoclonus occurred when benzodiazepine was administered and phenytoin was gradually tapered. Testing for antiglutamic acid decarboxylase antibodies may be indicated in patients with palatal myoclonus and with convulsive disorders refractory to therapy.
Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction
Authors: Baringer J. Richard , Pisani Pamela
Published: January 2005

Herpes simplex virus (HSV) is known to establish latency in human trigeminal ganglia. It has been speculated that the virus might also be present in latent fashion in normal human brain, where it might be responsible for conditions such as herpes simplex encephalitis, and less plausibly as a cause for multiple sclerosis or Alzheimer's disease. To test the possibility that HSV exists in normal human brain, we utilized the polymerase chain reaction to assess the frequency and distribution of HSV genomes in the nervous system tissues of patients dying of nonneurological causes. Nine samples were obtained in a systematic fashion from olfatory bulb, gyrus rectus, hippocampus amygdala, calcarine cortex, pons, medulla, cerebellum, and trigeminal ganglia from each of 40 individuals dying of nonneurological disease. HSV genomes were sought in each sample using primers from four regions of the HSV genome. The primers identified in 26 (65%) of 40 samples of trigeminal ganglia. From 30 patients seropositive to HSV, sequences were amplified from 23 (77%). HSV genomic sequences could be amplified and detected in 14 (35%) of 40 brains. The positive areas included medulla, olfactory bulbs, pons, gyrus rectus, amygdala, and hippocampus. The study has confirmed the previous demonstration of latent HSV in trigeminal ganglia in normal humans. The frequency of latent HSV in trigeminal ganglia is in general agreement with results obtained by explanation of ganglia. In addition HSV sequences could be amplified from a variety of other central nervous system structures, suggesting the presence of the virus in latent state in normal central nervous system. Wheter the virus is important in the pathogenesis of nervous system diseases is not answered by these studies. However, it appears that the virus, commonly latent in trigeminal ganglia, may be detectable with lesser frequency in normal brain.
Hippocampal neuronal loss and regional hypometabolism in temporal lobe epilepsy
Authors: Henry Thomas R. , Babb Thomas L. , Engel Jerome , Mazziotta John C. , Phelps Michael E. , Crandall Paul H.
Published: January 2005

The pathophysiology of widespread interictal hypometabolism in temporal lobe epilepsy is unknown but might reflect neuronal loss and diaschisis. We found no significant correlation between any cortical region's metabolism on preoperative {18F} fluorodeoxyglucose positron emission tomography and neuronal density of resected hippocampi in 40 patients. We conclude that hippocampal neuronal loss and diaschisis cannot account for the regional interictal hypometabolism of temporal lobe epilepsy.
Myopathy and paraproteinemia with serum igm binding to a high‐ molecular‐weight muscle fiber surface protein
Authors: Al‐Lozi M. T. , Pestronk A. , Yee W. C. , Flaris N.
Published: January 2005

We evaluated a 69‐year‐old man with Waldenström's macroglobulinemia (IgM‐κ M‐protein) and progressive weakness over 2 to 3 years. The neurological examination showed symmetrical, predominantly proximal weakness. Electrophysiological testing revealed small brief motor unit potentials with fibrillations and positive sharp waves consistent with an irritative myopathy. The muscle biopsy specimen showed myopathic changes including variation in fiber size and increased connective tissue but no inflammation. IgM‐κ but not IgM‐λ was deposited along the surface of muscle fiber membranes. Serum IgM‐κ but not IgM‐λ from the patient stained the surface of normal human muscle fibers but not other regions of muscle fibers or other tissues. The serum IgM‐κ at dilutions up to 1: 512,000 bound to a high‐molecular‐weight muscle protein by Western and dot blot studies. By enzyme‐linked immunosorbent assay and Western blot analysis, serum IgM‐κ bound specifically to the muscle protein and not to other muscle or neural antigens, including GM1 ganglioside, myelin‐associated glycoprotein, and sulfatide. We conclude that the myopathy in our patient is probably related to the presence of serum IgM‐κ antibodies directed against a muscle surface antigen. Characterization of the target antigen, a high‐molecular‐weight protein located specifically in muscle, should further elucidate the pathogenesis of this presumably humorally mediated immune myopathy.
The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease
Authors: Saitoh T. , Xia Y. , Chen X. , Masliah E. , Galasko D. , Shults C. , Thal L. J. , Hansen L. A. , Katzman R.
Published: January 2005

Approximately one‐fourth of neuropathologically confirmed cases of Alzheimer's disease (AD) also have brainstem and neocortical Lewy bodies, constituting a Lewy body variant of AD. Because Lewy bodies are a pathologic hallmark of Parkinson's disease (PD), this subpopulation of AD subjects may have the same risk factors as PD subjects. Analyses of the cytochrome P450 CYP2D6‐debrisoquine 4‐hydroxylase mutant B allele, a susceptibility gene for PD, revealed a higher representation of this allele in the Lewy body variant of AD than in pure AD or non‐AD without Lewy bodies.
Drenching sweats as an off phenomenon in parkinson's disease: Treatment and relation to plasma levodopa profile
Authors: Sage Jacob I. , Mark Margery H.
Published: January 2005

We followed 4 patients with Parkinson's disease and severe, intermittent, drenching sweats. One patient was studied with serial plasma levodopa levels and simultaneous clinical examinations. She was observed during a severe sweating episode; this was associated with subtherapeutic plasma levodopa levels (low dopa state). All 4 patients' sweats responded favourably to the institution of agonist therapy. Drenching sweats should be considered part of the spectrum of off‐period levodopa‐related fluctuations in Parkinson's disease.
Staggering gait in medical history
Authors: Schiller Francis
Published: January 2005

Drunkenness and senility were recognized early as the basis of a staggering gait. To these were added venereal excesses, hence syphilis. Medical and scientific concerns began to be focused on “locomotor ataxia” in the 19th century with the systematic development of neuroanatomy and physiology. Rolando and Flourens were followed by Romberg and Todd, and later Friedreich, who all gave the spinal cord temporal precedence as a culprit over the cerebellum–and there were some forerunners. New spinal sensory pathways were delineated by Goll, Flechsig, and Gowers. In France, we must specially credit Duchenne as well as Bouillaud, and later Babinski, Marie, and Dejerine, for correcting, differentaiting, extending, and underpinning current concepts. Failures of input and output, of conduction and central coordination were invoked and explained, among them the vestibular apparatus, as well as the causation by neoplasms, demyelination, degeneration, and infarction affecting even the frontal lobe, thalamus, and basal ganglia Clinical testing was brought up to 20th‐century standards essentially by Sherrington and Bárány, followed by Dandy, the neurosurgeon who showed how to replace ventricular fluid by air, more recently made obsolete by modern roentgenographic procedures. And tabes dorsalis, once the chief culprit, has practically become a medical anachronism thanks to penicillin.
Acute human stroke studied by whole brain echo planar diffusion‐weighted magnetic resonance imaging
Authors: Warach Steven , Gaa Jochen , Siewert Bettina , Wielopolski Piotr , Edelman Robert R.
Published: January 2005

Our purpose was to use whole brain echo planar magnetic resonance imaging (MRI) to identify and characterize diffusion abnormalities in acute cerebral ischemia. We studied 40 patients as early as 3 hours after onset of signs and symptoms of cerebral ischemia. Diffusion‐weighted imaging (DWI) of the entire brain could be completed in 3 seconds or, using seven different diffusion sensitivities (maximum b=1,271 sec/2), in 48 seconds. Measurements and synthetic maps were made of apparent diffusion coefficients (ADC), a physiological parameter that characterizes the self‐diffusion of water in tissue. Early ischemic lesions were identified with DWI as hyperintense regions of decreased ADC in all patients who subsequently developed infarction, before changes were evident on conventional MRI in cases studied earlier than 6 hours after onset of ischemic symptoms. Lesions as small as 4 mm in diameter were identified. The extent of lesions within white matter was best defined by controlling for the anisotropic effect of axonal orientation. The mean ADC (± SD) for control regions in the 36 patients was 9.15 (± 2.91) × 10−4 mm2/sec. Mean ADC of ischemic regions was 56% of control values at 6 hours or less and stayed significantly reduced for 3 to 4 days after onset of ischemia. The relative ADC increased progressively over time to be pseudonormalized at 5 to 10 days and elevated in the chronic state, making the distinction of acute lesions adjacent to chronic infarcts readily apparent. DWI with echo planar imaging measures a unique physiological parameter that is sensitive to ischemic changes before conventional MRI. Its potential role in the quantitative study of human stroke pathophysiology and therapeutics is the subject of further investigation.