bluuebunny/crossref_metadata_2025 huggingface dataset:
Responsiveness of the somatosensory system after nerve injury and amputation in the human hand
Authors: Schady W. , Braune S. , Watson S. , Torebjörk H. E. , Schmidt R.
Published: January 2005

We studied the responsiveness of the somatosensory system in humans after prolonged deprivation of peripheral input. Eight patients with traumatic transection of the median or ulnar nerve and 6 patients with amputation of a finger or hand underwent microneurography and intraneural stimulation. Bundles of nerve fibers were electrically stimulated through a microelectrode placed in the affected nerve proximally to the site of damage or in the case of amputees, in a nerve fascicle supplying the stump. During intraneural stimulation the subjects with nerve injuries reported distinct percepts in the hypoesthetic skin. Their projections were usually confined to the territory of a single or two adjacent palmar digital nerves, similar to the fascicular territories of healthy nerves in control subjects, but there was much less microneurographically recordable afferent activity than in normal subjects. In amputees intraneural stimulation evoked sensations in a phantom digit or digits in over three fourths of the fascicles studied. We conclude that (1) the somatosensory system remains able to process information from a nerve fascicle that has lost its cutaneous territory, and (2) somatosensory localization remains accurate despite the presumed central reorganization that takes place after nerve division or amputation. This lack of functional adaptation has important implications with regard to our understanding of human central nervous system plasticity.
Parkinson's disease and brain levels of organochlorine pesticides
Authors: Fleming Lora , Mann John B. , Bean Judy , Briggle Thomas , Sanchez‐Ramos Juan R.
Published: January 2005

Epidemiological studies have suggested an etiologic relationship between pesticide exposure and Parkinson's disease (PD). Organochlorine pesticides were assayed in postmortem brain samples from 20 PD, 7 Alzheimer's disease (AD), and 14 nonneurological control cases. The three groups were similar in age at death, sex, and demographic variables. Only two of 16 pesticide residues screened were detected. A long‐lasting residue of DDT (pp‐DDE) was found in the majority of cases of PD and AD, as well as in all the control cases; pp‐DDT was significantly more likely to be found in AD controls than the PD cases (Fisher's exact two‐tailed, p = 0.04). Dieldrin was detected in 6 of 20 PD brains, 1 of 7 AD, and in none of 14 control samples. Despite the relatively small number of brains assayed, the association between Dieldrin and the diagnosis of PD was highly significant (p = 0.03). Dieldrin, a lipid‐soluble, long‐lasting mitochondrial poison, should be investigated as a potential etiological agent of Parkinsonism.
Sequence heterogeneity of HTLV‐I proviral DNA in the central nervous system of patients with HTLV‐I–associated myelopathy
Authors: Kira Jun‐ichi , Koyanagi Yoshio , Yamada Takeshi , Itoyama Yasuto , Tateishi Jun , Akizuki Shin‐ichiro , Kishikawa Masao , Baba Eishi , Nakamura Minoru , Suzuki Jun , Nakamura Tatsufumi , Nakamura Naomi , Yamamoto Naoki , Goto Ikuo
Published: January 2005

The nucleotide sequence of human T‐lymphotropic virus type I (HTLV‐I) in central nervous system tissue was determined in 3 autopsy cases with HTLV‐I–associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 1 seropositive carrier without HAM/TSP but with multiple sclerosis. All HAM/TSP samples (3 spinal cords and 2 brains) and the sample from the seropositive carrier without HAM/TSP (brain) were positive for HTLV‐I env (5146–6681), pX5′ (6549–7494), and pX3′ (7354–8276) regions by the two‐step polymerase chain reaction method. A nucleotide sequence analysis of the pX5′ and pX3′ polymerase chain reaction products from nucleotides 6631 to 8259 revealed heterogeneity of the HTLV‐I genome in all cases. It is notable that 13 of 50 clones derived from the pX3′ polymerase chain reaction products were defective in the tax open reading frame while 7 were defective in the rex open reading frame in the HAM/TSP samples. All 17 clones from 1 HAM/TSP case were defective in the pX open reading frame II. One nucleotide insertion at 7784 creating a frame shift in both tax and rex was seen in all 3 HAM/TSP cases but not in the HTLV‐I carrier without HAM/TSP. The pX‐defective mutants found frequently in the central nervous system may contribute to the neural damage, since the pX gene products are essential for the transactivation of various cellular genes as well as for viral replication.
X‐linked pachygyria and agenesis of the corpus callosum: Evidence for an X chromosome lissencephaly locus
Authors: Berry‐Kravis Elizabeth , Israel Jeanette
Published: January 2005

A family of 5 affected male infants in 2 generations with an X‐linked pattern of inheritance is described. All affected infants manifested intractable seizures, severe psychomotor retardation, growth failure, microphallus, and death during infancy. Three of the affected patients had radiological studies that demonstrated findings consistent with pachygyria‐agyria and agenesis of the corpus callosum. We believe that this family represents a form of X‐linked pachygyria‐agyria (lissencephaly) that has not been described previously and suggests a locus for lissencephaly on the X chromosome.
Positron emission tomographic measurement of cerebral blood flow and temporal lobectomy
Authors: Theodore William H. , Gaillard William D. , Sato Susumu , Kufta Conrad , Leiderman Deborah
Published: January 2005

We used positron emission tomography (PET) and bolus injection of H215O to measure interictal cerebral blood flow (CBF) in 32 patients who had temporal lobectomy for uncontrolled complex partial seizures. Seizure focus localization was confirmed by ictal video–electroencephalographic (video‐EEG) telemetry, and patients who had imaging findings suggesting the presence of a tumor were excluded. PET‐CBF studies were interpreted using a standard template by raters blinded to EEG and clinical data, and were not used in surgical planning. After surgery, patients were followed for 32 ± 18 months. Twenty‐six patients were seizure free and 6 had persistent seizures. Mean lateral temporal hypoperfusion was 8 ± 14% in patients who became seizure free and 9 ± 6% in patients with persistent seizures. Fourteen patients had at least 15%, and 11 at least 20% hypoperfusion, but were not more likely to be seizure free. Three additional patients had 15 to 20% hypoperfusion in the temporal lobe contralateral to their EEG focus. PET measurement of CBF using bolus H215O should not be used to help select patients for temporal lobectomy.
Viability thresholds and the penumbra of focal ischemia
Authors: Hossmann K‐A.
Published: January 2005

The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought ot suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolariztion (<0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy‐dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.
Polymyositis inpatients infected with human T‐cell leukemia virus type I: The role of the virus in the cause of the disease
Authors: Leon‐Monzon Marta , Illa Isabel , Dalakas Marinos C.
Published: January 2005

To investigate the mechanism of polymyositis in human T‐cell leukemia virus type 1 (HTLV‐I) infection, we studied 6 HTLV‐I–positive patients, 3 with polymyositis and 3 with adult T‐cell leukemia but without clinical signs of muscle disease, by (a) quantitative single or double immunocytochemistry on serial 4‐μm‐thick muscle biopsy sections using antibodies to lymphocyte subsets, major histocompatibility complex (MHC) antigens, and HTLV‐I proteins; (b) polymerase chain reaction using HTLV‐I primers in the RNA and DNA extrcted from 50 μg of muscle tissue or from serial 5‐μm‐thick fresh‐frozen tissue sections; and (c) cocultures of the patients' HTLV‐I–positive peripher blood lymphocytes with their homologous muscles searching for replication of HTLV‐I within the myotubes. In the muscle of patients with HTLV‐I–associated myopathy, the predominant endomysial cells surrounding healthy muscle fibers were CD8+ cells followed by CD4+ cells and macrophages. MHC‐I antigens were ubiquitous in the muscles of all 6 patients, even in those without endomysial inflammation. HTLV‐I sequences were amplified from the whole muscle biopsy specimens but the cells harboring viral antigens were rare endomysial macrophages and not muscle fibers. Although HTLV‐I sequences were amplified from all the patients' peripheral blood lymphocytes, these cells did not exert myotoxicity or resulted in viral replication in cocultures with their homologous myotubes. We conclude that in HTLV‐I polymyositis (a) the HTLV‐I sequences amplified from the whole muscle biopsy specimens are related to scattered HTLV‐I–positive endomysial macrophages; (b) HTLV‐I and HTLV‐I–positive lymphocytes do not infect the muscle in vivo or in vitro; and (c) the virus, which perists in tissues other than muscle, triggers the activationof autoaggressive T cells that cause a T‐cell–mediated and MHC‐I–restricted myocytotoxicity.
Age‐dependent decline of nigrostriatal dopaminergic function: A positron emission tomographic study of grandparents and their grandchildren
Authors: Cordes Michael , Snow Barry J. , Cooper Sandra , Schulzer Michael , Pate Brian D. , Ruth Thomas J. , Calne Donald B.
Published: January 2005

Despite postmortem evidence for an age‐related decline in nigrostriatal dopaminergic function, positron emission tomography (PET) studies have produced inconsistent results. This may be due to differences inmethods or of subject selection. To investigate further the effect of age on dopaminergic function, we performed PET with 6‐L‐[18F]fluorodopa (FD) on 12 pairs of grandchildren and their grandparents. The FD uptake rate constant (Ki) was calculated using a graphical method for the whole striatum to avoid confounding of the results by striatal atrophy. The mean Ki was significantly lower in grandparents (p = 0.020). These PET observations represent in vivo confirmation of postmortem evidence that nigrostriatal dopaminergic function declines with aging.
Oral administration of acetylcholine receptor: Effects on experimental myasthenia gravis
Authors: Okumura Seiichi , McIntosh Kevin , Drachman Daniel B.
Published: January 2005

The abnormality in myasthenia gravis (MG) is a deficiency of acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody‐mediated autoimmune attack. Although immunosuppressive drugs are usually beneficial in MG, they produce generalized suppression of the immune system. Treatment should specifically inhibit the immune response to AChR. Oral administration of an antigen may induce specific tolerance and has recently been tested for treatment of several cell‐mediated experimental and human autoimmune diseases. In this study, we investigated the effects of oral administration of AChR in an experimental rat model of MG (EAMG), which is antibody mediated. Lewis rats were fed various doses of purified or unpurified Torpedo AChR, or a control antigen, ovalbumin (OVA). They were then immunized with AChR or OVA. We measured antibody responses to Torpedo AChR or OVR, autoantibody responses to rat AChR, cellular responses, cellular suppressive effects, and clinical status. Our results showed that AChR feeding prevented clinical signs of EAMG. It initially primed, then inhibited, antibody responses to foreign (Torpedo) AChR and self (rat) AChR, with a delayed onset. Cellular responses to AChR, measured by lymphocyte proliferation and interleukin‐2 production, were markedly inhibited. The effects were dose dependent. Unpurified AChR given in comparable amounts was far less effective than pure AChR. OVA feeding had similar, but even more potent effects on humoral and cellular immune responses to OVA, but did not inhibit clinical EAMG or AChR responses. Moderate nonspecific suppression by splenic T cells from orally trated animals was demonstrated in vitro. We conclude that oral therapy is beneficial in EAMG and may prove effective in MG patients. Early priming and delayed inhibition suggest that a molecule with less immunogenic potential than intact AChR might be more effective as a therapeutic agent.
Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia
Authors: Mesulam ‐Marsel , Geula Changiz
Published: January 2005

In a sample of consecutively received, 4 demented and 4 age‐matched nondemented brains, the total cortical area covered by plaque‐like Aβ amyloid and butyrylcholinesterase deposits was measured at two regions of the temporal cortex with the help of computed densitometry. Demented as well as age‐matched nondemented brains contained Aβ and butyrylcholinesterase‐positive plaques. The total cortical area covered by the Aβ precipitates was higher in demented individuals but there was overlap with the values seen in the specimens from nondemented individuals. The proportinal plaque area displaying butyrylcholinesterase reactivity was very significantly and fivefold to sixfold higher in the demented than in the nondemented group and there was no overlap between the two populations. Diffuse Aβ deposits in nondemented elderly brains may represent a benign or preclinical stage of plaque deposition with relatively little pathological effect on brain tissue and mental function. Our results suggest that the progressively more extensive butyrylcholinesterase reactivity of plaques may participate in their transformation from a relatively benign form to pathogenic structures associated with neuritic degeneration and dementia.
Very long chain fatty acids in X‐linked adrenoleukodystrophy brain after treatment with Lorenzo's oil
Authors: Poulos Alfred , Gibson Robert , Sharp Peter , Beckman Kaye , Rattan‐Smith Padraic G
Published: January 2005

The fatty acid composition of postmortem brain and liver from an adrenoleukodystrophy patient whose diet was supplemented with Lorenzo's oil (glycerol trioleate and glycerol trierucate) for 9 months was determined. The diet depressed plasma and liver saturated very long chain fatty acids (24:0 and 26:0) and increased plasma and liver erucic (22:1) and nervonic (24:1) acids. The levels of plasma linoleic (18:2 n‐6), eicosopentaenoic (20:5 n‐3), and docosahexaenoic (22:6 n‐3) acids were also reduced, while the biochemical marker for essential fatty acid deficiency (20:3 n‐9) was markedly increased in liver. However, we were unable to detect any corresponding changes in brain indicating that little erucic acid crossed the blood–brain barrier. Our findings suggest that dietary supplementation with Lorenzo's oil is of limited value in correcting the accumulation of saturated very long chain fatty acids in the brain of patients with adrenoleukodystrophy.
Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains
Authors: Bö Lars , Dawson Ted M. , Wesselingh Steven , Möurk Sverre , Choi Steven , Kong Pei Ann , Hanley Daniel , Trapp Bruce D.
Published: January 2005

The amount of messenger RNA encoding human inducible nitric oxide synthase and the presence and distribution of NADPH diaphorase were determined in tissue sections from multiple sclerosis (MS) and control brains. Levels of human nitric oxide synthase messenger RNA were markedly elevated in MS brains when compared to normal control brains. NADPH diaphorase activity, a histochemical stain reflecting nitric oxide synthase catalytic activity, was detected in reactive astrocytes in active demyelinating MS lesions and at the edge of chronic active demyelinating lesions. Control brains did not contain NADPH diaphorase–positive astrocytes. These results implicate the free radical nitric oxide in the pathogenesis of demyelinating MS lesions.
Manganese intoxication and chronic liver failure
Authors: Hauser Robert A. , Zesiewicz Theresa A. , Rosemurgy Alexander S. , Martinez Carlos , Olanow C. W.
Published: January 2005

Manganese intoxication and chronic liver failure are associated with strikingly similar clinical, imaging, and pathological abnormalities. As manganese is primarily cleared by the liver, inadequate elimination of manganese absorbed from the normal diet may lead to manganese overload in patients with liver disease. We report a significant elevation of blood manganese concentration in 3 patients with biopsy‐proved hepatic cirrhosis who exhibited neurological dysfunction and characterstic abnormal signal hyperintensity in the globi pallidi and substantia nigra on T1‐weighted magnetic resonance imaging. We speculate that manganese accumulation in the brain accounts for the magnetic resonance imaging abnormalities and contributes to neurological dysfunction in patients with liver disease.
Histometric effects of ciliary neurotrophic factor in wobbler mouse motor neuron disease
Authors: Ikeda Ken , Wong Vivien , Holmlund Thomas H. , Greene Tom , Cedarbaum Jesse M. , Lindsay Ronald M. , Mitsumoto Hiroshi
Published: January 2005

We investigated the histological effects of ciliary neurotrophic factor on degenerating motor neurons, their axons, and skeletal muscles in 68 wobbler mice with motor neuron disease. Treatment consisted of recombinant rat or human ciliary neurotrophic factor (or a vehicle solution), 1‐mg/kg subcutaneous injection, three times per week for 4 weeks after the clinical diagnosis. The number of motor neurons immunoreactive for calcitonin gene‐‐related peptide was higher in mice receiving rat ciliary neurotrophic factor (p < 0.03), although the number of choline acetyltransferase‐reactive neurons was the same in both treated and untreated control groups. Treatment did not prevent vacuolar degeneration of motor neurons. In mice treated with human ciliary neurotrophic factor, the percentage of axons undergoing acute axonal degeneration (myelin ovoids) was smaller in the entire C5 ventral root (p < 0.02) and in the musculocutaneous nerve (p < 0.04), and the number of myelinated nerve fibers was 30% higher in both nerves (p < 0.01 and p < 0.04, respectively) than in controls. In ciliary neurotrophic factor‐treated mice, the biceps muscle weight was 20% greater, the mean muscle fiber diameter was 30% larger, and the number of atrophied muscle fibers was 75% lower than that in the vehicle‐treated wobbler mice (p < 0.001 for all three results). The number of terminal axonal branching points and the mean length of motor end‐plates were also higher in the ciliary neurotrophic factor‐treated mice (p < 0.001 and p < 0.02, respectively). Our study thus suggests that ciliary neurotrophic factor slowed neuronal degeneration, enhanced axonal regeneration at both the proximal and distal motor axons, and reduced muscle atrophy in this motor neuron disease.
Differentiation of multiple system atrophy from idiopathic Parkinson's disease using proton magnetic resonance spectroscopy
Authors: Davie C. A. , Wenning G. K. , Barker G. J. , Tofts P. S. , Kendall B. E. , Quinn N. , McDonald W. I. , Marsden C. D. , Miller D. H.
Published: January 2005

Proton magnetic resonance spectroscopy, localized to the lentiform nucleus, was carried out in 7 patients with the pure or predominantly striatonigral variant (SND) of multiple system atrophy (MSA), 5 patients with the olivopontocerebellar variant of MSA, 9 patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD), and 9 healthy age‐matched controls. The MSA group with predominantly striatonigral involvement showed a significant reduction in the N‐acetylaspartate (NAA)/creatine ratio (median, 1.19; range, 0.96–2.0; p < 0.02) compared with the NAA/creatine ratio (median, 1.82; range, 1.19–2.31; p > 0.5). The NAA/creatine ratio was markedly reduced in 6 of the SND patients and in only 1 IPD patient. The choline/creatine ratio was also significantly lower in the SND group (median, 1.02; range, 0.91–1.23; p < 0.04) compared with the control group (median, 1.22; range, 1.05–1.65). The IPD group showed a normal lentiform choline/creatine ratio (median, 1.13; range, 0.89–1.65; p = 0.25) compared with controls. The olivopontocerebellar group also showed a significant reduction in the NAA/creatine ratio from the lentiform nucleus (median, 1.47; range, 1.22–1.68; p < 0.01) compared with the controls as well as a nonsignificant reduction in the choline/creatine ratio (median, 0.93; range, 0.85–1.27; p < 0.4). In vivo quantification of absolute metabolite concentrations was possible in 7 MSA patients and 6 controls and confirmed an absolute reduction of choline‐containing compounds and NAA in the MSA group compared with controls with no significant difference in the creatine concentrations between the MSA groups probably reflects neuronal loss, occurring predominantly in the putamen. Proton magnetic resonance spectroscopy is a useful, noninvasive technique to help differentiate MSA from IPD.
A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p
Authors: Vahedi Katayoun , Joutel Anne , van Bogaert Patrick , Ducros Anne , Maciazeck Jacqueline , Bach Jean FrancOis , Bousser Marie Germaine , Tournier‐Lasserve Elisabeth
Published: January 2005

Hereditary paroxysmal cerebellar ataxia (HPCA) is an autosomal dominant disorder characterized by the recurrence of intermittent attacks of vestibulocerebellar ataxia lasting from 15 minutes to a few days. The number of attacks is often significantly decreased by acetazolamide treatment. Neurological examination shows a permanent gaze‐evoked nystagmus, as well as a mild cerebellar ataxia in most patients. The paroxysmal feature of this condition is shared by another autosomal dominat neurological condition, familial hemiplegic migraine (FHM), a condition in which permanent cerebellar signs have also been reported in some families. Although hemiplegic migraine has never been reported in patients with HPCA, we hypothesized, based on the latter observations, that HPCA and FHM may be allelic disorders. We previously mapped a gene responsible for FHM on the short arm of chromosome 19. We performed linkage analysis with 6 markers spanning the FHM interval on a large HPCA family. Significant lod scores were obtained with 3 markers: D19S244 (LS =; 3.71), D19S221 (3.60), and D19S226 (3.54) at theta = 0. Haplotype and multipoint linkage analysis established that the most likely location was the same interval of 30 cM encompassing the chromosome 19 FHM locus.
An allelic association study of monoamine oxidase B in parkinson's disease
Authors: Ho S. L. , Kapadi A. L. , Ramsden D. B. , Williams A. C.
Published: January 2005

A single‐stranded conformational polymorphism in the monoamine oxidase B gene was shown to be A or G, 36 bases upstream from the intron 13‐exon 14 boundary. An allelic association study revealed no statistically significant associations between this single‐base polymorphism and Parkinson's disease, unlike the results of a previous study.
Visual system abnormalities in adrenomyeloneuropathy
Authors: Kaplan Peter W. , Kruse Bernd , Tusa Ronald J. , Shankroff Jan , Rignani Joellen , Moser Hugo W.
Published: January 2005

We studied the visual system in 59 men with adrenomyeloneuropathy. Pattern‐reversal visual evoked potentials, magnetic resonance imaging, and clinical examination revealed that visual pathways are affected in 63% of patients, involving the optic discs, optic nerves, lateral geniculate bodies, optic radiations, and parietooccipital cortex. This indicates both primary demyelination of the optic nerves and discs, and more diffuse involvement of postchiasmal structures.
Positron emission tomography studies on the dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atrophy
Authors: Rinne J. O. , Burn D. J. , Dphil C. J. Mathias , Quinn N. P. , Marsden C. D. , Brooks D. J.
Published: January 2005

Ten patients with sporadic olivopontocerebellar atrophy and autonomic failure were studied with positron emission tomography. Subjects underwent both an {11C}diprenorphine and an {18F}fluorodopa scan. The mean caudateoccipital uptake ratio for {11C}diprenorphine was significantly reduced to 88% and the putamen‐occipital uptake ratio to 85% of the control values. Individually, 4 of the 10 patients had significantly reduced opioid binding in the putamen. Mean putamen {18F}fluorodopa uptake was significantly diminished (to 71% of the control mean); individually 7 patients had significantly reduced uptake. There was a significant positive correlation between putamen‐occipital uptake ratios for {11C}diprenorphine and putamen uptake of {18F}fluorodopa. Our results suggest that subclinical nigrostriatal dysfunction is present in the majority of patients with sporadic olivopontocerebellar atrophy, in accordance with it being part of the spectrum of multiple system atrophy.
Dentatorubral‐pallidoluysian atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat
Authors: Ikeuchi Takeshi , Koide Reiji , Tanaka Hajime , Onodera Osamu , Igarashi Shuichi , Takahashi Hitoshi , Kondo Rui , Ishikawa Atsushi , Tomoda Akemi , Miike Teruhisa , Keiko Sato  , Ihara Yuetsu , Hayabara Toshiyuki , Isa Fumiko , Tanabe Hitoshi , Tokiguchi Susumu , Hayashi Masataka , Shimizu Natsue , Ikuta Fusahiro , Naito Haruhiko , Tsuji Shoji
Published: January 2005

Dentatorubral‐pallidoluysian atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of dentatorubral‐pallidoluysian atrophy. The size of the expanded alleles was well correlated with the age at onset (r = ‐0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62‐79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non‐progressive myoclonus epilepsy phenotype showed smaller expansions (54‐67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of dentatorubral‐pallidoluysian atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of dentatorubral‐pallidoluysian atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.
Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation
Authors: Shoffner John M. , Brown Michael D. , Stugard Carol , June Albert S. , Pollock Stephen , Haas Richard H. , Kaufman Allan , Koontz Deborah , Kim Yoon , Graham Jennifer R. , Smith Edwin , Dixon John , Wallace Douglas C.
Published: January 2005

A Novemberel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue‐specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigress. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The dAugusthter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood‐onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's herediatary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.
Leptomeningeal tumor in primarchy central nervous system lymphoma: Recognition, significance, and implications
Authors: Balmaceda Casilda , Gaynor Jeffrey J. , Sun Ming , Gluck Jose Torres , DeAngelis Lisa M.
Published: January 2005

The true incidence of leptomeningeal tumor in priMarchy central nervous system lymphoma is unknown. We studied prospectively the cerebrospinal fluid profile of 96 patients without acquired immunodeficiency syndrome but with priMarchy central nervous system lymphoma at diagnosis, at completion of treatment, and at recurrence. Magnetic resonance images and pathology slides were examined for evidence of leptomeningeal tumor. Leptomeningeal tumor was diagnosed by (1) positive findings on cerebrospinal fluid cytology, (2) leptomeningeal or subependymal enhancement on magnetic resonance imaging, or (3) pathological evidence of leptomeningeal tumor. We recorded whether treatment directed against the leptomeninges was given. Cerebrospinal fluid was examined in 86 of 96 patients at diagnosis and 29 of 42 at recurrence. The incidence of leptomeningeal tumor was 42% at diagnosis and 41% at recurrence. Only elevated levels of protein and lactate dehydrogenase isoenzyme‐5 were significantly associated with leptomeningeal tumor (r= 0.012,p= 0.016, respectively). Treatment against the leptomeninges was significantly associated with the probability of achieving a complete response and a longer freedom from relapse. Patients older than 50 years had a worse disease‐specific survival but a similar probability of responding to therapy as younger patients. Our data show that leptomeningeal tumor in priMarchy central nervous system lymphoma is more prevalent than originally thought, and indicate the need for therapy inclusive of the leptomeninges in all patients.
Aging, energy, and oxidative stress in neurodegenerative diseases
Authors: Beal M. Flint
Published: January 2005

The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism, excitotoxicity, and for oxidative damage is increasingly compelling. It is likely that there is a complex interplay between these mechanisms. A defect in energy metabolism may lead to neuronal depolarization, activation of N‐methyl‐D‐aspartate excitatory amino acid‐receptors, and increases in intracellular calcium, which are buffered by mitochondria. Mitochondria are the major intracellular source of free radicals, and increased mitochondrial calcium concentrations enhance free radical generation. Mitochondrial DNA is particularly susceptible to oxidative stress, and there is evidence of age‐dependent damage and deterioration of respiratory enzyme activities with normal aging. This may contribute to the delayed onset and age dependence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Potential therapeutic approaches include glutamate release inhibitors, excitatory amino acid antagonists, strategies to improve mitochondrial function, free radical scavengers, and trophic factors. All of these approaches appear promising in experimental studies and are now being applied to human studies.
A Greek‐American kindred with autosomal dominant, levodopa‐responsive parkinsonism and anticipation
Authors: Markopoulou K. , Wszolek Z. K. , Pfeiffer R. F.
Published: January 2005

Interest is increasing concerning the role of genetic factors in the etiology of Parkinson's disease. We report the analysis of a Greek‐American kindred with levodopa‐responsive parkinsonism. Of the 98 individuals present in six generations of this pedigree, 16 individuals in three successive generations have developed parkinsonism. Affected members were examined both in Greece and in the United States. The clinical presentation consisted of asymmetric rigidity, resting tremor, bradykinesia, and postural instability, and symptoms were responsive to levodopa. The disease appears to be inherited in an autosomal dominant manner. The inheritance pattern and the development of parkinsonism in successive generations on two continents challenges environmental factors as the primary cause in the pathogenesis of parkinsonism in this kindred. Anticipation is present in this pedigree. The affected members in the third generation developed symptoms at ages 50 to 71, in the fourth at ages 40 to 55, and in the fifth at age 31 years. This is another example of a neurodegenerative disease with autosomal dominant inheritance and anticipation. A molecular genetic analysis of this pedigree is in progress.
Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease
Authors: Freeman Thomas B. , Olanow C. Warren , Hauser Robert A. , Nauert G. Michael , Smith Donald A. , Borlongan Cesario V. , Sanberg Paul R. , Holt Douglas A. , Kordower Jeffrey H. , Vingerhoets Francois J. G. , Snow Barry J. , Calne Donald , Gauger Lisa L.
Published: January 2005

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18‐fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the „off”︁ state, Schwab‐England disability score during the „off”︁ state, percent „off”︁ time, and percent „on”︁ time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.
Distinction between peroxisomal bifunctional enzyme and acyl‐CoA oxidase deficiencies
Authors: Watkins Paul A. , McGuinness Martina C. , Raymond Gerald V. , Hicks Beth A. , Sisk Jeanne M. , Moser Ann B. , Moser Hugo W.
Published: January 2005

The clinical distinction between patients with a disorder of peroxisome assembly (e.g., Zellweger syndrome) and those with a defect in a peroxisomal fatty acid β‐oxidation enzyme can be difficult. We studied 29 patients suspected of belonging to the latter group. Using complementation analysis, 24 were found to be deficient in enoylcoenzyme A hydratase/3‐hydroxyacylcoenzyme A dehydrogenase bifunctiona enzyme and 5 were deficient in acyl‐CoA oxidase. Elevated plasma very long‐chain fatty acids (VLCFA), impaired fibroblast VLCFA β‐oxidation, decreased fibroblast phytanic acid oxidation, normal plasmalogen synthesis, normal plasma l‐pipecolic acid level, and normal subcellular catalase distribution were characteristic findings in both disorders. The elevation in plasma VLCFA levels and impairment in fibroblast VLCFA β‐oxidation were more severe in bifunctional‐deficient than in oxidase‐deficient patients. The clinical course in bifunctional deficiency (profound hypotonia, neonatal seizures, dysmorphic features, age at death ∼9 months) was more severe than in oxidase deficiency (moderate hypotonia without dysmorphic features, development of a leukodystrophy, age at death ∼4 yr). Based on these findings, accurate early diagnosis of these deficiencies of peroxisomal β‐oxidation enzymes is possible.
Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia
Authors: Glass Jonathan D. , Fedor Helen , Wesselingh Steven L. , McArthur Justin C.
Published: January 2005

The pathogenesis of human immunodeficiency virus (HIV)‐associated dementia is unclear, and the underlying pathological substrate has been a matter of debate. In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV‐associated dementia and the presence and relative quantity of immunocytochemical Marchkers for HIV‐1 (gp41 antibody), and for macrophages and microglia (HAM‐56 antibody). Sections from the basal ganglia and frontal lobes from the brains of 51 patients were studied, and the data were stratified for severity of dementia (16 nondemented, 12 mildly demented, 23 severely demented), rate of dementia progression, duration of AIDS, use of antiretrovirals, and several other demographic features. We found a highly significant correlation between the degree of macrophage staining and the severity of dementia but only a borderline correlation between the presence and amount of gp41‐positive cells and dementia. Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity. Other correlations with the immunostaining data, including antiretroviral use, were not significant. We conclude that the presence of macrophages and microglia is a better correlate with HIV‐associated dementia than is the presence and amount of HIV‐infected cells in the brain. These data support the concept that the pathogenesis of HIV‐associated dementia is likely due to indirect effects of HIV‐infection of the brain, possibly through the actions of macrophages and microglia.
Monocyte/macrophage differentiation in early multiple sclerosis lesions
Authors: Brück Wolfgang , Porada Phyllis , Poser Sigrid , Rieckmann Peter , Hanefeld Folker , Kretzschmarch Hans A. , Lassmann Hans
Published: January 2005

Monocyte/macrophage differentiation was studied in biopsy samples of multiple sclerosis (MS) lesions obtained in the early course of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different macrophage‐activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products. The pan‐macrophage Marchker Ki‐M1P revealed the highest numbers of macrophages in early and late active lesions. Lower numbers were encountered in inactive, demyelinated, or remyelinated lesions. The acute stage inflammatory macrophage Marchkers MRP14 and 27E10 were expressed in either only early active (MRP14) or early and late active (27E10) lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage Marchker 25F9, in contrast, showed increasing expression with decreasing lesional activity. These findings indicate a differentiated pattern of macrophage activation in MS lesions and allow the staging of demyelinating lesions in routinely fixed and paraffin‐embedded tissue.
Anti‐ganglioside GM1 antibodies in guillain‐barré syndrome and their relationship to Campylobacter jejuni infection
Authors: Rees Jeremy H. , Gregson Norman A. , Hughes Richard A. C.
Published: January 2005

To clarify the association between Campylobacter jejunei (Cj) infection and antibodies to ganglioside GM1 (anti‐GM1) in Guillain‐Barré syndrome (GBS), we have carried out a prospective case‐control study of 96 patients with GBS. Cj infection occurred in 25 (26%) patients. IgG and/or IgM anti‐GM1 were identified in 24 (25%) patients and in 1 of 71 (1.4%) household controls (p < 0.001). Thirteen of the 25 (52%) Cj‐postive patients had anti‐GM1 compared with 11 of the 71 (15%) Cj‐negative patients (p < 0.001). Neither the peak overall disability nor the 1‐year disability differed between the anti‐GM1‐positive and anti‐GM1‐negative patients. However, patients with the combimation of Cj infection and anti‐GM1 positivity recovered more slowly than Cj/anti‐GM1‐negative patients (p = 0.05), were more likely to have axonal degeneration, and were significantly more disabled at the end of 1 year (p = 0.02). The presence of Cj infection is more important than anti‐GM1 postivity in determining the extent of axonal involvement and, hence, prognosis. Since the presence of anti‐GM1 is not a significant poor‐prognostic factor, a search should be made for other properties of Cj infection that would account for its relationship to axonal degeneration.
Neurological sequelae of cyanide intoxication — the patterns of clinical, magnetic resonance imaging, and positron emission tomography findings
Authors: Rosenow F. , Herholz K. , Lanfermann H. , Weuthen G. , Ebner R. , Kessler J. , Ghaemi M. , Heiss W.‐D.
Published: January 2005

We report 2 patients with neurological sequelae of oral cyanide intoxication who were evaluated clinically and neuropsychologically, with high‐resolution magnetic resonance imaging and one of them with positron emission tomography. The clinical syndrome was characterized by extrapyramidal motor and cerebellar symptoms such as bradykinesia, hypomimia, slowed speech, anteropulsion, and Marchked retropulsion, but little tremor. The sensory and pyramidal motor systems were normal or relatively spared. On neuropsychological testing the intellectual capacity and memory functions were normal, whereas the speed of motor reaction and verbal fluency were reduced. Magnetic resonance imaging showed damage of the globus pallidus, putamen, substantia nigra, subthalamic nucleus, and cerebellum in both patients, whereas the sensory‐motor cortex and hippocampus were relatively spared. 18F‐6‐Fluoro‐dopa positron emission tomography revealed a symmetrical reduction of striatal dopa uptake by 42% on average that was similar in the putamen and caudate. 18F‐2‐Fluoro‐2‐deoxyglucose positron emission tomography showed a regional reduction of the glucose metabolism in the posterior putamen and temporo‐parieto‐occipital and cerebellar cortex.
Neural apoptosis
Authors: Bredesen Dale E.
Published: January 2005

Apoptosis is a mode of cell death in which the cell plays an active role in its own demise. The study of neural apoptosis, the identification of genes controlling apoptosis, and the examination of the mechanisms by which these genes achieve their effects have assumed increasing importance over the past few years. This is because (1) neural apoptosis occurs not only in development, but also in pathophysiological states such as stroke, glutamate toxicity, and β‐amyloid peptide toxicity; (2) genes that control apoptotic cell death, such asbcl‐2, p35, p53, andp75NTR, also modulate necrotic neural death in some cases; (3) the emerging mechanisms by which these genes control apoptosis may be relevant for understanding neurodegenerative processes, and for the design of therapeutic agents; and (4) the findings that the cell plays an active role in its own demise, and that specific gene products are involved, suggest that therapeutic intervention may be feasible.
Neuromuscular effects of papuan taipan snake venom
Authors: Connolly S. , Trevett A. J. , Nwokolo N. C. , Lalloo D. G. , Naraqi S. , Mantle D. , Schofield I. S. , Fawcett P. R. W. , Harris J. B. , Warrell D. A.
Published: January 2005

Snakebite is a cause of significant morbidity in Central Province, Papua New Guinea. Three adult patients with clinical evidence of neurotoxicity following envenomation by the Papuan taipan had serial neurophysiological examinations over the course of their subsequent hospitalization. All required artificial ventilation for 2.5 to 5 days. The compound muscle action potential (CMAP) amplitudes declined over the first 2 to 4 days after envenoming and then gradually increased in parallel with clinical recovery. Repetitive stimulation studies revealed a distinctive pattern of abnormality. Activation resulted in brief potentiation of the CMAP followed by significantly greater decrement than observed at rest. This effect lasted up to 30 minutes and was not altered after intravenous edrophonium. Single‐fiber electromyographic recordings during the recovery phase of the illness were abnormal with marked blocking and increased jitter. All patients were able to return home.
Acute optic neuritis: Myelin basic protein and proteolipid protein antibodies, affinity, and the HLA system
Authors: Sellebjerg F. , Madsen H. O. , Frederiksen J. L. , Ryder L. P. , Svejgaard A.
Published: January 2005

Anti—myelin basic protein, anti—proteolipid protein, and anti—myelin basic protein peptide (amino acid residues 1–20, 63–88, and 89–101) antibody—secreting cells were studied in 20 patients with idiopathic optic neuritis, 20 with optic neuritis as part of multiple sclerosis, and 20 neurological control subjects. Antibody‐secreting cells were enumerated with an immunospot assay; the relative binding affinity of the antibodies was estimated by elution with thiocyanate. Patients with optic neuritis had more anti—myelin basic protein and anti—proteolipid protein antibodies than did control subjects (both p < 0.05); there was no difference between idiopathic optic neuritis and optic neuritis as a symptom of multiple sclerosis. Presence of the multiple sclerosis—associated DRB1 1501 gene was not associated with preferential synthesis of high‐affinity antibodies reactive with a single myelin basic protein peptide or with preferential synthesis of either anti—myelin basic protein or anti—proteolipid protein antibodies. The results demonstrate a potential for intrathecal synthesis of both anti—myelin basic protein and anti—proteolipid protein antibodies of high apparent affinity in patients with optic neuritis.