bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunosuppressive treatment in multifocal motor neuropathy
Authors: Feldman Eva L. , Bromberg Mark B. , Albers James W. , Pestronk Alan
Published: January 2005

We report the results of immunosuppressive treatments of 13 patients with multifocal motor neuropathy and elevated titers of serum antibodies to the GM1 ganglioside. All patients failed to respond to oral prednisone. There was no clinical response in 4 patients treated with plasma exchange. Nine patients received cyclophosphamide, with clinical improvement and fall in antibody titers in 8. In 3 patients, cyclophosphamide was discontinued with ensuing clinical relapse and rise in the titers of serum anti‐GM1 antibodies. These patients provide further evidence for the efficacy of cyclophosphamide therapy in patients with multifocal motor neuropathy.
Segmental spinal muscular atrophy and dermatological findings in a patient with chromosome 18q deletion
Authors: Weiss B. J. , Kamholz J. , Ritter A. , Zackai E. H. , McDonald‐McGinn D. M. , Emanuel B. , Fischbeck K. H.
Published: January 2005

We have evaluated a young woman with segmental spinal muscular atrophy, who has a deletion of a portion of the long arm of chromosome 18. She also has vitiligo and lichen sclerosis et atrophicus. She has neither the facial dysmorphism nor the mental deficit usually associated with the 18q− syndrome. Magnetic resonance imaging scan of her brain demonstrates high signal intensity consistent with abnormal myelination. Southern blot analysis of her DNA demonstrates that the deletion includes the gene for human myelin basic protein. Neither spinal muscular atrophy nor this patient's skin manifestations have been previously reported in association with 18q−.
Stroke prevention in nonvalvular atrial fibrillation: A review of prospective randomized trials
Authors: Albers Gregory W. , Sherman David G. , Gress Daryl R. , Paulseth J. E. , Petersen Palle
Published: January 2005

Patients with atrial fibrillation are at risk for cerebral embolism; however, the roles of chronic anticoagulation or antiplatelet therapy for stroke prevention in patients with nonvalvular atrial fibrillation have been controversial. Recently, the results of three large prospective randomized trials that examined the risks and benefits of warfarin or aspirin for stroke prophylaxis in patients with nonvalular atrial fibrillation were reported. All three studies revealed a reduction in the stroke rate for patients treated with warfarin and a small incidence of major bleeding. One of the studies also reported a reduced stroke rate in aspirin‐treated patients. The reduction of thromboembolic events associated with chronic warfarin therapy appears to outweigh the risks of significant bleeding for most patients with nonvalvular atrial fibrillation. Aspirin may offer an alternative for subgroups of patients who are at low risk for stroke or those who are not good candidates for anticoagulation.
Seronegative myasthenia gravis: A plasma factor inhibiting agonist‐induced acetylcholine receptor function copurifies with IgM
Authors: Yamamoto Takeshi , Vincent Angela , Ciulla Thomas A. , Lang Bethan , Johnston Irene , Newsom‐Davis John
Published: January 2005

Anti—acetylcholine receptor antibodies cannot be detected by standard radioimmunoassay in 10 to 15% of patients with generalized myasthenia gravis (seronegative myasthenia gravis). We investigated the effect of seronegative myasthenia gravis plasma on 22Na+ flux through acetylcholine receptors and voltage‐gated sodium channels in the human rhabdomyosarcoma cell line, TE671. Fourteen of 19 seronegative MG plasmas inhibited acetylcholine receptor 22Na+ flux; none inhibited voltage‐gated sodium channel flux. The inhibitory activity was found in the IgG‐depleted fraction, and copurified with IgM after gel‐filtration chromatography. Inhibitory activity was absent from the plasma of 8 healthy control subjects and of 6 patients with the Lambert‐Eaton myasthenic syndrome, but was present in the IgG‐depleted plasma fraction of 4 of 6 seropositive patients with myasthenia gravis and all 5 patients with demyelinating polyneuropathy. We conclude that a low‐affinity serum factor, probably an IgM antibody, found in a high proportion in patients with seronegative and those with seropositive myasthenia gravis may contribute to the muscle weakness in myasthenia gravis, but its role in these and other neuroimmunological disorders requires further investigation.
Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in parkinson's disease
Authors: Hattori Nobutaka , Tanaka Masashi , Ozawa Takayuki , Mizuno Yoshikuni
Published: January 2005

We examined the substantia nigra of 8 patients with Parkinson's disease immunohistochemically using antisera against complexes I, II, III, and IV of the mitochondrial electron transport system. In the patients with Parkinson's disease, a fair proportion of the nigral neurons showed reduced staining against the complex I antibody. The proportion of the neurons with reduced staining ranged from 12.7 to 74.1% of the melanized nigral neurons. Although neurons with reduced immunostaining for complex I were also observed in control subjects, the proportion among the nigral neurons was significantly smaller than in parkinsonian patients. Staining for complexes III and IV appeared normal. Staining of substantia nigra for complex II was decreased in 3 parkinsonian patients. These results are consistent with our findings that there is a deletion of gene coding for the four subunits in the mitochondrial DNA located in the striata of parkinsonian patients.
Quantitative measurements of capillary transport in human brain tumors by computed tomography
Authors: Groothuis Dennis R. , Vriesendorp Francine J. , Kupfer Barry , Warnke Peter C. , Lapin Gregory D. , Kuruvilla Abraham , Vick Nicholas A. , Mikhael Michael A. , Patlak Clifford S.
Published: January 2005

The rate at which water‐soluble chemotherapeutic drugs enter brain tumors can be extremely variable. The ability to measure or predict the rate of drug entry may have an important role in treatment. We have developed a method that uses information from contrast‐enhanced computed tomographic scans to measure quantitatively the rate of transcapillary transport of iodinated compounds in brain tumors. In a group of 10 patients with brain tumors, we obtained serial measurements of tissue (Am) and arterial plasma (Cp) iodine concentration from timed computed tomographic scans done over 30 minutes, after intravenous infusion of meglumine iothalamate (Conray‐60). These measurements were analyzed with a two‐compartment pharmacokinetic model and nonlinear least‐squares regression methods to obtain K1, a blood‐to‐tissue transfer constant; k2, a tissue‐to‐blood rate constant; and Vp, tissue plasma vascular volume. Images of K1, k2, and Vp were reconstructed after calculating these values for each 0.8 × 0.8 × 5‐mm volume element of the original data. Mean whole tumor K1 values varied from 2.0 μl gm−1 min−1 in a thalamic astrocytoma to 33.9 μ1 gm−1 min−1 in a glioblastoma multiforme. The value of k2 varied from 0.034 to 0.108 min−1, and Vp varied from 2.4 to 7.9 ml 100 gm−1. In tumor‐free brain, the K1 of meglumine iothalamate was 2.9 μ1 gm−1 min−1; k2 was 0.058 min−1; and Vp was 2.1 ml 100 gm−1. There was pronounced variability in transcapillary transport values between different malignant brain tumors, as well as regional variability within individual tumors, with focal increases in K1 up to 50‐fold normal brain values. This approach provides a quantitative method to measure the rate of transcapillary transport of passively distributed iodinated compounds in human brain tumors. These types of measurements can be used to study serial changes of capillary permeability in individual patients that occur as a result of therapeutic manipulation and may, potentially, be used to individualize chemotherapy.
Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro
Authors: Avoli M. , Drapeau C. , Louvel J. , Pumain R. , Olivier A. , Villemure J.‐G.
Published: January 2005

Extracellular field potentials and [K+]o were recorded in slices of human epileptogenic neocortex maintained in vitro during perfusion with Mg2+‐free artificial cerebrospinal fluid (ACSF). The human neocortex was obtained during neurosurgical procedures for the relief of seizures that were resistant to medical treatment. Spontaneous epileptiform activity and episodes of spreading depression appeared within 1.5 to 2 hours of perfusion with Mg2+‐free ACSF. The epileptiform discharges consisted of negative field potential shifts (amplitude, 0.8–10 mV) that lasted 2.5 to 80 seconds and recurred at intervals ranging between 4 and 160 seconds. Both duration and frequency occurrence of epileptiform events were not significantly different when measured in slices obtained from spiking tissue compared with those gathered from nonspiking neocortical areas. Transient increases in [K+]o of up to 10.5 mM were associated with each epileptiform discharge; these changes were maximal and fastest in the middle neocortical layers. Spreading depression episodes were characterized by 20 to 30‐mV negative shifts that lasted up to 200 seconds and were accompanied by increases in [K+]o of approximately 100 mM. Epileptiform discharges and spreading depressions did not occur during perfusion with Mg2+‐free ACSF that contained either competitive or noncompetitive antagonists of the N‐methyl‐D‐aspartate (NMDA) receptor subtype. In contrast, pharmacological blockade of non‐NMDA receptors did not influence the epileptiform activity observed in Mg2+‐free ACSF. These findings demonstrate that decreasing [Mg2+]o leads to the appearance of both spontaneous epileptiform discharges and spreading depression in the human epileptogenic neocortex. Both activities are solely dependent on NMDA‐activated conductances, suggesting that removal of the voltage‐dependent gating effect exerted by extracellular Mg2+ on the NMDA ionophore is a condition sufficient for neurons in the human neocortex to generate spontaneous, synchronous epileptiform activity. We propose that this experimental paradigm might represent a model suitable for analyzing the cellular mechanisms underlying human neocortical epileptogenesis in vitro as well as for preliminary screening of antiepileptic drugs.
Pleuropulmonary disease associated with dopamine agonist therapy
Authors: Bhatt M. H. , Keenan S. P. , Fleetham J. A. , Calne D. B.
Published: January 2005

Artificial dopamine agonists are widely employed for the treatment of idiopathic parkinsonism. Pleuropulmonary disease has previously been reported to occur with the use of bromocriptine and mesulergine. We report similar adverse effects induced by the newer agonists lisuride and cabergoline. All these agents are tetracyclic ergot derivatives. This suggests a causal link between ergot‐derived dopamine agonists and pleuropulmonary disease.
Nighttime levodopa infusions to treat motor fluctuations in advanced parkinson's disease: Preliminary observations
Authors: Sage Jacob I. , Mark Margery H.
Published: January 2005

We report the clinical response of a parkinsonian patient with severe motor fluctuations who was begun on continuous, nighttime‐only levodopa infusions accompanied by oral carbidopa/levodopa use during the day. Sleep disturbances improved immediately. There was a gradual reduction in “off” time and severity of dyskinesias during the waking day. Nighttime‐only levodopa infusions have a carryover benefit to the waking hours and may be suitable for long‐term therapy to reduce daily motor fluctuations in some patients with Parkinson's disease.
Hereditary branching enzyme dysfunction in adult polyglucosan body disease: A possible metabolic cause in two patients
Authors: Lossos A. , Barash V. , Soffer D. , Argov Z. , Gomori M. , Ben‐Nariah Z. , Abramsky O. , Steiner I.
Published: January 2005

We describe 2 unrelated patients with adult polyglucosan body disease (APBD) diagnosed by sural nerve biopsy. Both patients were offspring of consanguineous marriages. They presented clinically with late onset pyramidal tetraparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities in both. In search of a possible metabolic defect, we evaluated glycogen metabolism in these patients and their clinically unaffected children. Branching enzyme activity in the patients' polymorphonuclear leukocytes was about 15% of control values, whereas their children displayed values of 50 to 60%, suggesting a possible autosomal recessive mode of transmission. This is the first report of an inherited metabolic defect in patients with adult polyglucosan body disease. We suggest that branching enzyme dysfunction may be implicated in the pathogenesis of some patients with adult polyglucosan body disease.
Hypertension in the elderly is associated with white matter lesions and cognitive decline
Authors: van Swieten J. C. , Geyskes G. G. , Derix M. M. A. , Peeck B. M. , Ramos L. M. P. , van Latum J. C. , van Gijn J.
Published: January 2005

Forty‐two elderly patients (mean age, 66.2 ± 5.1 yr) with hypertension, treated for an average of 17.3 years (standard deviation, 10.3), and 42 control subjects (mean age, 66.5 ± 4.8yr), matched for age, sex, and level of education, were studied with regard to the detection of lesions in the cerebral white matter with magnetic resonance imaging (MRI), particularly with axial T2‐weighted images. The assessment of the MRI scans was blinded. Ten hypertensive patients showed confluent lesions in the white matter, versus only 1 control subject (Chi‐square test, p = 0.01). The presence of diffuse lesions of the white matter was related to age but not to the known duration of hypertension, nor to the presence of any other cardiovascular risk factors. Cognitive function was measured in 34 hypertensive patients and in 18 control subjects. Results of the Mini‐Mental State Examination, the Stroop color‐word test, Trailmaking test, and the visual subtest of the Wechsler Memory scale were worse in patients with confluent lesions of the white matter; there was no difference in mental functioning between hypertensive patients and control subjects with normal white matter or with only small focal lesions. Our findings suggest that long‐standing hypertension in some patients may cause not only strokes but also chronic end‐organ damage in the form of demyelination of the white matter, with cognitive decline.
Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primates
Authors: Koliatsos Vassilis E. , Clatterbuck Richard E. , Nauta Haring J. W. , Knüsel Beat , Burton Louis E. , Hefti Franz F. , Mobley William C , Price Donald L.
Published: January 2005

Basal forebrain cholinergic neurons respond to nerve growth factor (NGF), and it has been suggested that the administration of NGF might prevent their degereration in patients with Alzheimer's disease. One major prerequisite to be fulfilled before the consideration of clinical trials of NGF in patients with Alzheimer's disease is the demonstration that human NGF affects basal forebrain cholinergic neurons in primates. In the present study, we used a recombunant human nerve growth facotr (rhNGF), which we previousl showed to be active on rat basa forebrain cholinergic neurons, in nonhuman primates with a unilateral transection of the fornix (a well‐established model for the induction of retrograde degenerative changes in septal cholinergic neurons). After the lesion, one group of animals received rhNGF and a second group received vehicle solution for 2 weeks. In animals receiving vehicle, the medical septal nucleus ipsilateral to the lesion showed reductions in numbers (55°) and size of cell bodies immunoreactive for NGF receptor and choline acetyltransferase. In Sissl stains, many cells showed frduced size and basophilia. The rhNGF completely prevented alternation in the number and size of NGF receptor—and choline acetyltransferase—immunnoreactive neurons in the medical septal nucles and reversed atrophy in a subpopulation of large, basophilic medical which we have previously used in the same primate lesion paradigm. The restoration of the phenotype of injured acetylcholine‐dependent memory impariments that occur in aged nonhuman primates. In concert, results of the present investigation provide critical information for the futrue use of NGF in in patients with neurological disorders that affect NGF‐responsive cells in the peripherl and central nervous system.
Sensorimotor disinhibition in Parkinson's disease: Effects of levodopa
Authors: Caligiuri Michael P. , Heindel William C. , Lohr James B.
Published: January 2005

It has been known for some time that patients with Parkinson's disease (PD) have difficulty executing simultaneous motor acts, yet the pathophysiology underlying this impairment remains uncertain. We examined the possibility that these dual‐task deficits stem from defective sensorimotor mechanisms producing interference between the motor programs underlying the two tasks. Patients with PD and normal control subjects were tested on their ability to maintain steady‐state force with one hand while performing a force–reaction time task with the other hand. Although performance was worse on the dual‐task than on the single‐task condition for both subject groups, only the patients with PD demonstrated significant interference between the two tasks. The interference across tasks improved in 87% of the patients with PD when tested after treatment with carbidopa/levodopa (Sinemet). These findings support the contention that, in patients with PD, disturbances in the execution of simultaneous motor performance may be due to sensorimotor disinhibition.
Lethal cytomegalovirus infection in preterm infants: Clinical, radiological, and neuropathological findings
Authors: Perlman Jeffrey M. , Argyle Craig
Published: January 2005

Fifteen premature infants with lethal congenital cytomegalovirus infection were studied to determine the clinical, neuroradiological, and neuropathological characteristics of the disease in this population. Nine infants were liveborn but died at a postnatal age of 18 ± 21 days; 6 infants were stillborn. Clinical findings in liveborn infants included microcephaly (77%), seizures (55%), hypotonia (33%), and multiple contractures (18%). Ophthalmological findings included chorioretinitis, optic atrophy, and corneal opacities. Neuroradiological findings included the postnatal evolution of periventricular calcification in 1 infant, and cerebellar hypoplasia diagnosed by magnetic resonance imaging in 1 infant. Neuropathological findings included periventricular necrosis and calcification (12), associated diffuse calcification frequently involving the convexity of the gyri (6), cerebellar hypoplasia (5), periventricular leukomalacia (2), intraventricular hemorrhage (2), hydrocephalus (2), and porencephalic cyst (1). Intranuclear inclusion bodies within the brain were observed in 4 infants, whereas systemic inclusion bodies were present in all infants. These data indicate several atypical findings in preterm infants rarely reported in term infants, including hypotonia, multiple contractures, periventricular leukomalacia, and optic atrophy.
Osmolality and nonsynaptic epileptiform bursts in rat CA1 and dentate gyrus
Authors: Roper Steven N. , Obenaus Andre , Dudek F. Edward
Published: January 2005

In several clinical situations, such as hyposmolar states and hypoxia‐ischemia, reductions in the size of the extracellular space are associated with increased seizure susceptibility. Nonsynaptic interactions provide a likely means of mediating the effect of extracellular space on seizure susceptibility. Synchronous bursting of CA1 hippocampal neurons occurs via nonsynaptic mechanisms in solutions containing very low {Ca2+} and excitatory amino acid antagonists. We tested the hypothesis that lowering the osmolality of the extracellular medium could induce nonsynaptic bursting in the dentate gyrus, even though it is normally resistant to this treatment. Extracellular field potentials were recorded in the dentate gyrus and CA1 area of rat hippocampal slices. In the low‐{Ca2+} solution with normal osmolality, bursts of population spikes were recorded from the dentate gyrus in only 7% of the slices, but solutions with decreased osmolality induced bursting in 63%. Corresponding values for the CA1 area were 60 and 73%, respectively. Mannitol, which reversed the hyposmolar state, abolished bursting in both regions. This study demonstrates that reducing the size of the extracellular space by lowering extracellular osmolality can transform a seizure‐resistant area into one that exhibits robust epileptiform activity.
Contrasting effects of alpha, beta, and gamma interferons on nonspecific suppressor function in multiple sclerosis
Authors: Noronha Avertano , Toscas Angela , Jensen Mark A.
Published: January 2005

Interferons are biological molecules with antiviral, antiproliferative, and immunomodulatory actions. Interferon alpha (IFN‐α) and ‐β are potentially useful in the treatment of multiple sclerosis (MS). IFN‐γ, in contrast, increases the frequency of exacerbations of MS. In this study, we compared the effect of recombinant human IFN‐α, ‐β, and ‐γ on suppressor function in patients with MS. Nonspecific suppressor cell function, measured in a concanavalin A suppressor assay, was significantly decreased in 16 patients with progressive MS (mean percent suppression ± SEM, 14.4 ± 5.5 in patients with MS, 33.5 ± 4.8 in 16 normal subjects; p < 0.001). Recombinant human IFN‐β augmented suppressor function in MS to 45.4 ± 5.1% (p < 0.001) and in control subjects to 56.8 ± 3.8% (p < 0.001). Similarly, recombinant human IFN‐α improved suppression in MS to 43.0 ± 5.6% (p < 0.001) and in control subjects to 51.1 ± 5.9% (p < 0.001). In contrast, recombinant human IFN‐γ had no effect on suppressor function in patients with MS and in control subjects. This study shows that IFN‐α and ‐β augment deficient suppressor function in MS, whereas IFN‐γ has no effect on suppressor function in the progressive phase of the disease.
Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?
Authors: Beal M. Flint
Published: January 2005

The etiology of nerve cell death in neuronal degenerative diseases is unknown, but it has been hypothesized that excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however, is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage‐dependent N‐methyl‐D‐apartate (NMDA) receptor ion channels would be more easily activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration closely resembling that seen in Huntington's disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by 1‐methyl‐4‐phenylpyridium, which has been implicated in experimental models of Parkinson's disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.
Transplantation of fetal dopamine neurons in Parkinson's disease: PET {18F}6‐L‐fluorodopa studies in two patients with putaminal implants
Authors: Sawle Guy V. , Bloomfield Peter M. , Ourklund Anders Bj , Brooks David J. , Brundin Patrik , Leenders Klaus L. , Lindvall Olle , Marsden C. David , Rehncrona Stig , Widner Håkan , Frackowiak Richard S. J.
Published: January 2005

Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and {18F}6‐L‐fluorodopa ({18F}dopa). The uptake of {18F}dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen {18F}dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, {18F}dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of {18F}dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of {18F}dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.
1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders
Authors: van der Knaap Marjo S. , van der Grond Jeroen , Luyten Peter R. , Den Hollander Jan A. , Nauta Jos J. P. , Valk Jaap
Published: January 2005

Proton and phosphorus magnetic resonance spectroscopy of the brain was performed in 35 patients with degenerative cerebral disorders: 24 patients had demyelinating (white matter) disorders and 11 patients had neuronal (gray matter) disorders. Four grades of demyelination and three grades of cerebral atrophy were distinguished by magnetic resonance imaging criteria. The spectroscopic data were compared with normal values previously obtained. With increasing degrees of demyelination, lower ratios of phosphodiesters to β‐ATP were found. This trend was statistically significant. Decreased phosphodiester–β‐ATP ratios occurred simultaneously with imaging abnormalities. The decrease in phosphodiester–β‐ATP ratio in demyelinated areas is attributed to white matter rarefaction. Increasing cerebral atrophy was accompanied by lower ratios of N‐acetyl aspartate to creatine. This trend was statistically significant. The decrease in the N‐acetyl aspartate–creatine ratio was demonstrated before the magnetic resonance images showed signs of cerebral atrophy in patients with neuronal disorders. As N‐acetyl aspartate is located exclusively in neurons and their branches, a decrease of the N‐acetyl aspartate–creatine ratio can be attributed to neuronal and axonal damage and loss.
Mild senile dementia of the Alzheimer type. 4. Evaluation of intervention
Authors: Berg Leonard , Miller J. Philip , Baty Jack , Rubin Eugene H. , Morris John C. , Figiel Gary
Published: January 2005

The design of trials of interventions intended to slow or arrest the progression of senile dementia of the Alzheimer type must be based on analysis of the natural hisotry of the disease. Using a random coefficients statistical model, we analyzed the natural hisotry of senile dementia of the Alzheimer type in carefully defined subjects with milde disease (n = 68) for periods of up to 10 years. Subject performance was assessed longitudinally on batteries of clinical and psychometric measures. The characteristics of these measures were analyzed relevant to their utility as outcome measures for long‐term trials in patients with senile dementia of the Alzheimer type. Estimates were made of sample sizes required to show arrest, and 50% or 25% slowing in the progression of mild disease. We suggest that a clinically relevant global measure, such as the Sum of Boxes of the Clinical Dementia Rating scale, and a performance‐based clinical scale or psychometric measure would be appropriate in a 12‐ or 24‐month trial enrolling subjects with mild senile dementia of the Alzheimer type.
Late‐onset metachromatic leukodystrophy: Molecular pathology in two siblings
Authors: Kappler Joachim , von Figura Kurt , Gieselmann Volkmar
Published: January 2005

We report on a new allele at the arylsulfatase A (ARSA) locus causing late‐onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early‐onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD.
Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: A laser microprobe (LAMMA) study
Authors: Good Paul F. , Perl Daniel P. , Bierer Linda M. , Schmeidler James
Published: January 2005

We report the results of an examination of the elemental content of neurofibrillary tangle–bearing and neurofibrillary tangle–free neurons identified within the hippocampus of 10 subjects with Alzheimer's disease and 4 neuropathologically intact age‐matched control subjects. The study employed laser microprobe mass analysis (LAMMA), a technique that provides extremely sensitive multielement detection in plastic‐embedded, semithin‐sectioned tissues. Evidence for the selective accumulation of aluminum within the neurofibrillary tangle–bearing neurons was obtained in all 10 subjects with Alzheimer's disease. The site of aluminum deposition within these cells was the neurofibrillary tangle itself, and not the “nuclear region”, as we previously reported. Iron accumulation was also detected within neurofibrillary tangles. Evaluation for the accumulation of other elements within the tangle‐bearing neurons failed to reveal any other metallic element as being consistently present. In addition, probe sites directed to neurons identified in snapfrozen cryostat sections from 2 subjects with Alzheimer's disease revealed similar spectra with prominent aluminum‐related peaks, confirming that our findings are not related to exogenous contamination through fixation, embedding, or other procedures prior to analysis. This study further confirms the association of aluminum and neurofibrillary tangle formation in Alzheimer's disease.
Collagen cross‐linking of skin in patients with amyotrophic lateral sclerosis
Authors: Ono Seiitsu , Yamauchi Mitsuo
Published: January 2005

Collagen cross‐links of skin tissue (left upper arm) from 11 patients with amyotrophic lateral sclerosis (ALS) and 9 age‐matched control subjects were quantified. It was found that patients with ALS had a significant reduction in the content of an age‐related, stable cross‐link, histidinohydroxylysinonorleucine, that was negatively correlated with the duration of illness. The contents of sodium borohydride–reducible labile cross‐links, dehydro‐hydroxylysinonorleucine and dehydro‐histidinohydroxymerodesmosine, were significantly increased and were positively associated with the duration of illness (r = 0.703, p < 0.05 and r = 0.684, p < 0.05, respectively). The results clearly indicate that during the course of ALS, the cross‐linking pathway of skin collagen runs counter to its normal aging, resulting in a “rejuvenation” phenomenon of skin collagen. Thus, cross‐linking of skin collagen is affected in ALS.
GM1 gangliosidosis in adults: Clinical and molecular analysis of 16 Japanese patients
Authors: Yoshida Kunihiro , Oshima Akihiro , Sakuraba Hitoshi , Nakano Takeshi , Yanagisawa Nobuo , Inui Koji , Okada Shintaro , Uyama Ei‐ichiro , Namba Reiko , Kondo Kiyohiko , Iwasaki Shin‐ichi , Takamiya Kiyoshi , Suzuki Yoshiyuki
Published: January 2005

Clinical findings were compared with the results of molecular analysis in 16 Japanes patients from 10 unrelated families with the adult/chronic form of GM1 gangliosidosis. Age of onset ranged from 3 to 30 years. Major clinical manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic postures and movements, facial grimacing, and parkinsonian manifestations were commonly seen. Cerebellar signs, myoclonus, severe intellectual impairment, dysmorphism, or visceromegaly were not observed. A common single‐base substitution, 51Ile(ATC)→Thr(ACC), reported in a previous study of ours, was confirmed in 14 patients by the Bsu361 restriction site analysis; one was a compound heterozygote with another mutation (457Agr{CGA}→Gln{CAA}) and the others were homozygotes of this mutation. Clinically, the compound‐heterozygous patient showed more severe neurological manifestations and a more rapid clinical course than those of homozygotes. The homozygotes showed considerable variations in the age of onset and subsequent clinical course. The 51Ile→Thr mutant allele expressed a significant amount of β‐galactosidase activity, whereas the 457Arg→Gln mutant allele extremely low activity in human GM1 gangliosidosis fibroblasts. We conclude that these gene mutations causing different residual enzyme activities are related to the severity of clinical manifestations, but some other genetic or environmental factors contribute to clinical heterogeneity. The Bsu361 retriction site analysis was performed in 7 families and provided clear results for the diagnosis of heterozygotes as well as homozygotes of this specific clinical form of GM1 gangliosidosis. The technique is applicable to prenatal diagnosis and genetic counseling.
Cytokine expression in the brain during the acquired immunodeficiency syndrome
Authors: Tyor William R. , Glass Jonathan D. , Griffin John W. , Becker P. Scott , McArthur Justin C. , Bezman Lena , Griffin Diane E.
Published: January 2005

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin‐1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV‐seropositive and ‐seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin‐1 and ‐6, tumor necrosis factor‐α and ‐β, and interferon γ. Levels of soluble CD4, CD8, and interleukin‐2 receptor, as well as interferon γ, tumor necrosis factor‐α, β2‐microglobulin, neopterin, and interleukin‐6 and ‐1 β were assayed in the cerbrospinal fluid and plasma of many of these individuals during life. The HIV‐seropositive group included individuals without neurological disease, those with CNS oppotunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present, on microglial cells, which were frequently positive for tumor necrosis factor‐α. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin‐1 and interferon γ and less frequently for tumor necrosis factor and interleukin‐6. There were gliosis and significant increases in MHC class II antigen, interleukin‐1, and tumor necrosis factor‐α in HIV‐positive patients compared to HIV‐negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, β2‐microglobulin, and neopterin. There was no correlationin HIV‐positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of “immune activation” in the brains of HIV‐positive compared to HIV‐negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.
Memory disturbances following anterior communicating artery rupture
Authors: Irle Eva , Wowra Berndt , Kunert Hanns J. , Hampl Jürgen , Kunze Stefan
Published: January 2005

Thirty patients with lesions due to the rupture and repair of an aneurysm of the anterior communicating artery were compared neuropsychologically with 27 patients with ruptures but no lesions and 30 normal control subjects. Patients with combined lesions in the basal forebrain and striatum (n = 5), or basal forebrain, striatum, and ventral frontal cortex (n = 7), had severe memory deficits, whereas patients with lesions in the basal forebrain (n = 7) or the striatum (n = 5) alone showed virtually no deficits. Patients with lesions of the basal forebrain and ventral frontal cortex together (n = 6) showed mild memory deficits. In contrast to the memory effects, emotional changes were most pronounced in patients with striate lesions alone. Basal forebrain or ventral frontal lesions ameliorated rather than aggravated the emotional effects of striate lesions. It is suggested that the basal forebrain and the striatum form links of different pathways related to mnemonic information processing. Both systems may be able to compensate for a dysfunction of the other, but lesions of both systems together may lead to strong and unrecoverable memory deficits.
Corticotropin‐releasing hormone–induced seizures in infant rats originate in the amygdala
Authors: Baram Tallie Z. , Hirsch Edouard , Snead O. Carter , Schultz Linda
Published: January 2005

The neuroanatomical substrate of seizures induced by picomolar amounts of corticotropin‐releasing hormone in infant rats was investigated. Electrographic and behavioral phenomena were monitored in 42 rat pups aged 5 to 22 days. Rat pups carried bipolar electrodes implanted in subcortical limbic structures, as well as cortical electrodes and intracerebroventricular cannulae. The administration of corticotropin‐releasing hormone produced age‐specific seizures within minutes, which correlated with rhythmic amygdala discharges. Paroxysmal hippocampal and cortical discharges developed subsequently in some rats. Corticotropin‐releasing hormone–induced electrographic and behavioral seizures originate in the amygdala.
Oxidative metabolism in muscle mitochondria from patients with chronic alcoholism
Authors: Cardellach F. , Galofré J. , Grau J. M. , Casademont J. , Hoek J. B. , Rubin E. , Urbano‐Márquez A.
Published: January 2005

We investigated the effect of long‐term ethanol intake on the function of skeletal muscle mitochondria from 30 human alcoholics. Mitochondrial studies included (1) oxidative phosphorylation, (2) the activity of the individual complexes of the respiratory chain, and (3) the cytochrome content. State 3 and state 4 oxidation rates with glutamate‐malate, succinate, tetramethyl‐p‐phenylenediamine–ascorbate, and acetylcarnitine‐malate, the activity of the individual complexes of the respiratory chain, and the concentration of mitochondrial cytochromes were comparable in control subjects and alcoholic patients, and also in myopathic and nonmyopathic alcoholic patients. These results demonstrate that alcoholic myopathy is not associated with a deficiency in mitochondrial energy supply.
Shared T‐cell receptor gene usage in experimental allergic neuritis and encephalomyelitis
Authors: Clark Lise , Heber‐Katz Ellen , Rostami Abdolmohamad
Published: January 2005

Experimental allergic neuritis, an autoimmune disease of the peripheral nervous system, is a model for human Guillain‐Barré syndrome. Experimental allergic neuritis is mediated by CD4+ T cells reactive with myelin P2 protein. We demonstrate that these T cells use the same members of T‐cell receptor V gene families for both their alpha (Vα2) and beta (Vβ8) chains as T cells that cause experimental allergic encephalomyelitis, an autoimmune disease of the central nervous system. Furthermore, these T cells appear to be idiotypically related. Therefore, completely different T‐cell lines with different antigen specificities, producing entirely different diseases, share common T‐cell receptors.
3‐O‐methyldopa administration does not alter fluorodopa transport into the brain
Authors: Guttman Mark , Léger Gabriel , Cedarbaum Jesse M. , Reches Avinoam , Woodward William , Evans Alan , Diksic Mirko , Gjedde Albert
Published: January 2005

To determine if 3‐O‐methyldopa (3OMd) significantly inhibits the transport of 6‐{18F} fluorodopa (6‐FD) into the brain at the concentration normally encountered during L‐dopa administration, we performed 6‐FD studies with positron emission tomography in cynomolgus monkeys in the presence and absence of 3OMd. Infusion of 3OMd was designed to produce plasma concentrations equivalent to those seen in patients on chronic L‐dopa therapy. Plasma 3OMd levels of 39 ± μM did not alter the blood–brain transfer rate of 6‐FD. 6‐FD positron emission tomographic studies in parkinsonian patients will therefore not be altered by 3OMd present in the blood in those patients taking L‐dopa preparations. These results do not support the hypothesis that transport of L‐dopa into the brain is inhibited by 3OMd to cause the declining response seen in patients with advanced Parkinson's disease.
Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome
Authors: Chiba Atsuro , Kusunoki Susumu , Shimizu Teruo , Kanazawa Ichiro
Published: January 2005

We studied serum anti‐glycolipid antibodies by enzymelinked immunosorbent assay and thin‐layer chromatography–enzyme immunoassay in six consecutive patients with typical Miller Fisher syndrome. In all six, increased activity of IgG antibody against ganglioside GQ1b was present in the early phase and reduced with time, whereas such activity was not detected in normal control subjects and disease control subjects including those with Guillain‐Barrë syndrome. Anti‐GQ1b IgG antibody is a new possible diagnostic marker of Miller Fisher syndrome and could well be related to the disease process itself.
Sensory neuropathy associated with monoclonal immunoglobulin M to GD1b ganglioside
Authors: Daune Geneviè C. , Farrer Robert G. , Dalakas Marinos C. , Quarles Richard H.
Published: January 2005

A 67‐year‐old woman with a sensory polyneuropathy was shown to have a serum monoclonal immunoglobulin M λ antibody with a titer of 1:10,000 toward GD1b ganglioside. The immunoglobulin M also reacted with some other gangliosides containing disialosyl groups such as GD2, GD3, and GQ1b, but it did not react with GM1, LM1, or GD1a. The principal reactive ganglioside in human cauda equina was GD1b.
Human immunodeficiency virus type 1–infected monocytic cells can destroy human neural cells after cell‐to‐cell adhesion
Authors: Tardieu Marc , Héry Christiane , Peudenier Sylviane , Boespflug Odile , Montagnier Luc
Published: January 2005

Primary cultures of human embryonic neurons and astrocytes have been used to test the interactions between neural cells and either human immunodeficiency virus type 1 (HIV‐1) or HIV‐1–infected monocytes. After direct infection with HIV‐1, neither morphological alteration of neurons and astrocytes nor signs of viral replication were observed. Similarly, cultured human neurons and astrocytes were resistant to incubation with the supernatant of HIV‐1–infected U937 cells, a human monoblastoid cell line. In contrast, HIV‐1–infected U937 monocytic cells adhered to neural cells and induced large plaques of necrosis surrounding them. This cytopathic effect began at the time of viral replication (day 16 after infection). Its intensity depended on that of viral replication, and its range was identical to the region of diffusion of viral antigens, as judged by immunocytochemistry. The cytopathic effect was not dependent on the release of free radicals. It could not be induced by cytokines or cytokine‐stimulated U937 cells. It is likely that this cytopathic effect depends on the release of viral antigens either within the site of adherence itself or within close range of the astrocyte membrane.
Ganglioside GD1b is the target antigen for a biclonal IgM in a case of sensory‐motor axonal polyneuropathy: Involvement of N‐acetylneuraminic acid in the epitope
Authors: Younes‐Chennoufi Amena Ben , Léger Jean‐Marc , Hauw Jean‐Jacques , Preud'Homme Jean‐Louis , Bouche Pierre , Aucouturier Pierre , Ratinahirana Heri , Lubetzki Catherine , Lyon‐Caen Olivier , Baumann Nicole
Published: January 2005

We report on a 54‐year‐old man with a sensory‐motor polyneuropathy associated with a biclonal IgM‐k gammopathy, which reacted with the ganglioside GD1b. Examination of nerve biopsy specimens showed some reduction in the density of myelinated fibers and axonal degeneration with a loss of large fibers and a relative increase in the density of small fibers. Immunodetection on thin‐layer chromatography of the glycolipid antigens showed strong reactivity of the patient's serum IgM‐k with GD1b ganglioside and weak binding to GD1a. The biclonal IgM antibodies did not react with GM1, asialo‐GM1, GT1b, GD2, or GD3. Indirect immunofluorescence staining showed binding of IgM‐k mainly in a crescent‐like pattern on the internal side of myelin sheaths, which could correspond either to an enlarged periaxonal (adaxonal) space or to the internal mesaxon or to both. The immunostaining was abolished after absorption of the serum with GD1b.
Physiological abnormalities in hereditary hyperekplexia
Authors: Matsumoto Joseph , Fuh Peter , Nigro Michael , Hallett Mark
Published: January 2005

Five patients from a kindred with hereditary hyperekplexia had physiological testing. The surface‐recorded electromyographic pattern of audiogenic muscle jerks was identical to that of the normal acoustic startle reflex. Testing at graded stimulus intensities indicated an increase in the gain of the acoustic startle reflex. Nose‐tap stimuli resulted in short‐latency generalized electromyographic bursts that were similar to the R1 component of the blink reflex. Electrical stimulation of peripheral nerves elicited a pattern of generalized muscle jerks that was similar to that of the acoustic startle reflex. Somatosensory evoked potentials, brainstem auditory evoked potentials, and cortical auditory evoked potentials were normal. The primary physiological abnormality in hereditary hyperekplexia is widespread elevated gain of vestigial withdrawal reflexes in the brainstem and possibly the spinal cord, most likely resulting from increased excitability of reticular neurons.
Dystonia induced by combined treatment with L‐dopa and MK‐801 in parkinsonian monkeys
Authors: Rupniak N. M. J. , Boyce S. , Steventon M. J. , Iversen S. D. , Marsden C. D.
Published: January 2005

We examined whether the N‐methyl‐D‐aspartate antagonist MK‐801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L‐dopa in primates treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK‐801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK‐801 (0.1 mg/kg) with L‐dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK‐801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.