bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased risk of mortality in alzheimer's disease patients with more advanced educational and occupational attainment
Authors: Stern Yaakov , Tang Ming Xi , Denaro Jean , Mayeux Richard
Published: January 2005

A reserve hypothesis suggests that clinical symptoms of Alzheimer's disease (AD) begin earlier in individuals with less education. Therefore, patients with less education might survive longer after diagnosis than those with more education. Two hundred forty‐six subjects with probable AD were following for 1 to 4 years. There were 78 deaths; 30 deaths occurred in the 127 patients whose education was ≤8 years, while 48 deaths occured in the 119 patients with <8 years of education. Cox proportional hazards models adjusted for age, gender, and clinical dementia rating (CDR) showed that patients with more education had increased mortality (continuous variable: RR = 1.06 for each years of education; 95% confidence interval {CI}, 1.01‐1.11; dichotomous variable at 8 yr: RR = 1.76; CI, 1.11‐2.77). This observation might at first seem counterintuitve, since groups with lower socioeconomic status are often at greater mortality risk. It implies that at any level of assessed clinical severity, the underlying pathology of AD is more advanced in patients with more education, resulting in shorter duration of diagnosed disease before death. These findings suggest either that education systematically influences global ratings of disease severity or that education provides a reserve against the clinical manifestation of AD pathology.
Acetylcholine release in myasthenia gravis: Regulation at single end‐plate level
Authors: Plomp Jaap J. , van Kempen Gertrudis TH. H. , de Baets Marc BscH. , Graus Yvo M. F. , Kuks Jan B. M. , Molenaar Peter C.
Published: January 2005

In myasthenia gravis, loss of acetylcholine receptors at motor end‐plates is induced by antireceptor autoantibodies. At end‐plates in rats in which myasthenia gravis–like symptoms are induced by chronic treatment with α‐bungarotoxin, acetylcholine release is increased. Within muscles from such rats there is a strong correlation between the increase of acetylcholine release at an end‐plate and the loss of postsynaptic acetylcholine receptors, caused by the toxin. The question is whether upregulation of acetylcholine release is a clinically relevant compensatory mechanism in myasthenia gravis or only a feature of the animal model using α‐bungarotoxin. We investigated electrophysiologically the in vitro acetylcholine release at end‐plates of muscles from patients with myasthenia gravis and rats with experimental autoimmune myasthenia gravis where acetylcholine receptor reduction is caused by autoantibody attack. In both human and rat autoimmune myasthenic muscle, the mean quantal content was considerably increased compared with control levels. At each individual myasthenic end‐plate, the increase in quantal content appeared to be correlated with the reduction of the amplitude of the miniature end‐plate potential. This finding suggests the existence of an important compensatory mechanism in myasthenia gravis, in which retrograde acting factors (i.e., from muscle fiber to nerve terminal) upregulate acetylcholine release.
The vasculopathy of varicella‐zoster virus encephalitis
Authors: Amlie‐Lefond Catherine , Kleinschmidt‐Demasters Bette K. , Mahalingam Ravi , Davis Larry E. , Gilden Donald H.
Published: January 2005

Varicella‐zoster virus (VZV) encephalitis has become more prevalent in the era of acquired immunodeficiency syndrome and other immunosuppressive diseases and poses diagnostic and therapeutic challenges for clinicians, radiologists, and pathologists. Six cases studied at our institutions shed light on the patterns and pathogenesis of the disease. VZV encephalitis is predominantly a vasculopathy, involving small and large vessels, that generates seizures, mental changes, and focal deficits. Brain imaging reveals large and small ischemic or hemorrhagic infarcts, often both, of cortex and subcortical gray and white matter. Deep‐seated white matter lesions often predominate and are ischemic and/or demyelinative, depending on the size of blood vessels involved and the amount of additional demyelination caused by infection of oligodendrocytes. The demyelinative lesions are smaller and less coalescent than those seen in progressive multifocal leukoencephalopathy.
Interleukin‐6 and interleukin‐1 receptor antagonist in acute stroke
Authors: Beamer Nancy B. , Coull Bruce M. , Clark Wayne M. , Hazel J. Samantha , Silberger Jenny R.
Published: January 2005

Elevated plasma levels of interleukin‐6 (IL‐6), a key regulator of the acute phase response that includes increased fibrinogen synthesis, have recently been detected in patients with acute stroke. Nevertheless, the role of the acute phase response in stroke has been controversial, with some studies suggesting that preexisting infection accounts for most of the acute phase response. Increased IL‐6 could signal the involvement of antiinflammatory activity, since IL‐6 stimulates the production of endogenous antiinflammatory mediators such as interleukin‐1 receptor antagonist (IL‐1RA). To better understand the interaction of pro‐ and antiinflammatory acute phase processes in brain infarction, plasma levels of IL‐1RA, IL‐6, and acute phase proteins including fibrinogen and c‐reactive protein (CRP) were measured within 4 ± 2 days of onset in 50 patients with acute ischemic stroke and in 20 age‐matched healthy controls. After excluding patients with evidence of infection, both IL‐1RA and IL‐6 were significantly elevated in stoke patients compared with controls (p<0.0001). IL‐1RA and IL‐6 were both significantly correlated with levels of CRP, p<0.05 and p<0.001, respectively, but not with each other. Levels of IL‐6 and IL‐1RA, together with fibrinogen and CRP were higher in patients with infarcts of greater than 3 cm and lowest in patients with lacunar syndromes. Detection of increased peripheral levels of IL‐1RA, IL‐6, and additional acute phase reactants, including CRP, in acute stroke uncomplicated by infection suggests that an acute phase response to brain infarction occurs and that the magnitude of this response may be related to the volume of infarcted brain.
Regional distribution of protease‐resistant prion protein in fatal familial insomnia
Authors: Parchi Piero , Castellani Rudy , Cortelli Pietro , Montagna Pasquale , Chen Shu G. , Petersen Robert B. , Manetto Valeria , Vnencak‐Jones Cindy L. , McLean Michael J. , Sheller James R. , Lugaresi Elio , Autilio‐Gambetti Lucila , Gambetti Pierluigi
Published: January 2005

Protease‐resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 ± 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 ± 11 months). In all subjects, protease‐resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease‐resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease‐resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease‐resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease‐resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration. These findings indicate that in fatal familial insomnia, the pathological phenotype is the result of the variability, in different brain regions, of the (1) timing and rate of accumulation of protease‐resistant prion protein, and (2) vulnerability to the presence of protease‐resistant prion protein.
Mutational analysis of familial and sporadic hyperekplexia
Authors: Shiang Rita , Ryan Stephen G. , Zhu Ya‐Zhen , Fielder Thomas J. , Allen Richard J. , Fryer Alan , Yamashita Sumimasa , O'Connell Peter , Wasmuth John J.
Published: January 2005

Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the ϵ1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg271 by a glutamine (R271Q) in one case and a leucine (R271L) in the other. Here, 5 additional hyperekplexia families are shown to have the most common G‐to‐A transition mutation at nucleotide 1192. Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times). In 2 additional families, a third mutation is also presented that changes a tyrosine at amino acid 279 to a cysteine (Y279C). Five patients with atypical clinical features and equivocal or absent family history of hyperekplexia and 1 patient with a classical presentation but no family history are presented in whom a mutation in the GLRA1 gene was not detected. Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.
Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease
Authors: Sorbi Sandro , Nacmias Benedetta , Forleo Paolo , Piacentini Silvia , Latorraca Stefania , Amaducci Luigi
Published: January 2005

We found a new familial Alzheimer's disease kindred in which the disease cosegregates with the APP717Val‐→Ile mutation and in which all of the three most common apolipoprotein E (ApoE) alleles are represented. We studied the relationship between ApoE genotype and the clinical expression of the disease and found that in this amyloid precursor protein‐mutated family, ApoE genotype influences the age at onset of the disease. Three mutated subjects heterozygous for the ϵ4 allele had the earliest age at onset in this family, subjects heterozygous for the ϵ2 allele had the latest age at onset, and subjects homozygous for the ϵ3 allele had an intermediate age at onset. In this large kindred we also found an amyloid precursor protein‐mutated subject 2.4 standard deviations older than the mean age at onset without clinical signs and symptoms of the disease and carrying the ϵ2/ϵ3 genotype.
Multifocal enhancing magnetic resonance imaging lesions following cranial irradiation
Authors: Peterson Kendra , Brent Clark H. , Hall Walter A. , Truwit Charles L.
Published: January 2005

Radiation necrosis is a delayed complication of cranial irradiation, typically presenting as a single intracerebral mass that is radiographically indistinguishable from recurrent tumor. We describe 6 patients with a distinct radiographic syndrome of multifocal enhancing lesions on magnetic resonance images, and their variable clinical courses: some fluctuating, some spontaneously resolving, and some demonstrating fulminant progression to frank necrosis.
Cellular activity underlying altered brain metabolism during focal epileptic activity
Authors: Bruehl Claus , Witte Otto W.
Published: January 2005

Demonstration of focal alterations of brain metabolism with positron emission tomography has become a widely used method for identifying epileptic foci. Here we investigated how neuronal and glial cell activity relates to alterations of brain metabolism. Acutely induced epileptic activity in the motor cortex of rat brain increased metabolism in the focus and homotopic contralateral areas, and decreased metabolism in the ipsilateral somatosensory area. Increases and decreases of deoxyglucose uptake did not directly correlate with excitations and inhibitions; instead, deoxyglucose uptake was related to the overall strength of synaptic activity, and both strong excitations and strong inhibitions increased brain metabolism. Reduction of metabolism below normal values was associated with reduced synaptic activity and with tonic hyperpolarization of the cells. Our results show that in the absence of structural abnormalities, hypometabolism indicates functional disturbances which may be both reversible and remote from the epileptogenic focus.
Influx of nonactivated T lymphocytes into the cerebrospinal fluid during relapse of multiple sclerosis
Authors: Oksaranta Olli , Tarvonen Sinikka , Ilonen Jorma , Poikonen Kari , Reunanen Mauri , Panelius Martin , Salonen Reijo
Published: January 2005

T lymphocytes were analyzed in the cerebrospinal fluid of 17 patients with multiple sclerosis during and 2 months after an exacerbation. The percentage of activated (HLA‐DR+) T lymphocytes was decreased in the cerebrospinal fluid during the relapse but returned thereafter to the level comparable to that in patients with noninflammatory neurological diseases, whereas no fluctuation in the total number of these cells was found. This suggests an influx of nonactivated T lymphocytes into the cerebrospinal fluid at the beginning of the relapse.
The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease
Authors: Chen Xiaohua , Xia Yu , Alford Michael , DeTeresa Richard , Hansen Lawrence , Klauber Melville R. , Katzman Robert , Thal Leon , Masliah Eliezer , Saitoh Tsunao
Published: January 2005

Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele, in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic Marchkers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.
Aphasia in acute stroke: Incidence, determinants, and recovery
Authors: Pedersen Palle Møller , Stig Jørgensen Henrik , Nakayama Hirofumi , Raaschou Hans Otto , Olsen Tom Skyhøj
Published: January 2005

Knowledge of the frequency and remission of aphasia is essential for the rehabilitation of stroke patients and provides insight into the brain organization of language. We studied prospectively and consecutively an unselected and community‐based sample of 881 patients with acute stroke. Assessment of aphasia was done at admission, weekly during the hospital stay, and at a 6‐months follow‐up using the aphasia score of the Scandinavian Stroke Scale. Thirty‐eight percent had aphasia at the time of admission; at discharge 18% had aphasia. Sex was not a determinant of aphasia in stroke, and no sex difference in the anterior‐posterior distribution of lesions was found. The remission curve was steep: Stationary language function in 95% was reached within 2 weeks in those with initial mild aphasia, within 6 weeks in those with moderate, and within 10 weeks in those with severe aphasia. A valid prognosis of aphasia could be made within 1 to 4 weeks after the stroke depending on the initial severity of aphasia. Initial severity of aphasia was the only clinically relevant predictor of aphasia outcome. Sex, handedness, and side of stroke lesion were not independent outcome predictors, and the influence of age was minimal.
Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system
Authors: Pachner Andrew R. , Delaney Elizabeth , O'Neill Tim
Published: January 2005

Neurological involvement in Lyme disease is common, and is frequently difficult to diagnose and treat. Little is known about the fate of the causative spirochete Borrelia burgdorferi in the central nervous system (CNS). To determine the frequency of parenchymal infection and to determine localization of the organism, polymerase chain reaction/hybridization assays were performed in a newly described model of Lyme neuroborreliosis in nonhuman primates infected with B. burgdorferi. Polymerase chain reaction/hybridization of CNS tissues from 5 infected nonhuman primates was performed. Substantial amounts of B. burgdorferi DNA were detected in the CNS in all infected animals, with a predilection toward subtentorial structures. These data suggest that Lyme neuroboreliosis represents persistent infection with B. burgdorferi.
Chronic inflammatory demyelinating polyneuropathy complicating liver transplantation
Authors: Taylor Bruce V. , Wijdicks Eelco F. M. , Poterucha John J. , Weisner Russel H.
Published: January 2005

We report on a patient who had chronic inflammatory demyelinating polyradiculoneuropathy following liver transplantation for hepatitis B‐induced fulminate hepatic failure. Possible symptomatic recurrence of hepatitis B in the graft prompted a reduction in the cyclosporine dosage, which may have triggered the immune response leading to demyelination. Initial plasma exchange and then intravenous immune globulin after relapse led to Marchked clinical improvement.
Preferential loss of preproenkephalin versus preprotachykinin neurons from the striatum of Huntington's disease patients
Authors: Richfield Eric K. , Maguire‐Zeiss Kathleen A. , Vonkeman Harald E. , Voorn Pieter
Published: January 2005

Preferential loss of basal ganglia neurons and terminals occurs in Huntington's disease (HD). Terminals of preproen‐kephalin medium‐size spiny neurons are more vulnerable than terminals of preprotachykinin neurons, but the peptidergic neurons of origin have not yet been shown to die preferentially. We sought to determine, in the striatum, whether preproenkephalin neurons were lost to a greater extent than preprotachykinin neurons and to determine whether there were decreases in specific messenger RNA (mRNA) levels of preproenkephalin, preprotachykinin, and calbindin D28k. We found a grade‐related decrease in the number of preprotachykinin‐ and calbindin D28k—labeled neurons per measuring field in the caudate nucleus of patients with HD. Three measures of the neuronal level of preprotachykinin mRNA were all significantly reduced (6–65% of control values) in HD caudate nucleus. No decline in calbindin D28k mRNA levels per neuron were found in HD striata compared to control striata. We found a greater loss of preproenkephalin neurons per field than preprotachykinin neurons per field in the caudate nucleus of HD brains compared to control brains. Preprotachykinin neurons are lost in HD in a grade‐related manner and surviving preprotachykinin neurons are impaired in function. However, preproenkephalin neurons are lost to a greater extent than preprotachykinin neurons, which may explain preferential changes found in projection regions of the striatum. Declines in neuropeptide mRNA may be specific in HD, since calbindin D28k mRNA levels were unchanged. Alterations in the levels of expression of preproenkephalin and preprotachykinin mRNA may be direct or indirect effects of the HD mutation.
Cerebellar outflow lesions: A comparison of movement deficits resulting from lesions at the levels of the cerebellum and thalamus
Authors: Bastian A. J. , Thach W. T.
Published: January 2005

Previous work has shown that lesions in the lateral cerebellum involving the dentate nucleus impair both reaching and pinching movements in humans and monkeys. This study addressed the question of whether disruption of the cerebellar‐thalamo‐cortical pathway at the level of the thalamus would produce behavioral deficits similar to those seen after dentate damage. We compared the performance of both reaching and pinching movements in patients with lateral cerebellar lesions and in patients with discrete lesions of the ventrolateral thalamus. The patients with thalamic lesions had minimal or no sensory loss and no corticospinal signs, suggesting that the abnormal movements were due to disruption of the cerebellar projection to the thalamus. We found that lesions of the ventrolateral thalamus resulted in impaired pinching movements, but remarkably normal reaching movements with the exception of a slight tremor. This is in contrast to the profound pinching and reaching impairments of patients with lateral cerebellar lesions involving the dentate nucleus. Implications about the functional organization of cerebellar output are discussed.
Apolipoprotein E ϵ4 in inclusion body myositis
Authors: Garlepp Michael J. , Tabarias Hyacinth , van Bockxmeer Frank M. , Zilko Paul J. , Laing Beverley , Mastaglia Frank L.
Published: January 2005

The genetic predisposition to inclusion body myositis (IBM) is probably multifactorial. The deposition of the β‐amyloid protein is a characteristic histological feature of both IBM and Alzheimer's disease (AD). The ϵ4 allele of apolipoprotein E (APO E) has been strongly associated with familial and late‐onset AD. We therefore compared the APO E allele frequencies in a group of 14 patients with IBM with those in a group of patients with other inflammatory muscle diseases and in the general population. The frequency of the ϵ4 allele in IBM was increased (0.29) compared with that in patients with other inflammatory muscle diseases (0.15) and the general population (0.13) (p < 0.05). These data suggest that APO E genotype may be one of the factors involved in determining the predisposition to the development of IBM.
Pathology of the motor‐sensory axonal Guillain‐Barré syndrome
Authors: Griffin J. W. , Li C. Y. , Ho T. W. , Tian M. , Gao C. Y. , Xue P. , Mishu B. , Cornblath D. R. , Macko C. , McKhann G. M. , Asbury A. K.
Published: January 2005

The concept of a severe motor‐sensory neuropathy of acute onset caused by an immune attack on the axon (“axonal” Guillain‐Barré syndrome) has been advanced primarily based on electrodiagnostic and limited pathological data, but remains controversial. At autopsy some cases demonstrate unusually severe inflammatory demyelinating neuropathy. There are conflicting data about whether antecedent Campylobacter jejuni infection is associated with “axonal” Guillain‐ Barré syndrome. We report 4 individuals from Hebei Province, China, who died 7, 7, 18, and 60 days after onset of a syndrome diagnosed clinically as Guillain‐Barré syndrome. High titers of antibodies recognizing C. jejuni, consistent with recent infection, were found in the 2 patients tested. At autopsy the 3 with early disease had ongoing wallerian‐ like degeneration of fibers in the ventral and dorsal roots and in the peripheral nerves, with only minimal demyelination or lymphocytic infiltration. All 3 had numerous macrophages in the periaxonal space of myelinated internodes, and rare intraaxonal macrophages as well. Examination of the patient having the syndrome for 60 days confirmed the extensive loss of large fibers in the spinal roots and nerves, and the paucity of demyelination and remyelination. These observations confirm predictions that some patients with severe motor‐sensory Guillain‐Barré syndrome, as defined clinically, have predominantly axonal lesions of both motor and sensory fibers, even in the early stages of the disease, and that axonal Guillain‐Barré syndrome can follow C. jejuni infection. The pathology supports the possibility that such cases of motor‐sensory axonal Guillain‐Barré syndrome represent the most severe end of a spectrum of immune attack directed toward epitopes on the axon.
Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa
Authors:   Parkinson Study Group
Published: January 2005

The Deprenyl and Tocopherol Antioxidant Therapy of Parkinsonism (DATATOP) trial was designed to test outcomes from treatment with 10 mg of deprenyl and/or 2,000 mg of tocopherollday in 800 untreated patients with Parkinson's disease. The need of subjects for symptomatic treatment with levodopa and the conversion of all subjects to open‐label deprenyl made it possible to study the long‐term effect of early deprenyl and tocopherol treatment on the later development of levodopa‐associated side effects. The rate of developing these side effects did not differ among the original treatment groups (early versus late deprenyl and tocopherol versus nontocopherol). About 50% of subjects developed “wearing off,” 30% dyskinesias, and 25% “freezing” in each group. At the end of the study, the groups were similarly disabled on the Hoehn‐Yahr, Schwab‐England, and Unified Parkinsonapos;s Disease Rating scales and took similar amounts of levodopa. Young subjects were more likely to develop wearing off, women to develop dyskinesias, and older subjects with rapidly progressive disease to develop freezing. We conclude that prior treatment with deprenyl or tocopherol did not reduce the occurrence of subsequent levodopa‐associated adverse effects in this population.
Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease
Authors: Gomez‐Isla Teresa , West Howard L. , Rebeck G. William , Harr Steven D. , Growdon John H. , Locascio Joseph J. , Perls Thomas T. , Lipsitz Lewis A. , Hyman Bradley T.
Published: January 2005

Inheritance of the apolipoprotein E (apoE) ε4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE ε4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty‐one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and Aβ deposits were assessed in a high‐order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the ε4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. Aβ deposition, by contrast, was not related to clinical features but was elevated in association with apoE ε4. These results indicate that apoE ε4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE ε4 on amyloid deposition.
Proton magnetic resonance spectroscopic imaging in patients with cerebellar degeneration
Authors: Tedeschi Gioacchino , Bertolino Alessandro , Massaquoi Steve G. , Campbell Gregory , Patronas Nicholas J. , Bonavita Simona , Barnett Alan S. , Alger Jeffrey R. , Hallett Mark
Published: January 2005

Using proton magnetic resonance spectroscopic imaging, we studied the cerebellum of 9 patients with cerebellar degeneration and of 9 age‐matched normal control subjects. This technique permits the simultaneous measurement of N‐ acetylaspartate, choline‐containing compounds, creatine/phosphocreatine, and lactate signal intensities from four 15‐mm slices divided into 0.84‐ml single‐volume elements. Because patients with cerebellar degeneration often show substan‐ tial atrophy on magnetic resonance imaging (MRI), we specifically chose to analyze the spectroscopic signals only from tissue that did not have an atrophic appearance on the MRI. The spectroscopic findings showed a significant reduction of N‐acetylaspartate in all parts of the cerebellum, a significant correlation with MRI scores of cerebellar atrophy, and a significant correlation with clinical rating scores of cerebellar disturbance. Our method of analysis suggests the presence of a neurodegenerative process in cerebellar areas that do not appear to be atrophic on the MRI. Some limitations of proton magnetic resonance spectroscopic imaging in the present study were related to the partial field inhomogeneity characteristics of the posterior fossa, the anatomical location of the cerebellum, and the particularly severe cerebellar atrophy in some of the patients.
A placebo‐controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis
Authors: Miller Robert G. , Petajan Jack H. , Bryan Wilson W. , Armon Carmel , Barohn Richard J. , Goodpasture Jessie C. , Hoagland Rebecca J. , Parry Gareth J. , Ross Mark A. , Stromatt Scott C. ,   rhCNTF ALS Study Group
Published: January 2005

Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double‐blind, placebo‐controlled trial in 570 patients with US. Patients were randomized to receive 0.5, 2, or 5 μg/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on‐ treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities‐of‐daily‐living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no benefical effect on any measure of ALS progression. There were increased adverse events in the 5 μg/kg group and increased deaths.
Neuronal migration abnormality in peroxisomal bifunctional enzyme defect
Authors: Kaufmann Walter E. , Theda Christiane , Naidu Sakkubai , Watkins Paul A. , Moser Ann B. , Moser Hugo W.
Published: January 2005

Patterns of brain dysgenesis that resemble those in the Zellweger syndrome were demonstrated in a boy with an isolated defect of the peroxisomal bifunctional enzyme. There was bilateral centrosylvian pachygyria and polymicrogyria, diffuse hemispheric hypomyelination with heterotopic neurons, Purkinje cell heterotopias, and simplified convolutions of the dentate nucleus and inferior olive. This association of Zellweger syndrome–like brain dysgenesis with a defect of a single peroxisomal enzyme provides new opportunities for the study of pathogenetic mechanisms in peroxisomal disorders.
Cerebellar hypermetria associated with a selective decrease in the rate of rise of antagonist activity
Authors: Manto M. , Godaux E. , Jacquy J. , Hildebrand J.
Published: January 2005

Classically, cerebellar hypermetria observed during fast and accurate movements i s ascribed to a delayed onset of the electromyographic activity of the antagonist muscle. We describe here 3 patients presenting a late‐onset cerebellar degeneration and exhibiting a hypermetria during their fast and accurate movements in spite of a normal onset latency of the antagonist activity. Hypermetria was found to be due to a slower rate of rise of the antagonist activity.
Leigh syndrome: Clinical features and biochemical and DNA abnormalities
Authors: Rahman S. , Blok R. B. , Dahl H.‐H. M. , Danks D. M. , Kirby D. M. , Chow C. W. , Christodoulou J. , Thorburn D. R.
Published: January 2005

We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, ie, 80% in the tightly defined group and 41% in the “Leigh‐like” group. Eleven patients had mitochondrial DNA point mutations (nucleotide [nt] 8993 T to G, nt 8993 T to C, or nt 8344 A to G) and 1 Leigh‐like patient had a heteroplasmic deletion. Twenty‐nine patients had enzyme defects, ie, 13 respiratory chain complex I, 9 complex IV, and 7 pyruvate dehydrogenase complex (PDHC). Complex I deficiency is more common than recognized previously. Six PDHC‐deficient patients had mutations in the X‐chromosomal gene encoding the Elα subunit of PDHC. Parental consanguinity suggested autosomal recessive inheritance in two complex IV‐deficient sibships. We found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance (frequently made in the past) would have been wrong in nearly one‐half (1 1 of 28 tightly defined and 18 of 41 total patients) of those in whom a cause was found. A specific defect must be identified if reliable genetic counseling is to be provided.
Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors
Authors: Janss Anna J. , Yachnis Anthony T. , Silber Jeffrey H. , Trojanowski John Q. , Lee Virginia M.‐Y. , Sutton Leslie N. , Perilongo Giorgio , Rorke Lucy B. , Phillips Peter C.
Published: January 2005

Primitive neuroectodermal tumors (PNETs) of the central nervous system, including medulloblastomas (PNET/MB), are the most common malignant brain tumor of childhood. These tumors often express proteins characteristic of glial differentiation (glial fibrillary acidic protein, GFAP), neuronal differentiation (neurofilament proteins, NFPs), and/or photoreceptor differentiation (retinals antigen). To identify biological factors of prognostic significance in PNETs, the expression of glial, neuronal, or photoreceptor antigens was evaluated in the tumor specimens of 86 patients with PNETs by immunohistochemistry after microwave antigen enhancement. Patterns of differentiation were then compared with patient relapse‐free survival. Multivariate analysis of PNET immunohistochemistry and clinical variables indicated GFAP expression conferred a 6.7‐fold greater risk of relapse than tumors that did not express GFAP or NFPs. Increased risk of relapse was directly related to the amount of GFAP expression. Tumors exhibiting clumps or sheets of GFAP‐staining cells were associated with a 3.0‐fold increased risk of relapse compared with tumors that did not express GFAP, irrespective of immunohistochemical evidence of other differentiation, while scattered GFAP staining was not associated with increased risk of relapse. These findings indicate that expression of GFAP in PNETs has prognostic power comparable with the most significant clinical factors currently used to predict clinical outcome.
Brain protein and α‐ketoglutarate dehydrogenase complex activity in alzheimer‐s disease
Authors: Mastrogiacomo Frank , Lindsay J. Gordon , Bettendorff Lucien , Rice Jacqueline , Kish Stephen J.
Published: January 2005

To determine whether the reduction in brain α‐ketoglutarate dehydrogenase complex activity in Alzheimer's disease (AD) is associated with an abnormality in one of its three constituent enzyme subunits, we measured protein levels of α‐ketoglutarate dehydrogenase (El), dihydrolipoamide succinyltransferase (E2), and dihydrolipoamide dehydrogenase (E3), in postmortem brain of 29 patients with AD (mean age, 73 years; age range of onset, 50‐78 years) and 29 control subjects. In the AD group protein levels of all three subunits were significantly reduced by 23 to 41% in the temporal cortex, whereas in the parietal cortex (El: −28% E3: −32%) and hippocampus (E3: −33%) significant changes were limited to El and E3. α‐Ketoglutarate dehydrogenase complex activities were more markedly reduced (by 46‐68%) and did not correlate with protein levels, suggesting that decreased enzyme activity cannot be primarily explained by loss of α‐ketoglutarate dehydrogenase complex protein. We did not find two E2 immunoreactive forms in the brain of any patient, as has been reported in fibroblasts of patients with very‐early‐onset chromosome 14‐linked AD. We conclude that brain protein and activity levels of α‐ketoglutarate dehydrogenase complex are reduced in patients with AD who have onset after 50 years and suggest that these changes, which are also observed in other human brain disorders, may represent a nonspecific consequence of different neurodegenerative processes. Nevertheless, reduced levels of this ratelimiting enzyme of the Krebs cycle could contribute to the brain neurodegenerative mechanisms of AD.
Antiamphiphysin antibodies with small‐cell lung carcinoma and paraneoplastic encephalomyelitis
Authors: Dropcho Edward J.
Published: January 2005

Paraneoplastic encephalomyelitis developed as the presenting feature of small‐cell lung carcinoma in 3 patients. Two patients with paraneoplastic encephalomyelitis manifested predominantly as subacute sensory neuronopathy did not improve after prednisone treatment and chemotherapy. The third patient had seyere axial and limb rigidity and myoclonus, which partially improved after chemotherapy and treatment with intravenous immunoglobulin and prednisone. Serum from each patient immunocytochemically stained the neuropil and to a lesser degree the neuronal cytoplasm in human cerebral and cerebellar cortex. On immunoblots of human neuronal extracts, each patient's serum contained high‐titer IgG antibodies reacting with a protein band of apparent molecular mass 125 kd. This autoantibody pattern is indistinguishable from antibodies recently identified in several women with breast carcinoma and stiff‐man syndrome. Screening of a human brain complementary DNA expression library with patient serum yielded clones whose sequence is identical to that of the synaptic vesicle‐related protein amphiphysin. Reverse transcriptase‐polymerase chain reaction demonstrated expression of amphiphysin in 8 of 10 small‐cell lung carcinomas and in 5 of 14 breast carcinomas. These observations highlight the clinical and serological heterogeneity of paraneoplastic central nervous system disorders: Patients with a given clinical syndrome may have different antineuronal antibodies, and patients with a given autoantibody specificity have differing clinical presentations.
Localization of HIV‐1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry
Authors: Takahashi Kiyomi , Wesselingh Steven L. , Griffin Diane E. , McArthur Justin C. , Johnson Richard T. , Glass Jonathan D.
Published: January 2005

Human immunodeficiency virus type 1 (HIV‐1) infects the brains of a majority of patients with the acquired immunodeficiency syndrome (AIDS), and has been linked to the development of a progressive dementia termed “HIV‐associated dementia.” This disorder results in severe cognitive, behavioral, and motor deficits. Despite this neurological dysfunction, HIV‐1 infection of brain cells does not occur significantly in neurons, astrocytes, or oligodendrocytes, but is restricted to brain macrophages and microglia. To identify possible low‐level or latent infection of other brain cells, we combined the techniques of the polymerase chain reaction with in situ hybridization for the detection of HIV DNA, and used immunocytochemistry to identify the HIV‐expressing cells. In the 21 adult brains studied (15 AIDS and 6 seronegative control brains), we found that polymerase chain reaction/in situ hybridization was both sensitive and specific for identifying HIV‐infected cells. In all brains, the majority of infected cells were macrophages and microglia. In several brains, however, a substantial minority of cells harboring HIV DNA were identified as astrocytes. Neurons, oligodendrocytes, and endothelial cells were not infected with HIV, even in cases with HIV‐associated dementia. These findings confirm previous data regarding the importance of macrophage/microglial infection, and essentially exclude neuronal infection in pathogenetic models of HIV‐associated neurological disease. These data also demonstrate that latent or low‐level infection of astrocytes occurs in AIDS, a finding that may be of importance in understanding HIV neuropathogenesis.
Gender differences in autoimmune demyelination in the mouse: Implications for multiple sclerosis
Authors: Voskuhl Rhonda R. , Pitchekian‐Halabi Hilda , Mackenzie‐Graham Allan , McFarland Henry F. , Raine Cedric S.
Published: January 2005

Gender‐related differences in experimental allergic encephalomyelitis (EAE) were examined in the SJL mouse with the purpose of characterizing an animal model ideal for the study of gender‐related differences in multiple sclerosis (MS). For the model to allow for study of the induction and the effector phase of disease, the adoptive EAE model was characterized. First, the SJL strain was shown to be nonresponsive with regard to the development of antisyngeneic HY‐specific responses in females, thereby permitting intergender adoptive transfers of T lymphocytes during EAE induction. Then, when myelin basic protein (MBP)‐specific T cells derived from females were adoptively transferred into female and male recipients, female recipients demonstrated a more rapid onset of disease (p = 0.01), greater maximal acutephase clinical scores (p < 0.0001) and greater mean clinical scores (p < 0.0001) compared with male recipients. When MBP‐specific T cells derived from males were adoptively transferred, female recipients again tended to be more severely affected. Histopathologic analysis revealed quantitative differences between genders that paralleled clinical expression. These results document a clear gender‐related difference in adoptive EAE in the SJL, with clinical and histopathologic disease greater in females compared with males. This model will be a useful tool for addressing autoimmune mechanisms underlying gender‐related differences in MS.
Hemifacial seizures and cerebellar ganglioglioma: An epilepsy syndrome of infancy with seizures of cerebellar origin
Authors: Harvey A. Simon , Jayaka Prasanna , Duchowny Michael , Resnick Trevor , Prats Antonio , Altman Nolan , Renfroe J. Benjamin
Published: January 2005

We investigated a 6‐month‐old infant with daily episodes of left hemifacial contraction, head and eye deviation to the right, nystagmoid jerks to the right, autonomic dysfunction, and retained consciousness. The episodes began on day 1 of life and were unresponsive to antiepileptic medication. Interictal and ictal scalp electroencephalographic (EEG) recordings were unremarkable. Magnetic resonance imaging revealed a mass in the left cerebellar hemisphere and peduncle. Ictal single‐photon emission computed tomography revealed focal hyperperfusion in the region of the cerebellar mass. Ictal EEG recordings with implanted cerebellar electrodes demonstrated focal seizure discharges in the region of the mass. Resection of the mass resulted in remission of seizures and histopathology revealed ganglioglioma. Six previously reported infants with similar semiology (described as “hemifacial spasm”), imaging findings, and histopathology are reviewed. We believe the previously reported infants and our patient constitute a rare but important clinicopathological syndrome of infancy characterized by epileptic seizures of cerebellar origin.
A dopaminergic neurotoxin, (R)‐N‐methylsalsolinol, increases in parkinsonian cerebrospinal fluid
Authors: Maruyama Wakako , Abe Takashi , Tohgi Hideo , Dostert Philippe , Naoi Makoto
Published: January 2005

The concentration of (R)‐N‐methylsalsolinol, which is a dopamine‐derived neurotoxin selective to dopamine neurons and induces parkinsonism in rats, was found to be increased significantly in the cerebrospinal fluid of untreated patients with Parkinson's disease. The enantiospecific occurrence of (R)‐N‐methylsalsolinol in cerebrospinal fluid suggests its enzymatic synthesis in the human brain. The individual differences in the activities of the enzymes determining the metabolism of (R)‐N‐methylsalsolinol in the brain might be involved in the pathogenesis of Parkinson's disease.
Benzodiazepine receptors in focal epilepsy with cortical dysgenesis: An 11C‐flumazenil PET study
Authors: Richardson M. P. , Koepp M. J. , Duncan J. S. , Brooks D. J. , Fish D. R.
Published: January 2005

Previous imaging studies using 11C‐flumazenil in patients with mesial temporal lobe epilepsy and neocortical partial seizure disorders have found focal decreases in γ‐aminobutyric acid type A/benzodiazepine receptor binding. These studies used subjective visual assessment and a region of interest approach to quantitation. We performed three‐dimensional, 11C‐flumazenil positron emission tomography in 12 patients with cortical dysgenesis identified by high‐resolution volumetric magnetic resonance imaging and in 26 normal subjects. Spectral analysis was used to produce a parametric image of 11C‐flumazenil volume of distribution for each subjects. Using volumetric normalization and statistical parametric mapping, we compared the entire brain volume of each patient with the brains of the normal group to produce maps of regions of abnormal 11C‐flumazenil binding which were then rendered into the volumetric magnetic resonance images. This allowed a correlation of structure and function to be made. Of the 12 patients, 10 showed at least one region of abnromal 11C‐flumazenil binding; the abnormal regions were frequently more extensive than were the lesions seen with magnetic resonance imaging. 11C‐Flumazenil binding abnormalities were frequently seen in regions of cortex that had a normal magnetic resonance appearance. Lesions were characterized by increases in γ‐aminobutyric acid type A/benzodiazepine receptor availability, and by the decreases found in previous studies. These findings have implications for the neurobiology of seizure disorders associated with cortical dysgenesis and for the management of such patients if surgery is contemplated.