bluuebunny/crossref_metadata_2025 huggingface dataset:
Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis
Authors: Miller D. H. , Albert P. S. , Barkhof F. , Francis G. , Frank J. A. , Hodgkinson S. , Lublin F. D. , Paty D. W. , Reingold S. C. , Simon J.
Published: January 2005

Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing‐remitting and secondary progressive MS, monthly T2‐weighted and gadoliniumenhanced brain MRI is an excellent tool for short‐term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6‐ to 12‐month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N‐acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1‐weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.
Dietary lipids and antioxidants in Parkinson's disease: A population‐based, case‐control study
Authors: Logroscino Giancarlo , Marder Karen , Cote Lucien , Tang Ming‐Xin , Shea Steven , Mayeux Richard
Published: January 2005

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD). In a population‐based, case‐control study we examined whether dietary intake of antioxidants and other oxidative compounds was associated with PD. Dietary intake was assessed by a semiquantitative food‐frequency questionnaire in 110 PD case patients and 287 control subjects. A higher caloric intake was observed in patients with PD and did not vary with increasing duration of symptoms. Energy‐adjusted fat intake was significantly higher among patients with PD than control subjects (p for trend = 0.007). Intake of protein (p for trend = 0.17) and carbohydrates (p for trend = 0.46) did not differ in patients and control subjects. Analyses of the primary sources of fat indicated that increasing intake of animal fats was strongly related to PD (odds ratio, 5.3; 95% confidence interval, 1.8–15.5; p for trend = 0.001). No significant differences were observed for intake of vitamins with antioxidant activity. An increase in the consumption of animal fats among patients with PD is consistent with the hypothesis that oxidative stress and lipid peroxidation are important in the pathogenesis of this disease. No effect of vitamins with antioxidant activity, either from food or supplements, was observed.
SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries
Authors: Rouleau Guy A. , Clark Arthur W. , Rooke Karen , Pramatarova Albena , Krizus Aldis , Suchowersky Oksana , Julien Jean‐Pierre , Figlewicz Denise
Published: January 2005

Mutations in the Cu/Zn superoxide dismutase (SODl) gene are found in 15 to 20% of patients with familial amyotrophic lateral sclerosis (FALS). Increased levels of neurofilament subunits in transgenic mouse models of ALS also suggests a key role for these proteins in the pathogenesis of the disease. We report the coexistence of an Ile113 → Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient. These observations suggest that two mechanisms, SOD 1‐induced toxicity and neurofilament disruption, are acting together.
Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis
Authors: Gurney Mark E. , Cutting Frank B. , Zhai Ping , Doble Adam , Taylor Charles P. , Andrus Paula K. , Hall Edward D.
Published: January 2005

Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,Zn SOD). We have used a transgenic model of FALS based on expression of mutant human Cu,Zn SOD to explore the etiology and therapy of the genetic disease. Expression of mutant, but not wild‐type, human Cu,Zn SOD in mice places the brain and spinal cord under oxidative stress. This causes depletion of vitamin E, rather than the typical age‐dependent increase in vitamin E content as occurs in nontransgenic mice and in mice expressing wild‐type human Cu,Zn SOD. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model but does not prolong survival. In contrast, two putative inhibitors of the glutamatergic system, riluzole and gabapentin, prolong survival. However, riluzole did not delay disease onset. Thus, there was clear separation of effects on onset, progression, and survival by the three therapeutics tested. This suggests the hypothesis that oxidative damage produced by the expression of mutant Cu,Zn SOD causes slow or weak excitotoxicity that can be inhibited in part by altering glutamate release or biosynthesis presynaptically.
The insulin‐like growth factor I system in cerebellar degeneration
Authors: Torres‐Aleman Ignacio , Barrios Vicente , Lledo Alberto , Berciano José
Published: January 2005

Brain insulin‐like growth factor I (IGF‐I) and its related molecules may be involved in neurodegenerative processes in which IGF‐I‐containing pathways are compromised. Since IGF‐I is present in the olivocerebellar circuitry, two types of late‐onset cerebellar ataxias (olivopontocerebellar and idiopathic cerebellar cortical atrophy) were chosen to test this hypothesis. The following significant changes in the peripheral IGF‐I system of these patients were found: low IGF‐I levels, and high IGF‐binding protein 1 (BP‐1), and BP‐3 affinity for IGF‐1. Sixty percent of the patients also had significantly low insulin levels. Patients suffering from other neurological diseases with cerebellar dysfunction and ataxia not involving the olivocerebellar pathway also had low IGF‐I levels, while IGFBPs and insulin levels were normal. Our data indicate that degeneration of an IGF‐I‐containing neuronal pathway produces significant changes in the peripheral IGF system. This suggests strongly that the endocrine (bloodborne) and the paracrine/autocrine (brain) IGF systems are linked functionally. We propose that alterations in the blood IGF‐I system may constitute a marker of some cerebellar diseases.
Quantitation of human immunodeficiency virus in brains of demented and nondemented patients with acquired immunodeficiency syndrome
Authors: Johnson Richard T. , Glass Jonathan D. , McArthur Justin C. , Chesebro Bruce W.
Published: January 2005

We measured human immunodeficiency virus (HIV) DNA in brains of 15 patients who died with acquired immunodeficiency syndrome (AIDS). All had been followed prospectively prior to death; 7 were demented and 8 were not demented. HIV was detected in 13 of 15 brains by polymerase chain reaction (PCR) and in the remaining 2 by presence of viral RNA or viral antigen. Quantitative PCR showed a wide range in amounts of HIV DNA with no significant difference between brains of demented and nondemented patients. These results suggest that qualitative features of the virus, rather than increased virus load per se, may be responsible for the clinical differences between HIV‐infected patients with and without dementia.
T Cell–mediated ganglionitis associated with acute sensory neuronopathy
Authors: Hainfellner Johann Andreas , Kristoferitsch Wolfgang , Lassmann Hans , Bernheimer Hanno , Neisser Andrea , Drlicek Marcus , Beer Franz , Budka Herbert
Published: January 2005

A 67‐year‐old man presented with acute painful sensory loss, areflexia, ataxia, urinary retention, and severe constipation and became unable to walk within 2 weeks. He died suddenly 5 weeks after the onset of symptoms. Autopsy revealed widespread inflammation of sensory and autonomic ganglia with immunocytochemical evidence of a CD8+ T cell‐mediated cytotoxic attack against ganglion neurons. This observation suggests a novel pathogenetic mechanism of immune‐mediated human ganglion cell damage comparable to mechanisms operating in polymy‐ositis.
Obesity and endocrine disorders in women taking valproate for epilepsy
Authors: Isojärvi Jouko I. T. , Laatikainen Timo J. , Knip Mikael , Pakarinen Arto J. , Juntunen Kaisa T. S. , Myllyla Vilho V.
Published: January 2005

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy, especially when the medication was started before the age of 20 years. In the present study we evaluated the association of obesity and hyperinsulinemia with valproate‐related polycystic ovaries and hyperandrogenism in women with epilepsy. Sixty‐five women participated in the study. Twenty‐two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin‐like growth factor I, and the insulin‐like growth factor‐binding proteins 1 and 3 (IGFBP‐1 and IGFBP‐3) were measured. Fifty‐nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg, range, 8 ‐49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. These women were obese, and in addition to elevated serum androgen levels, they had high concentrations of fasting serum insulin and low levels of serum insulin‐like growth factor‐binding protein 1. Valproate therapy for epilepsy is associated with weight gain during treatment in approximately 50% of women patients. The weight gain can be progressive, and is associated with hyperinsulinemia and low serum levels of insulin‐like growth factor‐binding protein 1, which may lead to hyperandrogenism and polycystic ovaries.
Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography
Authors: Chugani Harry T. , da Silva Ednea , Chugani Diane C.
Published: January 2005

Positron emission tomography (PET) of brain glucose utilization is highly sensitive in detecting focal cortical abnormalities in patients with infantile spasms even when the computed tomographic (CT) and magnetic resonance imaging (MRI) scans are normal. Of 110 infants with spasms evaluated for potential surgical intervention during an 8‐year period, we encountered 18 infants (7 males, 11 females; age range, 10 mo to 5 yr) with a common metabolic pattern on positron emission tomography (PET) consisting of bilateral hypometabolism in the temporal lobes. CT and MRI scans did not reveal any focal abnormalities in the 18 infants. Video‐electroencephalographic monitoring indicated either bilateral or multifocal epileptogenicity, or failed to show any epileptic focus, so that none of the 18 infants were considered candidates for resective surgery. These patients were then enrolled in a prospective study aimed at determining long‐term outcome in the presence of bilateral temporal PET hypometabolism. Analysis of outcome in 14 of the 18 subjects (follow‐up period, 10 mo to 10 yr 5 mo; mean, 3 yr 11 mo ± 2 yr 4 mo [SD]) revealed the following: (1) all had severe developmental delay and had failed to gain significant milestones; (2) language development had been minimal or absent; (3) 10 of the 14 met the DSM‐IV criteria for autistic disorder. Our findings indicate that patients with infantile spasms and bitemporal glucose hypometabolism on PET comprise a relatively homogeneous group and are typically not candidates for cortical resection. The long‐term outcome of these infants is particularly poor and the majority are autistic.
Alzheimer's disease and apolipoprotein e‐4 allele in an amish population
Authors: Pericak‐Vance M. A. , Johnson C. C. , Rimmler J. B. , Saunders A. M. , Robinson L. C. , D'Hondr E. G. , Jackson C. E. , Haines J. L.
Published: January 2005

Alzheimer's Disease (AD) is a complex genetic disorder with four loci already identified. Mutations in three of these, the amyloid precursor protein, presenilin I, and preseuilin II, cause early‐onset AD. The apolipoprotein E (APOE) gene contributes primarily to late‐onset AD. The APOE‐4 allele acts in a doserelated fashion to increase risk and decrease the age‐of‐onset distribution in AD. We examined the effect of APOE on AD in a previously unstudied Amish population that has a lower prevalence of dementia compared with other populations. We sampled a large inbred family with 6 latehyphen: onset AD members. We also genotyped 53 individuals from the general Amish population as controls for the APOE allele frequency estimates. The frequency of the APOE‐4 allele in the Amish controls was 0.037 ± 0.02. This differed significantly compared with three independent sets of non‐Amish white controls (p < 2 × 10−4, p < 6 × 10−5, and p < 2 × 10−6). In addition, all Amish AD‐affected individuals had APOE 3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the lower frequency of dementia in the Amish may be partially explained by the decreased frequency of the APOE−4 allele in this population, and that the inbred nature of this pedigree, with its strong clustering of cases contrasted against the lower frequency of dementia, indicates that additional genetic factors influence late‐onset AD.
Molecular basis of phenotypic variability in sporadc creudeldt‐jakob disease
Authors: Parchi Piero , Castellani Rudolph , Capellari Sabina , Ghetti Bernardino , Young Katherine , Chen Shu G. , Farlow Martin , Dickson Dennis W. , Sima Anders A. F. , Trojanowski John Q. , Petersen Robert B. , Gambetti Pierluigi
Published: January 2005

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease‐resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt‐Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methioninelvaline polymorphism, and two types of protease‐resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt‐Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to “type 1” protease‐resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the “type 2” protease‐resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt‐Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease‐resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt‐Jakob disease.
Ultrastructural PMP22 expression in inherited demyelinating neuropathies
Authors: Vallat Jean‐Michel , Sindou Philippe , Preux Pierre‐Marie , Tabaraud Fransois , Milor André‐Michel , Couratier Philippe , Leguern Eric , Brice Alexis
Published: January 2005

Charcot‐Marie‐Tooth type 1A (CMT‐1A) disease results from a duplication of the PMP22 gene on chromosome 17p11.2. A deletion of the same region causes hereditary neuropathy with liability to pressure palsies (HNPP). We examined the expression of PMP22 in sural nerve biopsies from 2 unrelated patients with CMT‐1A, 2 unrelated patients with HNPP, and control patients. The ultrastructural immunocytochemical quantitative analysis of cases of CMT‐1A and HNPP showed, respectively, an elevated and reduced expression of PMP22 level compared with controls.
Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: 1‐year results of a pilot study
Authors: Baron Mark S. , Vitek Jerrold L. , Green Joanne , Kaneoke Yoshiki , Hashimoto Takao , Turner Robert S. , Woodard John L. , Delong Mahlon R. , Bakay Roy A. E. , Cole Steven A. , McDonald William M.
Published: January 2005

The effects of posterior internal pallidal ablation (GPi pallidotomy) on parkinsonian signs and symptoms were studied in 15 patients with medically intracally intractable Parkinson's disease(PD). The sensorimotor territory of the internal portion of the globus pallidus and the adjacent optic tract and internal capsule were identified with microelectrode recording and stimulation. Radiofrequency lesions were then created in the identified sensorimotor territory. Pallidotomy significantly improved all cardinal parkinsonian motor signs (tremor, rigidity, akinesia/bradykinesia, and gait dysfunction) and reduced drug‐induced motor fluctuations and dyskinesias. The improvements occurred predominately contralateral to the lesion, but were also present ipsilaterally. Early postoperative (3‐month), mean total United Parkinson's Disease Rating Scale scores improved by 30.1% from preoperative values. Mean combined “on/off” Schwab and England Scale scores, a measure of functional independence, increased from 48.8% to 73.0% postoperatively. The mean total United Parkinson's Disease Rating Scale and Schwab and England scores did not show a statistically significant decline over the 1‐year postoperative period. Surgery resulted in little morbidity, including a lack of significant deficits on neuropsychological and psychiatric testing. Physical and social functioning and vitality measures on the Medical Outcome Scale also showed significant improvement over the postoperative period. The findings of this pilot study demonstrate that ablation of the sensorimotor portion of the internal pallidum is a highly effective treatment for advanced PD, with benefits sustained at 1 year.
Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal
Authors: Arruda F. , Cendes F. , Andermann F. , Dubeau F. , Villemure J. G. , Jones‐Gotman M. , Poulin N. , Arnold D. L. , Olivier A.
Published: January 2005

We studied 74 consecutive patients with temporal lobe epilepsy who were treated surgically and in whom the volumes of mesial temporal structures were determined preoperatively by magnetic resonance imaging. We divided the patients into three groups according to the volumetric findings: unilateral (63.5% of the patients), bilateral (23%), or no atrophy (13.5%) of the amygdala–hippocampal formation. Two distinct surgical approaches were used: selective amygdalohippocampectomy (n = 37) or anterior temporal lobe resection (n = 37). Outcome was assessed at least 1 year after surgery, according to Engel's modified classification. Patients with unilateral mesial temporal atrophy had significantly better results compared with the other two groups (p < 0.001): We found excellent results (class I or II outcome) in 93.6% of the patients with unilateral atrophy, in 61.7% of those with bilateral atrophy, and in 50% of the group with no significant atrophy of mesial temporal structures. The two different surgical techniques were equally effective, regardless of the pattern of atrophy. In conclusion, magnetic resonance volumetric studies in temporal lobe epilepsy proved to be an important preoperative prognostic tool for surgical treatment, but they did not provide guidance for selecting one surgical approach compared to the other.
Progressive encephalomyelitis with rigidity responsive to plasmapheresis and immunosuppression
Authors: Fogan Lance
Published: January 2005

The stiff‐man syndrome is reported in a 55‐year‐old woman who also had signs of severe bulbar musculature hypercontraction. These clinical features correspond to the progressive encephalomyelitis with rigidity syndrome. Diazepam was minimally beneficial, but after treatment with plasmapheresis and corticosteroids, she was still asymptomatic when seen 5 years later.
Acute motor axonal neuropathy: An antibody‐mediated attack on axolemma
Authors: Hafer‐Macko Charlene , Hsieh Sung‐Tsang , Ho Tony W. , Sheikh Kazim , Cornblath David R. , Li Chun Yan , McKhann Guy M. , Asbury Arthur K. , Griffin John W.
Published: January 2005

The acute motor axonal neuropathy (AMAN) form of the Guillain‐Barré syndrome is a paralytic disorder of abrupt onset characterized pathologically by motor nerve fiber degeneration of variable severity and by sparing of sensory fibers. There is little demyelination or lymphocytic inflammation. Most cases have antecedent infection with Campylobacter jejuni and many have antibodies directed toward GM1 ganglioside‐like epitopes, but the mechanism of nerve‐fiber injury has not been defined. In 7 fatal cases of AMAN, immunocytochemistry demonstrated the presence of IgG and the complement activation product C3d bound to the axolemma of motor fibers. The most frequently involved site was the nodal axolemma, but in more severe cases IgG and C3d were found within the periaxonal space of the myelinated internodes, bound to the outer surface of the motor axon. These results suggest that AMAN is a novel disorder caused by an antibody‐ and complement‐mediated attack on the axolemma of motor fibers.
Immunoassays fail to detect antibodies against neuronal calcium channels in amyotrophic lateral sclerosis serum
Authors: Arsac Christine , Raymond Cécile , Martin‐Moutot Nicole , Dargent Bénédicte , Seagar Michael , Couraud François , Pouget Jean
Published: January 2005

Recent studies suggested that autoantibodies that bind to voltage‐dependent calcium channels and activate calcium entry may play a role in the progressive degeneration of motoneurons in sporadic amyotrophic lateral sclerosis. Immunoassays were performed to assess autoantibody titer in patients with amyotrophic lateral sclerosis or Lambert‐Eaton myasthenic syndrome, a disease in which the presnce of anti‐calcium channel antibodies is well documented. Based on immunoprecipitation assays for antibodies against N‐type calcium channels, only 8% (2/25) of amyotrophic lateral sclerosis patients had marginally positive titers, whereas 58% (18/31) of patients with Lambert‐Eaton myasthenic syndrome had positive titers. Enzyme‐linked immunosorbent assays with purified neuronal N‐type calcium channels revealed immunoreactivity in 2 of 25 amyotrophic lateral sclerosis sera and 12 of 31 Lambert‐Eaton myasthenic syndrome sera, which is not compatible with suggestions that enzyme‐linked immunosorbent assay is a more sensitive technique for the detection of autoantibodies in amyotrophic lateral sclerosis. Furthermore, based on immunoprecipitation assays, amyotrophic lateral sclerosis sera were totally negative for antibodies against L‐type calcium channels from skeletal muscle or brain. These data do not support the hypothesis that an autoimmune response against calcium channels plays a primary role in amyotrophic lateral sclerosis.
Proteolytic activity in amyotrophic lateral sclerosis IgG preparations
Authors: Nyormoi Okot
Published: January 2005

Sporadic amyotrophic lateral sclerosis is a motor neuron disease of unknown origin. Autoimmunity against voltagegated calcium channels is one mechanism hypothesized to be the cause of the disease. In support of this hypothesis, it was previously reported that amyotrophic lateral sclerosis IgG specifically blocked the binding of 8B7 monoclonal antibody to the α1 subunit of voltage‐gated calcium channels, suggesting overlapping epitopes of the two antibodies. It is, however, possible that the 8B7 epitope was destroyed by proteases. Data presented here show that the blocking of 8B7 binding to the α1 subunit by diethylaminoethyl cellulose (DEAE)‐purified amyotrophic lateral sclerosis IgG was not observed with Fab fragments of amyotrophic lateral sclerosis IgG. The blocking was prevented by serine protease inhibitors. Moreover, it was reproduced by plaminogen and urokinase. These observations suggest that raised proteolytic activity in amyotrophic lateral sclerosis IgG preparations may be responsible for the blockade of 8B7 monoclonal antibody demonstrated previously. They also indicate the need to be particularly cautious when interpreting the results of incubation in amyotrophic lateral sclerosis sera or IgG preparations. Furthermore, they suggest that proteases may be partly responsible for some of the effects previously described for amyotrophic lateral sclerosis IgG. However, the proteolytic activity needs to be better defined and its possible role in amyotrophic lateral sclerosis investigated.
Clinical features of neocoritcal temporal lobe epilepsy
Authors: Pacia Steven V. , Devinsky Orrin , Perrine Kenneth , Ravdin Lisa , Luciano Daniel , Vazquez Blanca , Doyle Werner K.
Published: January 2005

Few Studies have examined the clinical features of neocortical temporal lobe epilepsy (NTLE) in carefully selected patients. We reviewed records from 21 patients wtih NTLE, defined by intracranial electroencephal9ogram (EEG), who have been seizure free for 1 year or more following temporal lobectomy. The mean age of onset at the time of first seizure was 14 years (range, 1–41 years). Febrile seizures were reported in only 2 patients (9.5%). In contrast to prior mesial temporal lobe epilepsy (MTLE) studies, seizure‐free intervals between the initial cerebral insult or first seizure and habitual seizures were uncommon. Possible or known risk factors for epilepsy were reported in 13 of 21 patients (62%). Fifteen (71%) patients reproted auras, with experiential phenomena being the most common type. Magnetic resonance imaging was normal or nospecific in 15 patients, revealed mild hippocampal atrophy in 2, tumors in 2, and resonance imaging was normal or nospecifc in 15 patients, revealed mild hippocampal atrophy in 2, tumors in 2, and heterotopic gray matter and hippocampal atrophy in 1, and cortical dysgensis in 1. Neuropsychological testing showed deficits consistent with the seizure focus in 13 patients (62%), and Wada test showed ipsilateral memory deficits in 10 (48%). The most common behavioral manifestatin was a motionless stare at ictal onset (48%). In contrast to prior studies of MTLE, only 1 NTLE patient had frequent independent, contralateral temporal lobe epileptiform spikes on scalp EEG.
Clinical genetic analysis of Parkinson's disease in the contursi kindred
Authors: Golbe Lawrence I. , Lazzarini Alice M. , Duvoisin Roger C. , Iorio Giuseppe Di , Sanges Giuseppe , Bonavita Vincenzo , la Sala Salvatore
Published: January 2005

We performed a clinical genetic analysis of a kindred originating in the town of Contursi in Salerno province, Italy, in which 60 individuals in 5 generations are known to have had Parkinson's disease (PD). Two previously reported autopsy cases showed typical PD with Lewy bodies. The inheritance pattern is apparenly autosomally dominant with a segregation ratio of 40.1% for kindred members aged 50 years and older. The mean age at PD onset is 45.6 years (standard deviation, 13.48; range, 20–85) with a mean course to death of 9.2 years (standard deviation, 4.87; range, 2–20). Otherwise, clinical characteristics of PD in the kindred, including variance in onset age and incidence of tremor and levodopa responsiveness, are similar to those of PD in the community. The presence of tremor tended to be concordant in affected parent‐child pairs, but there was no parent‐child correlation for age at onset or intrasibship clustering of tremor or onset age. A suggestin of anticipation disappeared after adjustment for age‐relted ascertainment bias. The findings show that a presumably single mutation can prodcue a heterogeneous PD phenotype, even among siblings. This is consistent with the hypothesis that PD in the community may in fact be caused by sch a mutation, but one producing a lower penetrance and older age at onset than those in this kindred.
Interferon beta‐1b inhibits gelatinase secretion and in vitro migration of human T cells: A possible mechanism for treatment efficacy in multiple sclerosis
Authors: Leppert David , Waubant Emmanuelle , Bürk Martin R. , Oksenberg Jorge R. , Hauser Stephen L.
Published: January 2005

Treatment with interferon beta‐1b has substantial clinical benefit in the demyelinating disease multiple sclerosis, yet the mechanism of action in the disease remains largely unknown. Gelatinase A (matrix metalloproteinase‐2, 72‐kd gelatinase) and B (matrix metalloproteinase‐9, 92‐kd gelatinase) are matrix metalloproteinases capable of enzymatic digestion of subendothelial basement membrane constituents. In human T cells, interleukin‐2 induces gelatinase secretion and enhances gelatinase‐dependent migration across an artificial basement membrane‐like layer in vitro. Pretreatment of T cells with interferon beta‐lb for 48 hours decreased interleukin‐2‐induced gelatinase production and secretion as determined by zymography. In parallel to the downregulation of gelatinase secretion, pretreatment with interferon beta‐lb inhibited T‐cell migration across the basement membrane in vitro by up to 90%, but had only a minor impact on cell locomotion per se. For both gelatinase secretion and T‐cell migration, the inhibitory effect mediated by exposure to interferon beta‐1b was dose dependent. Fluorescence‐activated cell sorter analysis also showed that interferon beta‐1b downregulates the interleukin‐2 receptor α‐chain and lowered the affinity of interleukin‐2 to the cell surface by 30%, which may represent an additional mechanism for the observed effects of interferon beta‐1b. The dramatic effects of interferon beta‐1b on gelatinase expression and migration raise the possibility that its beneficial effects in multiple sclerosis may result from interference with the capacity of activated T cells to traverse the basement membrane and migrate to the central nervous system.
The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients
Authors: Ikeda Masaki , Sharma Vikram , Mark Sumi S. , Rogaeva Ekaterina A. , Poorkaj Parvoneh , Sherrington Robin , Nee Linda , Tsuda Takehide , Oda Nobuhito , Watanabe Mitsunori , Aoki Masashi , Shoji Mikio , Abe Koji , Itoymia Yasuto , Hirai Shurisaku , Schellenberg Gerard D. , Bird Thomas D. , George‐Hyslop P. H. St
Published: January 2005

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS‐1) gene in Japanese patients with early‐onset familial Alzheimer's disease (FAD). In the Ah4/JPN1 pedigree a missense mutation (C→T) was found at nucleotide 1102, which is predicted to cause an alanine‐to‐valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8–19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow‐Robin spaces and the presence of Pick‐like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C→T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS‐1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS‐1 mutations from other forms of early‐onset FAD, implying that direct mutation screening is required to identify these cases.
Clinical and pathological features in hydrocarbon‐induced Parkinsonism
Authors: Pezzoli G. , Strada O. , Silani V. , Zecchinelli A. , Perbellini L. , Javoy‐Agid F. , Ghidoni P. , Motti E. D. F. , Masini T. , Scarlato G. , Agid Y. , Hirsch E. C.
Published: January 2005

A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n‐hexane and halogenated compounds. The patient developed a rapid‐course disease that progressed even after with‐drawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.
Familial episodic ataxia: Clinical heterogeneity in four families linked to chromosome 19p
Authors: Baloh Robert W. , Yue Qing , Furman Joseph M. , Nelson Stanley F.
Published: January 2005

We describe the clinical and oculographic findings in 4 families with episodic ataxia and interictal nystagmus (EA‐2) linked to chromosome 19p. Episodes varied from pure ataxia to combinatins of symptoms suggesting involvement of the cerebellum, brainstem, and cortex. Some affected individuals exhibited a progressive ataxia syndrome phenotypically indistiguishable from the dominantly inherited spinocerebellar ataxia (SCA) syndromes. About one‐half of the affected individuals had migraine headaches and several had episodes typical of basilar migraine. Oculographic findings were localizing to the vestibulocerebellum and posterior vermis. Additional genetic and environmental factors must account for the marked clinical heterogeneity in these families with an abnormal gene on chromosome 19p.
Activation mapping in essential tremor with functional magnetic resonance imaging
Authors: Bucher Stefan F. , Seelos Klaus C. , Dodel Richard C. , Reiser Maximilian , Oertel Wolfgang H.
Published: January 2005

We used functional magnetic resonance imaging (FMRI) to study possible cerebral activation patterns associated with unilateral postural tremor in 12 patients with essential tremor (ET), with mimicked postrual tremor in 15 control subjects, and with passive wrist oscillation in both groups. During essential tremor, patients showed mainly contralateral activation of the primary motor and primary sensory areas, the globus pallidus, and the thalamus, but bilateral activation of the nucleus dentatus, the cerebellar hemispheres, and the red nucleus. Only 2 patients presented with activity in the medulla close to the olivary nucleus. Unilateral passive wrist oscillation of ET patients resulted in only unilateral activation of the cerebellum, nuclei dentati, and red nuclei. In contrast to the involuntary tremor condition of ET patients, the mimicked tremor condition of the control subjects was not associated with bilateral activity in the cerebellum, nuclei dentati, or red nuclei. Involuntary tremor of ET patients was associated with a significantly larger extent of activation in the cerebellar hemispheres and the red nucleus (p < 0.003) compared with mimicked tremor in the control group. Our FMRI study indicates that ET is mainly associated with an additional contralateral cerebellar pathway activation and overactivity in the cerebellum, red nucleus, and globus pallidus without significant intrinsic olivary activation.
Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion?
Authors: Vingerhoets Francois J. G. , Schulzer Michael , Calne Donald B. , Snow Barry J.
Published: January 2005

Clinical scales, based on the major signs of Parkinson's disease (PD), are commonly used to assess the effect of symptomatic treatment of PD. With the appearance of therapy aiming to rescue or protect the nigrostriatal neurons in PD, it becomes essential to define which of these signs best reflects the underlying neuronal deficit. Fluorodopa positron emission tomography has been shown to correlate with postmortem nigral cell counts. We correlated the major signs of PD with positron emission tomography results in 35 PD patients. We found that in the “practically defined off” state, (1) Purdue pegboard scores correlated best with the nigrostriatal dopaminergic deficit; (2) of the subscales of the modified Columbia score, the bradykinesia subscale correlated best; (3) rigidity and postural distrubance correlated less highly than bradykinesia, and their inclusion in a multiple regression did not improve the correlation of pegboard or bradykinesia scores alone; and (4) tremor did not correlate with the nigrostriatal dopaminergic deficit. We conclude that pegboard and bradykinesia scores represent the best clinical measures for studying the effect of treatment on the evolution of the nigrostriatal lesion of PD. Inclusion of other clinical signs provides additional information only for the study of functional impairments.
Inclusion body myositis and paraproteinemia: Incidence and immunopathologic correlations
Authors: Dalakas Marinos C. , Illa Isabel , Gallardo Eduard , Juarez Candido
Published: January 2005

Serum from 70 patients with sporadic inclusion body myositis (IBM) was subjected to agarose gel immunofixation electrophoresis. The IgG extracted from 9 patients with monoclonal proteins, 3 without, and 2 control subjects and was purified, biotinylated, and applied to muscle biopsy sections for immunocytochemistry and to purified muscle protein fractions for immunoblots. Sixteen of 70 (22.8%) patients with IBM, compared with 2% of agematched controls, had a monoclonal gammopathy characterized as IgGλ in 9 patients, IgGk in 4, IgMk in 2, and IgAλ in 1. The mean age of IBM patients with gammopathy was 60.6 years (range, 35–77 years), compared with 66.1 years (range, 42–80 years) of the IBM patients without gammopathy. The IgG of the patients, more often than that of the control subjects, immunostained myonuclei and recognized various muscle proteins of 35 to 145 kd. We conclude that IBM, regardless of age, is frequently associated with monoclonal gammopathies, which often recognize various muscle components, especially myonuclei, suggesting disturbed immunoregulation.
Collection and normal levels of the amyloid precursor protein in plasma
Authors: Whyte Scott , Wilson Neil , Currie Jon , Maruff Paul , Malone Valencia , ‐Antonacci Ruxsana Shafiq , Tyler Peter , Derry Kathryn L. , Underwood John , Li Qiao‐Xin , Beyreuther Konrad , Masters Colin L.
Published: January 2005

The amyloid precursor protein is contained in plantelet alpha granules and released with degranulation. Methods are described to control for amyloid precursor protein release from platelets during blood collection and processing. In normal subjects (n = 97; age range, 44–84 years), the average plasma level of amyloid precursor protein was 6.5 ± 1.8 ng/ml.
Energy metabolism defects in Huntington's disease and effects of coenzyme Q10
Authors: Koroshetz Walter J. , Jenkins Bruce G. , Rosen Bruce R. , Beal M. Flint
Published: January 2005

We investigated whether the Huntington's desease (HD) gene mutation may produce either primary or secondary effects on energy metalbolism. 31P magnetic resonance spectroscopy demonstrated a significant decrease in the phosphocreatine to inorganic phosphate ratio in resting muscle of 8 patients as compared with 8 control subjects. The cerebrospinal fluid lactate‐pyruvate ratio was significantly increased in 15 patients as compared with 13 control subjects. Lactate concentrations assessed using 1H magnetic resonance spectroscopy are increased in Huntington's disease cerebral cortex. Treatment with coenzyme Q10, an essential cofactor of the electron transport chain, resulted in significant decreases in cortical lactate concentrations in 18 patients, which reversed following withdrawal of therapy. These findings provide evidence for a generalized energy defect in Huntington's disease, and suggest a possible therapy.
Pupil‐involving third‐nerve palsy and carotid stenosis: Rapid recovery following endarterectomy
Authors: Balcer L. J. , Galetta S. L. , Yousem D. M. , Golden M. A. , Asbury A. K.
Published: January 2005

We report a patient who presented with a painful pupil‐involving third‐nerve palsy. Cerebral angiography revealed a high‐grade stenosis of the ipsilateral internal carotid artery with a 4‐cm intraluminal thrombus. Following emergent carotid endarterectomy, the patient's partial third‐nerve palsy resolved in 1 hour. A pupil‐involving third‐nerve palsy may be an unusual presentation of impending carotid occlusion.
Treatment of ramsay hunt syndrome with acyclovir‐prednisone: Significance of early diagnosis and treatment
Authors: Murakami Shingo , Hato Naohito , Horiuchi Joji , Honda Nobumitsu , Gyo Kiyofumi , Yanagihara Naoaki
Published: January 2005

Although the antiviral agent acyclovir is currently used for the treatment of Ramsay Hunt syndrome, its effects on facial nerve and hearing recovery remain controversial. We retrospectively analyzed the effects of acyclovir‐prednisone treatment in 80 Ramsay Hunt patients. Of 28 patients for whom treatment was begun within 3 days of the onset of facial paralysis, the recovery from paralysis was complete in 21 (75%). By comparison, of 23 patients for whom treatment was begun more than 7 days after onset, recovery from facial paralysis was complete in only 7 (30%). A significant difference in facial nerve recovery was found between these groups. Early administration of acyclovir‐prednisone was proved to reduce nerve degeneration by nerve excitability testing. Hearing recovery also tended to be better in patients with early treatment. There was no significant difference in facial nerve outcome between intravenous and oral acyclovir treatment.
Imaging of δ‐ and μ‐opioid receptors in temporal lobe epilepsy by positron emission tomography
Authors: Madar Igal , Lesser Ronald P. , Krauss Gregory , Zubieta Jon Kar , Lever John R. , Kinter Chris M. , Ravert Hayden T. , Musachio John L. , Mathews William B. , Dannals Robert F. , Frost J. James
Published: January 2005

The involvement of opioid neurotransmitter systems in seizure mechanisms is well documented. In previous positron emission tomography (PET) studies in patients with unilateral temporal lobe epilepsy, we have found evidence for differential regulation of the opioid‐receptor subtypes. The present study extends our previous observations to δ‐opioid receptors by using the δ‐receptor‐selective antagonist [11C]methylnatrindole ([11C]MeNTI). Paired measurements of δ‐ and μ‐opioid receptor binding and metabolic activity were performed with PET using [11C]MeNTI and [11C]carfentanil ([11C]CFN) and [18F]fluorodeoxyglucose ([18F]FDG), respectively. Binding of [11C]MeNTI and [11C]CFN increased and [18F]FDG uptake decreased in the temporal cortex (TC) ipsilateral to the focus. Decreases in [18F]FDG uptake were more widespread regionally than were increases in opioid receptors. Increases in the δ‐ and μ‐receptor binding showed different regional patterns. Increases in δ‐receptor binding were confined to the middle aspect of the inferior TC, whereas binding of δ receptors increased in the mid‐inferior TC and anterior aspect of the middle and superior TC. The increase in δ receptors suggests their anticonvulsant action, as previously shown for the δ‐receptor subtype, whereas the different regional pattern of receptor alterations suggest the distinct roles of different opioid‐receptor subtypes in seizure phenomena.
Use of desferrioxamine in the treatment of aceruloplasminemia
Authors: Miyajima Hiroaki , Takahashi Yoshitomo , Kamata Tadashi , Shimizu Hideaki , Sakai Naoki , Gitlin Jonathan D.
Published: January 2005

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism resulting in neurodegeneration of the retina and basal ganglia. We report here on the treatment of a patient who developed progressive extrapyramidal symptoms that included blepharospasm, grimacing, and rigidity associated with increased iron deposition in the brain and visceral organs. Treatment for 10 months with the iron chelator desferrioxamine decreased brain iron stores, prevented progression of the neurological symptoms, and reduced plasma lipid peroxidation. These data suggest that early treatment with this chelator may be useful in such patients to diminish central nervous system iron accumulation and to prevent or ameliorate neurological symptoms associated with neurodegeneration.
Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis
Authors: Kostic V. , Gurney M. E. , Deng H.‐X. , Siddique T. , Epstein C. J. , Przedborski S.
Published: January 2005

Familial amyotrophic lateral sclerosis has been linked in 15% of families to mutations in the gene encoding for copperzinc superoxide dismutase (Cu/Zn‐SOD), a key enzyme in the cellular defense mechanisms against free radical attack. We used a transgenic mouse model of familial amyotrophic lateral sclerosis (transgenic G1H mice) based on expression of mutant human Cu/Zn‐SOD to examine the influence of the transgene expression on midbrain dopaminergic neurons, cells that contain conspicuous amounts of this enzyme. At the time that 50% of motor neurons of the spinal cord were lost, we observed concurrent reductions in dopamine levels in the caudate‐putamen and the nucleus accumbens of transgenic G1H mice. In addition, numbers of tyrosine hydroxylase‐immunostained neurons were significantly reduced in both the substantia nigra (26%) and the ventral tegmental area (16%) compared to those in their nontransgenic littermates. Similar abnormalities were not observed in the brains of transgenic mice overexpressing wild‐type Cu/Zn‐SOD. These findings indicate that overexpression of the mutated Cu/Zn‐SOD protein caused a significant loss of midbrain dopaminergic neurons in addition to the loss of spinal motor neurons. The potential of the mutated enzyme to induce cell death extending beyond the motor neurons is consistent with the description of substantia nigra degeneration in some patients with familial amyotrophic lateral sclerosis. Furthermore, if mutated Cu/Zn‐SOD is conclusively shown to kill cells by oxidative stress, such an observation would be in keeping with the known sensitivity of dopaminergic neurons to free radical attack.