bluuebunny/crossref_metadata_2025 huggingface dataset:
Enlargement of human cerebral ischemic lesion volumes measured by diffusion‐weighted magnetic resonance imaging
Authors: Baird Alison E. , Benfield Andrew , Schlaug Gottfried , Siewert Bettina , Lövblad Karl‐Olof , Edelman Robert R. , Warach Steven
Published: January 2005

We aimed to determine the frequency and time course of the enlargement of ischemic cerebral lesions following human stroke and to study the effect of the state of perfusion on lesion enlargement. Acute lesion volumes were measured on diffusion‐weighted magnetic resonance images and compared with lesion volumes measured on T2‐weighted images at 7 days or later. Forty‐four measurements were performed between 2 and 53 hours after stroke onset in 28 patients. Thirteen patients also had magnetic resonance perfusion imaging performed. In 12 (43%) of 28 patients the initial lesion volume increased by 20% or more. The number of studies showing enlargement of the ischemic lesion volume ranged from 12 (43%) of 28 at or after 2 hours to 10 (38%) of 26 at or after 6 hours, 5 (33%) of 15 at or after 24 hours, and 2 (33%) of 6 at or after 48 hours. In 7 of the 10 patients in whom the hypoperfusion volume acutely exceeded the volume of the abnormality on diffusion‐weighted images, lesion volume increased by 20% or more. This study provided evidence that substantial enlargement of human cerebral ischemic lesion volumes can occur beyond the first 6, 12 or 24 hours after onset. A mismatch acutely between the region of hypoperfusion (larger) and the region of diffusion abnormality (smaller) may be predictive of ischemic lesion enlargement.
Brain impairment in well‐nourished chronic alcoholics is related to ethanol intake
Authors: Nicolás Josep M. , Estruch Ramón , Salamero Manel , Orteu Nuria , Fernandez‐Solà Joaquim , Sacanella Emilio , Urbano‐Márquez Alvaro
Published: January 2005

To determine the influence of chronic ethanol intake on the central nervous system, we studied 40 asymptomatic, well‐nourished, chronic alcoholics (mean age, 42.6 ± 9.1 years) and 20 age‐, sex‐, and education‐matched control subjects. Studies included neuropsychological testing, visual and short‐latency auditory evoked potentials, and morphometric analysis of computed tomography scans. The mean daily ethanol consumption of the alcoholics was 204 gm over an average of 26.4 years. Compared to control subjects, chronic alcoholics exhibited a significant prolongation of the P100 latency of visual evoked potentials, and a prolongation and reduction in the amplitude of the latency of the V wave of short‐latency auditory evoked potentials. These abnormalities were related to the lifetime dose of ethanol consumed. Brain morphometric analysis showed that alcoholics had a significantly greater degree of brain shrikage with age, compared to control subjects. The cortical atrophy index correlated significantly with the lifetime ethanol consumption. Neuropsychological testing in alcoholics compared to controls revealed a significant impairment of frontal skills that was related to age, degree of scholarship, and the presence of frontal atrophy. In conclusion, well‐nourished chronic alcoholics exhibited a significant brain impairment, as demonstrated by neuropsychological testing, evoked potentials, and brain morphometric analysis, which was correlated with the lifetime dose of ethanol consumed.
The absence of an apolipoprotein ϵ4 allele is associated with a more aggressive form of Alzheimer's disease
Authors: Stern Yaakov , Brandt Jason , Albert Marilyn , Jacobs Diane M. , Liu Xinhua , Bell Karen , Marder Karen , Sano Mary , Albert Steven , Castenada Caridad Del‐Castillo , Bylsma Fred , Tycko Ben , Mayeux Richard
Published: January 2005

We investigated the relationship between APOE genotype and rate of disease progression and survival in 99 patients with probable Alzheimer's disease (AD) who were followed biannually for up to 6 years. Patients were stratified into two groups, those with and without at least one APOE ϵ4 allele. The rate of decline in modified Mini‐Mental State Examination scores was slower, the presence of extrapyramidal signs was decreased, and the development of myoclonus occurred later among patients with APOE ϵ4 alleles compared with patients with other genotypes. Compared with patients with other genotypes. Compared with patients without an APOE ϵ4 allele, the risk of mortality was also decreased in patients with at least one ϵ4 allele (RR = 0.38; CI = 0.17−0.84, P < 0.02). Because the decline in mental ability as well as the development of myoclonus and extrapyramidal signs are consistent manifestations of disease progression, our results imply that APOE ϵ4 is associated with a less aggressive form of AD.
Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene
Authors: Navon Ruth , Khosravi Rami , Melki Judith , Drucker Liat , Fontaine Bertrand , Turpin Jean Claude , N'Guyen Bathein , Fardeau Michel , Rondot Pierre , Baumann Nicole
Published: January 2005

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg‐Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg‐Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269→Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A‐to‐T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.
Phenotypic variability in friedreich ataxia: Role of the associated GAA triplet repeat expansion
Authors: Montermini Laura , Richeter Andrea , Morgan Kenneth , Justice Cristina M. , Julien Dominique , Castellotti Barbara , Mercier Jocelyne , Poirier Josée , Capozzoli Fiorentino , Bouchard Jean‐Pierre , Lemieux Bernard , Mathieu Jean , Vanasse Michel , Seni Marie‐Hélene , Graham Gail , Andermann Frederick , Andermann Eva , Melançon Serge B. , Keats Bronya J. B. , Di Donato Stefano , Pandolfo Massimo
Published: January 2005

We studied genotype‐phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late‐onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA‐associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.
A new type of hereditary motor and sensory neuropathy linked to chromosome 3
Authors: Takashima Hiroshi , Nakagawa Masanori , Nakahara Keiichi , Suehara Masahito , Matsuzaki Toshio , Higuchi Itsuro , Higa Hidemasa , Arimura Kimiyoshi , Iwamasa Teruo , Izumo Shuji , Osame Mitsuhiro
Published: January 2005

We report the clinical, pathological, and genetic findings of 23 patients in 8 families with hereditary motor and sensory neuropathy (proximal dominant form) (HMSN‐P) in Okinawa, Japan. The clinical features were unique with respect to autosomal dominant inheritance, Kennedy‐Alter‐Sung syndrome‐like proximal dominant neurogenic atrophy, obvious sensory involvement, painful muscle cramp, fasciculations, areflexia, and high incidences of elevated creatine kinase levels, hyperlipidemia, and diabetes mellitus. Electrophysiological and pathological studies revealed typical motor and sensory axonal neuropathy, and decreased numbers of anterior horn and dorsal ganglion cells, which suggested the presence of neuronopathy in HMSN‐P. Genetic linkage studies showed a lod score of 4.04 (two‐point analysis) in DNA marker D3S1284. Haplotype analysis showed that the gene locus of the disease was mapped to 3p14.1‐q13 bracketed by D3S1285 and D3S1281. In this region, the patients' chromosomes showed an obvious increase in the allele frequency of five markers. One allele in D3S1591 was identical in all patients but had a low frequency in the control population. This finding suggested the presence of linkage disequilibrium and a common origin of this allele in all patients with HMSN‐P. The HMSN‐P described here is a new clinical entity characterized by unique clinical manifestations and a new gene locus.
Human T‐cell lymphotropic virus type I‐associated facial nerve palsy in trinidad and tobago
Authors: Bartholomew Courtenay , Cleghorn Farley , Jack Noreen , Edwards Jeffrey , Blattner William
Published: January 2005

To assess the association of the human T‐cell lymphotropic virus type I (HTLV‐I) and idiopathic facial nerve palsy of the lower motor neuron type, we studied 78 patients consecutively admitted to the Port of Spain General Hospital in Trinidad, the West Indies, with a confirmed diagnosis of idiopathic facial nerve palsy. Patients were compared with two control groups: a population‐based group of persons 20 years and older and a hospital‐based group of patients 15 to 84 years old admitted to the medical wards. Sixty‐two patients were Trinidadians of African origin and 16 were Trinidadians of East Indian origin. None of the East Indian patients was HTLV‐I antibody positive. Three Afro‐Trinidadians were infected with human immunodeficiency virus type 1 and 1 was coinfected with this virus and HTLV‐I. Of the remaining 58 Afro‐Trinidadians, 12 (20.7%) were HTLV‐I positive only. This rate was statistically higher than the HTLV‐I seroprevalence in the Afro‐Trinidadian general population (3.5%) and the hospital control group (5.6%). After age standardization, the HTLV‐I prevalence for patients with facial nerve palsy remained significantly elevated. HTLV‐I antibody assays should be performed on all patients with idiopathic facial nerve palsy of the lower motor neuron type who live in HTLV‐I endemic areas or are migrants from these areas.
Is there a genetic susceptibility locus for Parkinson's disease on chromosome 22q13?
Authors: Wilhelmsen K. , Mirel D. , Marder K. , Bernstein M. , Naini A. , Leal S. M. , Cote L. J. , Tang M.‐X. , Freyer G. , Graziano J. , Mayeux R.
Published: January 2005

The cytochrome P450 mono‐oxygenase gene, CYP2D6 on chromosome 22q13 (ch22q13), has been inconsistently associated with Parkinson's disease. Associations with CYP2D6 have either been absent altogether or have involved more than one polymorphism, many of which have the same metabolic effect on gene expression. We examined the association between CYP2D6 polymorphisms and Parkinson's disease in a case‐control study and included 10 polymorphic dinucleotide repeat markers linked to CYP2D6 to determine whether the association was present or due to linkage disequilibrium. There was no association between any polymorphism of CYP2D6 and Parkinson's disease, but two of 10 dinucleotide repeat markers linked to CYP2D6 were associated with the disease. These results provide evidence to suggest that there may be an unidentified locus for susceptibility to Parkinson's disease that is in linkage disequilibrium with dinucleotide repeat markers mapping near CYP2D6 on ch22q13.
α1‐Antichymotrypsin as a risk modifier for late‐onset Alzheimer's disease in Japanese apolipoprotein E ε4 allele carriers
Authors: Yoshiiwa A. , Kamino K. , Yamamoto H. , Kobayashi T. , Imagawa M. , Nonomura Y. , Yoneda H. , Sakai T. , Nishiwaki Y. , Sato N. , Rakugi H. , Miki T. , Ogihara T.
Published: January 2005

In the Japanese population, sporadic late‐onset Alzheimer's disease (LOAD) cases had significantly higher frequencies of the A allele of α1−antichymotrypsin (ACT) gene as well as the $4 allele of apolipoprotein E (APOE) gene than controls. The odds ratio for LOAD in APOE4 carriers with the ACT‐A allele was more than six times that in APOE4 carriers without the ACT‐A allele (21.1 vs 3.2). These results indicate that the ACT‐A allele is a risk modifier for LOAD in APOE4 carriers.
A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey
Authors: Dincer Pervin , Leturcq France , Richard Isabelle , Piccolo Federica , Yalnizoàlu Dilek , De Toma Claudia , Akçören Zuhal , Broux Odile , Deburgrave Nathalie , Brenguier Lydie , Roudaut Carinne , Urtizberea J. Andoni , Jung Daniel , Tan Ersin , Jeanpierre Marc , Campbell Kevin P. , Kaplan Jean‐Claude , Beckmann Jacques S. , Topaloàlu Haluk
Published: January 2005

Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain‐3 at LGMDA2A (15q15), and four members of the sarcoglycan (SG) complex, α‐SG at LGMD2D (17q21), β‐SG at LGMD2A (4q12), γ‐SG at LGMD2C (13q12), and dL‐SG at LGMD2F (5q33–q34). The gene product at LGMD2B (2p13–p16) is still unknown and at least one other gene is still unmapped. We investigated 20 Turkish families (18 consanguineous) diagnosed as having LGMD2. Most of our patients had onset of symptoms before age 10. The phenotypes varied from severe to benign. We analyzed the SG complex by immunofluorescence and/or western blot. Genotyping was performed using markers defining the six known loci and the suspected genes were screened for mutations. Six of 17 index cases showed deficiency of the SG complex, by immunofluorescence and/or western blot. Seven cases involved on e of the known genes of the SG complex (α, 2; β, 1; and γ, 4 cases), and five mutations were documented in the α‐ and γ‐SG genes. After linkage analysis, 10 families were characterized as having LGMD2A (calpain‐3 deficiency), and all mutations were eventually identified. One family was classified as having LGMD2B and 1 family that has normal SGs was linked to the chromosome 5q33–q34 locus (LGMD2F). In 1 family there was no linkage to any of the known LGMD2 loci. It appears that in Turkey, there is a broad spectrum of genes and defects involved in LGMD2. It may be possible to correlate genotype to phenotype in LGMD2. All severe cases belonged to the γ‐SG–deficiency group. Nine calpain‐3–deficient cases had intermediate and 1 had moderate clinical courses. The LGMD2B patient had a moderate clinical expression, whereas the LGMD2F case was truly benign.
Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia
Authors: Smith Derek R. , Balashov Konstantin E. , Hafler David A. , Khoury Samia J. , Weiner Howard L.
Published: January 2005

Multiple sclerosis (MS) is postulated to be a Th1‐type cell‐mediateds autiommune disease. Thus therapies that decrease T cell interferon (IFN)‐γ production or increase interleukin (IL)‐4 production would be expected to have an ameliorating effect on MS. Some progressive MS patients receiving pulse cyclophosphamide therapy developed periheral blood eosinophilia. We investigated whether cyclophosphamide‐treated patients had immune deviation toward Th2 responses. We measured cytokine production in patients receiving either monthly intravenous methylprednisolone (MP), intravenous cyclophosphamide plus methylprednisolone (CY/MP), methotrexate, IFN‐β1b, in untreated MS patients, and in healthy controls. Minimal IL‐4 was secreted in untreated patients (129 · 62 pg/ml), methotrexate‐treated patients (99 · 79 pg/ml), and healthy controls (50 · 13 pg/ml). A marked increase in IL‐4 was observed in CY/MP patients (1,503 · 291 pg/ml). Patients treated with MP (418 · 160 pg/ml) or IFN‐β1b (425 · 167 pg/ml) showed small increases. Eosinophilia in CY/MP‐treated patients (6.0 · 0.7%) correlated with increased IL‐4. IL‐10 production was also increased in CY/MP‐treated patients. Both CY/MP‐ and MP‐treated groups had decreased production of IFN‐γ compared with untreated MS. These findings demonstrate pronounced immune deviation favoring Th2‐type responses after pulse cyclophosphamide therapy.
Pathological τ proteins in postencephalitic parkinsonism: Comparison with Alzheimer's disease and other neurodegenerative disorders
Authors: Buée‐Scherrer Valérie , Buée Luc , Leveugle Bátrice , Perl Daniel P. , Vermersch Patrick , Hof Patrick R. , Delacourte André
Published: January 2005

Immunohistochemical and biochemical analyses of hyperphosphorylated τ proteins, the major component of neurofibrillary tangles, were performed in different brain regions from patients presenting with postencephalitic parkinsonism. Neurofibrillary tangles were found in hippocampus, neocortical areas (mostly in supragranular layers), and several subcortical structures. By immunobloting, a τ protein triplet similar to the one seen in Alzheimer's disease was observed. This biochemical approach allows for the definition of postencephalitic parkinsonism from certain neurodegenerative disorders such as progressive supranuclear palsy and corticobasal degeneration.
Huntingtin localization in brains of normal and Huntington's disease patients
Authors: Sapp E. , Schwarz C. , Chase K. , Bhide P. G. , Young A. B. , Penney J. , Vonsattel J. P. , Aronin N. , DiFiglia M.
Published: January 2005

The immunohistochemical localization of huntingtin was examined in the Huntington's disease (HD) brain with an antibody that recognizes the wild‐type and mutant proteins. Neuronal staining was reduced in areas of the HD striatum depleted of medium‐sized neurons; large striatal neurons, which are spared in HD, retained normal levels of huntingtin expression. Neuronal labeling was markedly reduced in both segments of the globus pallidus including in brains with minimal loss of pallidal neurons. In some HD cortical and striatal neurons with normal looking morphology, huntingtin was associated with punctate cytoplasmic granules that at the ultrastructural level resembled the multivesicular body, an organelle involved in retrograde transport and protein degradation. Some immunoreactive processes showed blebbing and segmentation similar to that induced experimentally by hypoxic–ischemic or excitotoxic injury. Huntingtin staining was more concentrated in the perinuclear cytoplasm and reduced or absent in processes of atrophic cortical neurons. Nuclear staining was also evident. Fibers in the subcortical white matter of HD patients had significantly increased huntingtin immunoreactivity compared with those of controls. Results suggest that there may be changes in the neuronal expression and transport of wild‐type and/or mutant huntingtin at early and late stages of neuronal degeneration in affected areas of the HD brain.
Familial parkinsonism, dementia, and lewy body disease: Study of family G
Authors: Denson Melody A. , Wszolek Zbigniew K. , Pfeiffer Ronald F. , Wszolek Elzbieta K. , Paschall Tanya M. , McComb Rodney D.
Published: January 2005

Genetic influences are thought by many to play an important role in the cause of Parkinson's disease. We studied two closely intermarried families (Family G) whose ancestors immigrated to the United States from Russia. We investigated this family clinically, genealogically, and pathologically. Our pedigree contained 102 members spanning six generations, with 10 affected individuals and 1 affected spouse. Detailed telephone interviews were conducted with affected individuals, with their spouses, and with their at‐risk siblings. Medical records of deceased and living affected patients were collected. Physical examinations were performed on 7 at‐risk and 5 affected persons. Typical levodopa‐responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes was seen in 4 members, dementia was present in 3, and 3 had both dementia and parkinsonism. An autopsy completed on 1 individual, our index case, demonstrated Lewy bodies in the brainstem and neocortex and ubiquitin‐positive neuritic degeneration in the CA2–3 region of the hippocampus, consistent with the limbic (transitional) form of Lewy body disease. This family is distinct both clinically and pathologically from several previously reported parkinsonian kindreds.
Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome
Authors: Ellis Ronald J. , Hsia Karen , Spector Stephen A. , Nelson Julie A. , Heaton Robert K. , Wallace Mark R. , Abramson Ian , Atkinson J. Hampton , Grant Igor , McCutchan J. Allen
Published: January 2005

To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)‐associated neurocognitive disorders, we quantified HIV type 1 (HIV‐1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV‐1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV‐1 RNA levels were quantified by using a reverse transcriptase–polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV‐infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) (<200 CD4 lymphocytes), NP impairment was associated with significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most impaired subjects met criteria for HIV‐associated dementia or minor cognitive–motor disorder. In subjects without AIDS, CSF RNA and NP impairment were unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we found elevated CSF HIV‐1 RNA levels in NP impaired subjects with AIDS. Before AIDS, systemic viral replication, possibly through CD4+ mononuclear cell trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion may unmask a correlation between increased productive central nervous system HIV infection and clinical neurocognitive disorders.
Relationship between human immunodeficiency virus—associated dementia and viral load in cerebrospinal fluid and brain
Authors: McArthur Justin C. , McClernon Daniel R. , Cronin Michael F. , Nance‐Sproson Tish E. , Saah Alfred J. , St Clair Marty , Lanier E. Randall
Published: January 2005

Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels were measured with the Nucleic Acid Sequence‐Based Amplification (NASBA) assay to determine the relationship with neurological status; 37 subjects with HIV dementia (HIV‐D) were compared with 77 with HIV with minor neurological signs (HIV‐MCMD) and 93 neurologically normal HIV‐seropositive individuals (HIV‐NML). The NASBA assay had a lower limit of detection of 100 copies per milliliter. Mean CSF log HIV RNA levels were significantly higher in those with dementia after adjusting for CD4 count and were correlated with dementia severity. Plasma levels did not distinguish comparably immunosuppressed subjects with or without dementia. CSF and plasma RNA levels were significantly intercorrelated for subjects with CD4 counts <200/mm3 and also correlated inversely with CSF β2‐microglobulin. CSF RNA levels were independent of CSF pleocytosis or antiretroviral exposure. Brain RNA levels were consistently higher than CSF but correlated with CSF values for dementia subjects. The NASBA assay can be used reliably to determine HIV RNA levels in CSF, brain, and plasma samples. CSF HIV RNA may be a surrogate marker for brain infection, based on the observed correlation with brain levels. The association between plasma HIV RNA and CSF levels of HIV and β2‐microglobulin suggests that both viral load and CNS immune activation are important determinants of neurological disease.
Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: A series of 100 patients
Authors: Cendes Fernando , Caramanos Zografos , Andermann Frederick , Dubeau François , Arnold Douglas L.
Published: January 2005

Surgery is a safe and effective treatment for drug‐resistant temporal lobe epilepsy (TLE). However, bilateral electroencephalographic (EEG) abnormalities are frequently present, making presurgical lateralization difficult. New magnetic resonance (MR) techniques can help; proton magnetic resonance spectroscopic imaging (MRSI) can detect and quantify focal neuronal damage or dysfunction based on reduced signals from the neuronal marker N‐acetylaspartate, and magnetic resonance imaging (MRI)‐based measurements of amygdala‐hippocampal volumes (MRIVol) can improve the detection of atrophy of these structures. We performed proton MRSI and MRIVol in 100 consecutive patients with medically intractable TLE to determine how well these techniques agreed with the lateralization by extensive EEG investigation. We found that the EEG, MRSI, and MRIVol findings were highly concordant. The MRSI was abnormal in 99 of 100 patients (bilateral in 54%). The MRIVol was abnormal in 86 of 98 patients (bilateral in 28%). We obtained lateralization in 83% of patients using MRIVol alone, in 86% using MRSI alone, and in 90% by combining MRSI and MRIVol (vs 93% lateralization by EEG). MRSI was abnormal in 12 patients with normal MRIVol. The combination of proton MRSI and MRIVol can lateralize TLE accurately and noninvasively in the great majority of patients. By reducing reliance on EEG, these imaging techniques could reduce prolonged presurgical evaluation and make seizure surgery available to more patients.
Correlation between PMP‐22 messenger mRNA expression and phenotype in hereditary neuropathy with liability to pressure palsies
Authors: Schenone Angelo , Nobbio Lucilla , Caponnetto Claudia , Abbruzzese Michele , Gherardi Gianfranco , Mancardi Gianluigi , Mandich Paola , Bellone Emilia , Ajmar Franco , Windebank Anthony J.
Published: January 2005

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p 11.2, which includes the gene for the peripheral myelin protein 22 (PMP‐22). A “gene dosage” effect is probably the mechanism underlying HNPP, but the amount of PMP‐22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP‐22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP‐22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP‐22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of “tomacula,” or nerve conduction parameters. Our findings further confirm that underexpression of PMP‐22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP‐22 levels suggests that underexpression of PMP‐22 may also affect axon development.
Morphometry of in vivo human white matter association pathways with diffusion‐weighted magnetic resonance imaging
Authors: Makris N. , Worth A. J. , Papadimitriou G. M. , Stakes J. W. , Caviness V. S. , Kennedy D. N. , Pandya D. N. , Kaplan E. , Sorensen A. G. , Wu O. , Reese T. G. , Wedeen V. J. , Rosen B. R. , Kennedy D. N. , Davis T. L.
Published: January 2005

The precise characterization of cortical connectivity is important for the understanding of brain morphological and functional organization. Such connectivity is conveyed by specific pathways or tracts in the white matter. Diffusion‐weighted magnetic resonance imaging detects the diffusivity of water molecules in three dimensions. Diffusivity in anisotropic in oriented tissues such as fiber tracts. In the present study, we used this method to map (in terms of orientation, location, and size) the “stem” (compact portion) of the principal association, projection, and commissural white matter pathways of the human brain in vivo, in 3 normal subjects. In addition, its use in clinical neurology is illustrated in a patient with left inferior parietal lobule embolic infarction in whom a significant reduction in relative size of the stem of the left superior longitudinal fasciculus was observed. This represents an important method for the characterization of major association pathways in the living human that are not discernible by conventional magnetic resonance imaging. In the clinical domain, this method will have a potential impact on the understanding of the diseases that involve white matter such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, head injury, and spinal cord injury.
Dendritic injury is a pathological substrate for human immunodeficiency virus—related cognitive disorders
Authors: Masliah Eliezer , Ellis Ronald J. , Mallory Margaret , Heaton Robert K. , Marcotte Thomas D. , Nelson Julie A. , Grant Igor , Atkinson J. Hampton , Wiley Clayton A. , Achim Cristian L. , McCutchan J. Allen
Published: January 2005

To determine the neuropathological substrate of human immunodeficiency virus (HIV)‐associated neurocognitive disorders, we examined persons with acquired immunodeficiency syndrome before their death and related their antemortem neuropsychological performance to postmortem indicators of HIV encephalitis, viral burden, and presynaptic and postsynaptic neuronal injury. Of 20 prospectively examined cases, 9 were neurocognitively normal, 5 showed neuropsychological impairment, 5 had minor cognitive/motor disorder, and 1 was demented. Degree of neurocognitive impairment was strongly related to the amount of dendritic simplification based on microtubule‐associated protein 2 immunohistochemical staining, somewhat less so to a semiquantitative viral burden score based on numbers of HIV gp41‐immunoreactive cells, and much less so to the presence of multinucleated giant cells or microglial nodules. It appears that even milder neurocognitive impairment reflects microneuroanatomical injury to synaptic structures.
Serial proton magnetic resonance spectroscopic imaging, contrast‐enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis
Authors: Narayana Ponnada A. , Doyle Timothy J. , Lai Dejian , Wolinsky Jerry S.
Published: January 2005

Serial magnetic resonnce (MR) studies that included proton MR spectroscopic imaging (MRSI), contrast‐enhanced MR imaging (MRI), and lesion volumetric studies were performed on 25 multiple sclerosis (MS) patients with mild to modest clinical deficits. Each patient was scanned at varying intervals for up to 2 years, resulting in a total of 124 usable MR sessions. In these longitudinal studies, metabolic changes were observed on MRSI for some subjects before the appearance of lesions on MRI scanning. Regional changes in metabolite levels were observed to be dynamic and reversible in some patients. Transient changes in N‐acetylaspartate (NAA) levels were sometimes found in acute plaques and indicate that a reduced NAA level does not necessarily imply axonal loss. An inverse correlation between the average NAA within the spectroscopic volume and the total lesion volume in the whole brain was observed. This negative correlation implies that NAA can serve as an objective marker of the disease burden. Strong lipid peaks in the absence of gadolinium enhancement and MRI‐defined lesions were observed in 4 patients. This observation suggests that demyelination can occur independent of perivenous inflammatory changes and supports the presence of more than one pathophysiological process leading to demyelination in MS.
A novel mutation in the mitochondrial tRNAVal gene associated with a complex neurological presentation
Authors: Tiranti Valeria , D'Agruma Leonardo , Pareyson Davide , Mora Marina , St Franco Carrara , Zelante Leopoldo , Gasparini Paolo , Zeviani Massimo
Published: January 2005

We describe a patient who presented with progressive ataxia, sezures, mental deterioration, mild myopathy, and hearing loss. A novel heteroplasmic G‐to‐A transition was found, affecting the acceptor stem of the mitochondrial (mt) tRNAVal gene. Mutant mtDNA was 67% of total mtDNA in the muscle of the proband and was also present at low levels in the muscle of his healthy mother. It was absent in all of the numerous control DNA samples that were tested. Analysis of single muscle fibers revealed a significantly greater level of mutant mtDNA in cytochrome c oxidase‐negative fibers. Mutations of mtDNA may be responsible of neurological syndromes that, like the case reported here, are clinically puzzling, and lack typical “mitochondrial” clues, such as elevated levels of blood lactate, overt defects of the respiratory complexes, and clinically documented maternal inheritance.
Loss of electrical excitability in an animal model of acute quadriplegic myopathy
Authors: Rich Mark M. , Pinter Martin J. , Kraner Susan D. , Barchi Robert L.
Published: January 2005

In rats treated with high‐dose corticosteroids, skeletal muscle that is denervated in vivo (steroid‐denervated [S‐D]) develops electrical inexcitability similar to that seen in patients with acute quadriplegic myopathy. In studies of affected muscles in vitro, the majority of S‐D fibers failed to generate action potentials in response to intracellular stimulation although the average resting potential of these fibers was no different from that of control denervated muscle. The downregulation of membrane chloride conductance (GC1) seen in normal muscle after denervation did not occur in S‐D muscle. Although block of chloride channels in S‐D muscle produced high specific membrane resistance, comparable to similarly treated control denervated muscle, and partially restored excitability in many fibers, action potential amplitude was still reduced in S‐D fibers, suggesting a concomitant reduction in sodium current. 3H‐saxitoxin binding measurements revealed a reduction in the density of the adult muscle sodium channel isoform in S‐D muscle, suggesting that a decrease in the number of sodium channels present may play a role in the reduction of sodium current, although altered properties of channels may also contribute. The weakness seen in S‐D muscle may involve the interaction of a number of factors that modify membrane excitability, including membrane depolarization, persistence of GC1, and reduced voltage‐gated sodium currents.
Cognitive, neuroimaging, and pathological studies in a patient with Pick's disease
Authors: Lieberman Andrew P. , Trojanowski John Q. , Lee Virginia M.‐Y. , Balin Brian J. , Ding Xin‐Shen , Greenberg Joel , Morrison Donald , Reivich Martin , Grossman Murray
Published: January 2005

We conducted cognitive, imaging, and neuropathological studies on a patient with Pick's disease. The patient was impaired at interpreting sentences with complex grammatical constructions, differing significantly from control subjects and patients with Alzheimer's disease (AD). Evaluation of regional brain functioning at rest, with positron emission tomography, revealed reduced left frontal activity compared with control subjects and AD patients. Autopsy demonstrated the classic pathology of Pick's disease, including massive neuron loss and gliosis in the frontal and cingulate cortex as well as numerous tau‐positive hippocampal Pick bodies. The abnormal tau proteins were phosphorylated at the same amino acid residues as AD paired helical filament tau (PHFtau), but they exhibited a unique migration profile on western blot. Our observations support the hypothesis that a distinct variety of hyperphosphorylated tau in Pick's disease compromises the long‐term viability of selectively vulnerable populations of neurons in frontal cortices that contribute to sentence processing.
Proinflammatory cytokines regulate antigen‐independent T‐cell Activation by two separate calcium‐signaling pathways in multiple sclerosis patients
Authors: Martino Gianvito , Grohovaz Fabio , Brambilla Elena , Codazzi Franca , Consiglio Antonella , Clementi Emilio , Filippi Massimo , Comi Giancarlo , Grimaldi Luigi M. E.
Published: January 2005

Central nervous system (CNS) lesions typical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen‐specific autoreactive T cells and a multitude of pathogenic non‐antigen‐specific mononuclear cells. Here, we report that in patients with MS the combined action of interferon‐γ (IFNγ), tumor necrosis factor‐α (TNFα), interleukin (IL)‐2, and IL‐6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFNγ and the other by the combination TNFα/IL‐2/IL‐6, is independent from myelin antigens and precedes by 2 weeks phases of disease activity (eg, clinical relapses and/or appearance of gadolinium‐enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow‐up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profile and one necessary for T‐cell growth and differentiation, can activate in an antigen‐independent fashion most peripheral T cells from MS patients. This mechanism is likely to contribute to the recruitment of nonspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune intervention in MS.
Cochlear origin of hearing loss in MELAS syndrome
Authors: Sue C. M. , Lipsett L. J. , Crimmins D. S. , DipAud C. S. Tsang , Boyages S. C. , Presgrave C. M. , Gibson W. P. R. , Byrne E. , Morris J. G. L.
Published: January 2005

There have been few studies investigating the mechanism and nature of the hearing loss that occurs in the mitochondrial disorders. We studied 18 patients with the MELAS A3243G point mutation from four different kindreds. Pure tone audiometry, speech discrimination testing, acoustic reflexes, tympanometry, and brain stem auditory evoked responses were performed to localize the site of pathology in the auditory pathways. In 12 patients, we performed electrocochleography and otoacoustic emissions to assess cochlear involvement. Neuroimaging and promontory nerve stimulation were performed to exclude retrocochlear pathology. Audiological testing confirmed sensorineural hearing loss in 14 of the 18 patients studied; hearing loss was usually gradual in onset, was symmetrical, and initially affected the higher frequencies. In some patients, there were features that distinguished the hearing loss from presbyacusis, including a young age at onset, asymmetrical involvement, stepwise progression, and partial recovery. We treated one patient who had profound bilateral hearing loss with cochlear implantion; this restored good functional hearing. Hearing loss in MELAS syndrome appears to be due to dysfunction of the cochlea, probably resultiong from metabolic failure of the stria vascularis and outer hair cells. Cochlear implantation is a therapeutic option worth considering in those patients who become deaf.
End‐plate voltage‐gated sodium channels are lost in clinical and experimental myasthenia gravis
Authors: Ruff Robert L. , Lennon Vanda A.
Published: January 2005

This study examined the loss of voltage‐gated Na+ channels as well as acetylcholine receptors (AChRs) form the endplate region in patients with acquired myasthenia gravis (MG) and in rats with experimental autoimmune passively transferred MG (PTMG). Rats received a monoclonal IgG antibody directed against an extracellular epitope of the nicotinc acetylcholine receptor of muscle (AChR) to produce PTMG. At the end‐plate border we examined miniature end‐plate potentials (MEPPs), sodium current (INa) amplitude, and action potential (AP) properties; the latter two were also examined on the extrajunctional membrane. In the normal situation, the safety factor for neuromuscular transmission is ensured by the large INa at the end plate, which reduces the AP threshold. Among different fiber types, INa was largest for type IIb fibers and smallest for type I fibers. When end‐plate border properties of fibers form 3 MG patients and 15 PTMG rats were compared with controls, INa was reduced, AP thresholds were higher, and rates of AP rise were reduced. Amplitudes of MEPPs and INa at the end plate indicated that loss of AChRs was greater than loss of Na+ channels in patients with MG and rats with PTMG; INa was reduced to about 60% of control values, whereas MEPPs were reduced to less than 30% of control values. On the extrajunctional membrane, INa and AP thresholds and rates ofrise were similar for MG patients, PTMG rats, and controls. This evidence for loss of voltage‐gated Na+ channels at the motor end plate in both patients with MG and in rats with PTMG reveals a hitherto unrecognized consequence of the end‐plate damage initiated by the binding of complement‐fixing IgG to end‐plate AChRs.
Selective inhibition of human glial inducible nitric oxide synthase by interferon‐β: Implications for multiple sclerosis
Authors: Hua Liwei L. , Liu Judy S. H. , Brosnan Celia F. , Lee Sunhee C.
Published: January 2005

Nitric oxide generated from the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of multiple sclerosis. Because significant species‐ and cell‐specific differences exist in the expression of iNOS, we used primary human glial cell cultures to screen for an inhibitor of iNOS expression. Remarkably, among numerous soluble factors tested, interferon‐β (IFN‐β) alone showed a selective and potent inhibition of interleukin‐1β/interferon‐γ (IL‐1β/IFN‐)–induced iNOS expression in astrocytes. Inhibition of iNOS may provide a mechanism by which IFN‐β can ameliorate inflammation and cytotoxicity in the central nervous system of patients with multiple sclerosis.
Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions
Authors: VanLandingham Kevan E , Heinz E. Ralph , Cavazos Jose E. , Lewis Darrell V.
Published: January 2005

Magnetic resonance imaging (MRI) was performed after complex febrile convulsion (CFCs) in 27 infants. Definite MRI abnormalities were seen in 6 of the 15 infants with focal or lateralized CFCs and in none of the 12 infants with generalized CFCs. In 2 of the 6 infants with lateralized CFCs and abnormal MRIs, the MR images showed preexisting bilateral hippocampal atrophy consistent with the history of perinatal insults in these infants. However, the remaining 4 infants with MRI abnormalities and lateralized CFCs had significantly longer seizures than other infants and had MRI changes suggesting acute edema with increased hippocampal T2‐weighted signal intensity and increased volume predominantly in the hippocampus in the hemisphere of seizure origin. Of those with acute edema, 1 had electrographical seizure activity recorded in the temporal region and another had a choroid fissure cyst displacing the affected hippocampus; both infants had follow‐up MRIs showing that hippocampal atrophy had developed. These patients demonstrate that prolonged and focal CFCs can occasionally produce acute hippocampal injury that evolves to hippocampal atrophy. Finally, evidence of preexisting hippocampal abnormalities in several infants and electrographical temporal lobe seizure activity in 1 suggests the possibility that CFCs actually originated in the temporal lobes in some patients.
Valproate, lamotrigine, and insulin‐mediated risks in women with epilepsy
Authors: Isojärvi Jouko I. T. , Rättyä Johanna , Myllylä Vilho V. , Knip Mikael , Koivunen Riitta , Pakarinen Arto J. , Tekay Aydin , Tapanainen Juha S.
Published: January 2005

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism associated with weight gain and hyperinsulinemia in women taking valproate for epilepsy. The purpose of this study was to evaluate the risks related to valproate‐induced hyperinsulinemia and their reversibility after discontinuing the medication. Sixteen women with valproate‐related polycystic ovaries or hyperandrogenism participated in the study. Vaginal ultrasonography was performed, and endocrine and lipid parameters were measured. Thereafter, lamotrigine was substituted for valproate and the patients were observed for 12 months. Twenty‐four healthy age‐matched women served as control subjects. Twelve women completed the 12‐month follow‐up. While still on valproate they had centripetal obesity with associated hyper insulinemia and unfavorable serum lipid profiles. The body‐mass index and fasting serum insulin and testosterone concentrations decreased during the first year after replacing valproate with lamotrigine whereas the HDL‐cholesterol/total cholesterol ratios increased from 0.17 ± 0.06 to 0.26 ± 0.05. The total number of polycystic ovaries in these women decreased from 20 during valproate medication to 11 one year after replacing valproate with lamotrigine. Valproate induces a metabolic syndrome with centripetal obesity, hyperinsulinemia lipid abnormalities, and polycystic ovaries/hyperandrogenism in women with epilepsy. These valproate‐related risks can be reduced by substituting lamotrigine for valproate.
A permanent pure amnestic syndrome of insidious onset related to Alzheimer's disease
Authors: Didic M. , Chérif A. Ali , Gambarelli D. , Poncet M. , Boudouresques J.
Published: January 2005

A 55‐year‐old patient experienced a pure amnestic syndrome of insidious onset that worsened progressively. Subsequently, her memory disorder stablized and remained her only cognitive impairment for several years. She ultimately developed more widespread cognitive decline and terminal dementia. Postmortem examination 18 years after the onset revealed numerous senile plaques and neurofibrillary tangles consistent with Alzheimer's disease. A permanent pure amnestic syndrome of insidious onset may represent a further type of focal cerebral degeneration.
Neurotrophin‐4 is up‐regulated in ragged‐red fibers associated with pathogenic mitochondrial DNA mutations
Authors: Walker Ulrich A. , Schon Eric A.
Published: January 2005

Ragged‐red fibers (RRFs) are found more frequently in highly oxidative type I fibers than in glycolytic type II fibers in the muscle of many patients with mitochondrial myopathies. Neurotrophin‐4 (NT‐4), a neuronal signaling molecule, is also expressed in skeletal muscle, predominantly in type I fibers. We found that NT‐4 protein and mRNA were present in both type I and type II fibers but were up‐regulated in RRFs of patients with mitochondrial encephalomyopathies; it is noteworthy that NT‐4 was not up‐regulated in muscle fibers from healthy aerobically trained athletes. Thus, NT‐4 might represent a member of a new class of candidate molecules involved in the compensatory adjustments of muscle fibers to oxidative dysfunction, and may even play a role as a signaling molecule for mitochondrial proliferation.