bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer's disease
Authors: Jack Clifford R. , Petersen Ronald C. , Xu Yue Cheng , O'Brien Peter C. , Waring Stephen C. , Tangalos Eric G. , Smith Glenn E. , Ivnik Robert J. , Thibodeau Stephen N. , Kokmen Emre
Published: January 2005

A variety of anatomic and functional neuroimaging findings are associated with Alzheimer's disease (AD). One of the strongest imaging associations identified is between AD and hippocampal atrophy. The ∈4 allele of the apolipoprotein E (ApoE) gene increases the risk of developing AD and lowers the mean age of onset of the disease. The purpose of this study was to assess the association between hippocampal volume and ApoE polymorphisms in elderly control subjects and in patients with probable AD. We performed magnetic resonance imaging–based volume measurements of the hippocampus in 125 cognitively normal elderly controls and 62 patients with probable AD. ApoE genotyping was performed by using standard methods. Hippocampal volumes were significantly smaller in AD cases than in control subjects. Hippocampal volumes did not differ significantly within either clinical group on the basis of ApoE genotype. Both the ∈4 allele of ApoE and hippocampal atrophy were significantly but independently associated with AD.
Mortality in DATATOP: A Multicenter trial in early Parkinson's disease
Authors: Shoulson  ,   Parkinson Study Group
Published: January 2005

Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinson's disease, but the value of long‐term treatment with this type B monoamine oxidase inhibitor remains unsettled. We examined mortality among the 800 patients with early Parkinson's disease who were not requiring levodopa and who were randomly assigned in the DATATOP trial to receive deprenyl, tocopherol, combined treatments, or placebo. Ascertainment of the vital status of subjects in this double‐blinded trial was performed prospectively after the initial randomization, during open‐label de‐prenyl, and after a second independent randomization to continue active deprenyl or swithch to matching placebo. The study was conducted at 28 academic medical centers in the United States and Canada. After an average of 8.2 years of observation, the overall death rate of our subjects was 17.1% (137 of 800) or 2.1% per year. The mortality rate was unaffected by deprenyl, tocopherol, or combined treatment assignments and was about that expected for an age‐ and gender‐matched US population without Parkinson's disease. Neither deprenyl, tocopherol, nor their combined treatments affected the duration of life in our early Parkinson's disease patients. The deprenyl‐related delay in disability that we reported previously was not associated with a deprenyl‐related reduction in mortality.
Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices
Authors: Meyer Bernd‐Ulrich , Röricht Simone , Woiciechowsky Christian
Published: January 2005

In 1 split‐brain patient and 13 patients with circumscript surgical lesions within different parts of the corpus callosum (CC), the topography of fibers within the CC mediating an interhemispheric inhibition between the motor cortices was investigated in the phase of a stable disconnection syndrome. The aim of the study was to characterize the system of callosal fibers activated by transcranial magnetic brain stimulation in more detail as a basis for a diagnostic application of this technique. The locations and areas of the lesions were measured on sagittal magnetic resonance (MR) slices and attributed to five segments of the CC, because the borders of the anatomic subdivisions of the CC are not clearly defined. Transcallosal inhibition (TI) of tonic electromyographical hand muscle activity was elicited by focal transcranial magnetic stimulation over the primary motor cortex. In a reference group of normal subjects, TI started after 35.8 ± 3.6 msec had a duration of 24.8 ± 2.7 msec and an estimated transcallosal conduction time of 15.5 ± 3.0 msec (range, 10.2–20.0 msec, n = 24 hands). No significant differences were found for the TI originating from the right and left motor cortices. From the absence and presence of TI in patients with lesions in different parts of the CC it can be concluded that most of the fibers mediating TI pass through the posterior third and anterior fourth segment of the CC, that is, through the posterior half of the trunk of the CC. The clinical findings suggest a role for TI in the performance of fast and complex hand motor tasks.
Stiff‐leg syndrome: A focal form of stiff‐man syndrome
Authors: Saiz Albert , Graus Francesc , Valldeoriola Francesc , Valls‐Solé Josep , Tolosa Eduardo
Published: January 2005

We report on 2 patients who presented stiffness and spasms similar to those of stiff‐man syndrome (SMS) that were limited to one leg for up to 11 years. Patients had serum glutamic acid decarboxylase (GAD) autoantibodies in high titer, clinical evidence of organ‐specific autoimmunity, and electromyographic pattern of continuous motor unit activity with abnormally enhanced exteroceptive reflexes. The clinical and immunological profile suggests that this disorder may be a focal form of SMS.
Matrix metalloproteinases MMP‐9 and MMP‐7 are expressed in experimental autoimmune neuritis and the guillain‐barré syndrome
Authors: Kieseier B. C. , Clements J. M. , Pischel H. B. , Wells G. M. A. , Miller K. , Gearing A. J. H. , Hartung H.‐P.
Published: January 2005

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92‐kd gelatinase (MMP‐9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain‐Barre syndrome(GBS). Quantitative polymerase chain reaction analysis revealed an up‐regulation of MMP‐9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhaced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP‐9 could be localized primarily around blood vessels within the epineurium and enhoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP‐7) were found to be up‐regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP‐9 and MMP‐7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP‐9 activity was detected by zymography. These findings indicate that 92‐kd gelatinase and matrilysin are selectively up‐regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.
Angelman syndrome: Correlations between epilepsy phenotypes and genotypes
Authors: Minassian Berge A. , Delorey Timothy M. , Olsen Richard W. , Philippart Michel , Bronstein Yuri , Zhang Quanwei , Guerrini Renzo , van Ness Paul , Livet Marie O. , Delgado‐Escueta Antonio V.
Published: January 2005

We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15q11‐13 deletions (class I), uniparental disomy (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of closed‐circuit television videotaping and digitized electroencephalographic (EEG) telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high‐amplitude 1‐ to 3‐Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged‐matched class II, III, and IV patients had either no epilepsy or drug‐responsive mild epilepsy with relatively infrequent atypical absences, myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15q11‐13 deletions produce severe epilepsy. Loss‐of‐function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15q11‐13 deletion, such as GABRB3, may explain severe epilepsy in AS.
Expression of the early‐onset torsion dystonia gene (DYT1) in human brain
Authors: Augood Sarah J. , Penney John B. , Friberg Ingrid K. , Breakefield Xandra O. , Young Anne B. , Ozelius Laurie J. , Standaert David G.
Published: January 2005

Early‐onset torsion dystonia, an autosomal dominant disease associated with the DYT1 locus on 9q34, is the most frequent genetic form of dystonia. Recent work has revealed that the causative mutation in most cases is deletion of a glutamate residue from the carboxy terminal of torsinA, a 332 amino acid protein encoded by the DYT1 gene. To gain insight into how deletion of a single amino acid can produce such a profound movement disorder, we have mapped the expression of the DYT1 gene in normal human postmortem brain. DYT1 mRNA is highly enriched in the dopamine neurons of the substantia nigra pars compacta. Intense expression was also found in the cerebellum and hippocampal subfields. The prominent expression of the DYT1 gene within the substantia nigra pars compacta, which provides dopaminergic innervation to the basal ganglia, implicates a disturbance of dopaminergic function in the pathophysiology of early‐onset torsion dystonia.
Dynamic [18F]fluorodeoxyglucose positron emission tomography and hypometabolic zones in seizures: Reduced capillary influx
Authors: Cornford Eain M. , Gee Manyee N. , Swartz Barbara E. , Mandelkern Mark A. , Blahd William H. , Landaw Elliot M. , Delgado‐Escueta Antonio V.
Published: January 2005

We performed dynamic [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomographic (PET) analyses in 8 patients. Rate constants of influx (K1*), efflux (k2*), phosphorylation (k3*), and dephosphorylation (k4*) were derived for the regions of interest (ROIs), which included (1) the hypometabolic epilptogenic regions and (2) the homologous regions in the contralateral hemispheres. In addition, the four constants were determined from at least one clearly defined (control) ROI from the same plane and its homologous contralateral ROI. (K1*) in the eplieptogenic region was reduced in comparison with the contralateral ROI. Reductions in influx (K1*), which averaged 18 ± 13% (mean ± SD), [18F]FDG phosphorylation (k3*) (25 ± 20%), and brain glucose utization rates (26 ± 10%) were observed in the epileptogenic region. Reductions in efflux were not statistically significant (k2* = 13 ± 28%) but were comparable in magnitude to the average reduction in K1*. No ipsilateral versus contralateral differnces were seen for any rate constants measured outside the epileptogenic region. Influx correlated highly with phosphorylation in the epileptogenic region. Our data suggest that the hypometabolic epileptogenic focus seen in [18F]FDG‐PET studies is also a region of reduced blood‐brain barrier glucose transporter activity and that reductions in phosphorylation are proportional to reductions in [18]FDG influx.
Dystonia with motor delay in compound heterozygotes for GTP‐cyclohydrolase I gene mutations
Authors: Furukawa Yoshiaki , Kish Stephen J. , Bebin E. Martina , Jacobson Richard D. , Fryburg Julie S. , Wilson Willam G. , Shimadzu Mitsunobu , Hyland Keith , Trugman Joel M.
Published: January 2005

Mutations in the GTP‐cyclohydrolase I(GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa‐responsive dystonia (HPD/DRD) and autosomal recessive GCH‐deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH‐deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.
Synergistic immunomodulatory effects of interferon‐β1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing‐remitting multiple sclerosis
Authors: Weber Frank , Polak Thomas , Günther Astrid , Kubuschok Boris , Janovskaja Julia , Bitsch Andreas , Poser Sigrid , Rieckmann Peter
Published: January 2005

Subcutaneous application of interferon‐β1b (IFN‐β1b) is an established therapy for patients with relapsing‐remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)–specific T‐cell lines revealed a synergistic suppressive effect of IFN‐β1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor‐α (TNF‐α), lymphotoxin (LT), and interferon‐γ (IFN‐γ). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN‐β1b alone or in combination with oral PTX, was determined by semi‐quantitative reverse transcriptase polymerase chain reaction (RT‐PCR). Patients treated with IFN‐β1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF‐α as well as IFN‐γ mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)‐10 mRNA, which was accompanied by an increase in IL‐10 serum levels. Both in vitro and in vivo data suggest that co‐treatment of IFN‐β1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.
Phenotypic expression of the DYT1 mutation: A family with writer's cramp of juvenile onset
Authors: Gasser T. , Windgassen K. , Bereznai B. , Kabus C. , Ludolph A. C.
Published: January 2005

Recently, the mutation causing early‐onset generalized torsion dystonia has been identified as a GAG deletion in the gene for an adenosine triphosphate–binding protein named torsinA. We describe a German family with 5 clinically affected individuals carrying this mutation. In at least 4 of the 5 patients, the disease presented as a dystonic writer's cramp during late childhood or adolescence, which affected sequentially both sides but did not progress to a generalized form of dystonia. We conclude that familial writer's cramp may be a manifestation of the DYT1 mutation.
Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome
Authors: Dinkel Klaus , Meinck Hans‐Michael , Jury Karin M. , Karges Wolfram , Richter Wiltrud
Published: January 2005

Stiff‐man syndrome (SMS) is a rare disorder of the central nervous system thought to result from an impairment of γ‐aminobutyric acid (GABA)ergic neurotransmission. Autoantibodies to the GABA‐synthesizing enzyme glutamic acid decarboxylase (GAD), present in about 60% of SMS patients, have suggested an autoimmune pathogenesis of SMS. By using serum or cerebrospinal fluid from 25 SMS patients, we assessed the effect of GAD autoantibodies (GAD‐A) on GAD enzymatic activity in vitro; 83% of GAD‐A–positive SMS sera reduced GABA production in crude rat cerebellar extracts, whereas GAD‐A− sera from SMS patients or healthy blood donors did not alter the enzyme activity. Inhibition of GABA synthesis by SMS sera was dose dependent and mediated by the purified IgG fraction of the sera. Human monoclonal GAD65‐A and IgG purified from serum of GAD‐A–positive patients with insulin‐dependent diabetes or autoimmune polyendocrine syndrome did not effect GAD activity, suggesting that a specific epitope recognition of GAD‐A mediates inhibition of GAD. The disease‐specific detection of GAD‐inhibitory antibodies is compatible with their functional involvement in the etiopathology of SMS; the relevance of such antibodies in vivo, however, remains to be determined.
IgG Anti‐GM1 antibody is associated with reversible conduction failure and axonal degeneration in guillain‐barré syndrome
Authors: Kuwabara Satoshi , Yuki Nobuhiro , Koga Michiaki , Hattori Takamichi , Matsuura Daisuke , Miyake Masami , Noda Masatoshi
Published: January 2005

To investigate the pathophysiological role of anti‐GM1 antibody in Gullain‐Barre syndrome (GBS), we reviewed sequential nerve conduction studies of 345 nerves in 34 GBS patients. Statistically significant correlation between IgG anti‐GM1 antibodies and electrodiagnoses was found. Sixteen IgG anti‐GM1‐positive patients were classified as having acute motor sensory axonal neuropathy (AMAN or AMSAN) (12 patients), as having acute inflammatory demyelinating polyneuropathy (AIDP) (3 patientsrpar;, or as undetermined (1 patient) by electrodiagnostic criteria. Besides axonal features, there was rapid resolution of conduction slowing and block. In 3 patients initially diagnosed as having AIDP, conduction slowing was resolved within days, and 1 of them and 3 AMAN patients showed markedly rapid increases in amplitudes of distal compound muscle action potentials that were not accompanied by prolonged duration and polyphasia. The time courses of conduction abnormalities were distinct from those in IgG anti‐GM1‐negative AIDP patients. Rapid resolution of conduction slowing and block, and the absence of remyelinating slow components, suggest that conduction failure may be caused by impaired physiological conduction at the nodes of Ranvier. Reversible conduction failure as well as axonal degeneration constitutes the pathopsiological mechanisms in IgG anti‐GM1)positive GBS. In both cases, immune‐mediated attack probably occurs on the axolemma of motor fibers.
In vivo differentiation of astrocytic brain tumors and isolated demyelinating lesions of the type seen in multiple sclerosis using 1H magnetic resonance spectroscopic imaging
Authors: De Stefano Nicola , Caramanos Zografos , Preul Mark C. , Francis Gordon , Antel Jack P. , Arnold Douglas L.
Published: January 2005

We used computer pattern recognition of proton magnetic resonance spectroscopic image data to differentiate between brain tumors and large, isolated, demyelinating lesions of the type seen in multiple sclerosis. Leave‐one‐out linear discriminant analyses correctly classified resonance profiles from five acute demyelinating lesions, 20 low‐grade astrocytomas, 22 anoplastic astrocytomas, and 24 glioblastomas. Classification of nonacute lesions will require further development, as the metabolic profiles of demyelinating lesions evolve over time.
Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease
Authors: Hutchison W. D. , Allan R. J. , Opitz H. , Levy R. , Dostrovsky J. O. , Lang A. E. , Lozano A. M.
Published: January 2005

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37 ± 17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement‐related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71 ± 23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1–2 seconds) of electrical microstimulation of STN could produce tremor arrest but were and found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.
Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNAser(UCN) gene
Authors: Jaksch Michaela , Klopstock Thomas , Kurlemann Gerd , Dörner Marion , Hofmann Sabine , Kleinle Stephanie , Hegemann Stephan , Weissert Markus , MüLler‐Höcker Josef , Pongratz Dieter , Gerbitz Klus‐Dieter
Published: January 2005

We report seven unrelated families with mitochondrial tRNASer(UCN) gene mutations at three different loci. A novel G7497A mutation is found in two families, both of which present with progressive myopathy, ragged‐red fibers, lactic acidosis, and deficiency of repiratory chain complexes I and IV. This mutation presumably affects the tertiary tRNASer(UCN) dihydrouridine interaction. Mutations 7472 insC and T7512C, found in three and two families, respectively, are associated with myoclonus epilepsy, deafness, ataxia, cognitive impairment, and complex IV deficiency. No ragged‐red fibers or ultrastructural abnormalities are seen. It is interesting that 6 of our 7 index patients are apparently homoplasmic, indicating a minor pathogenetic power of the tRNASer(UCN) mutations.
Acquired slow–channel syndrome: A form of myasthenia gravis with prolonged open time of the acetylcholine receptor channel
Authors: Wintzen Axel R. , Plomp Jaap J. , Molenaar Peter C. , van Dijk J. Gert , van Kempen Gertrudis T. H. , Vos Renske M. , Wokke John H. J. , Vincent Angela
Published: January 2005

A 32‐year‐old female presented with a 2‐year history of fluctuating generalized weakness including extraocular, bulbar, and limb muscles, suggesting myasthenia gravis, but with poor response to pyridostigmine and unusual electromyographic findings. After rest, power increased on repeated maximal contractions, followed by progressive weakness. There were decremental responses at low‐frequency stimulation, but incremental responses at high frequencies, and single stimuli evoked repetitive compound muscle action potentials. Plasmapheresis was ineffective. In a conventional assay, antibodies against acetylcholine receptors (AChRs) were borderline. However, in an assay using cells expressing mainly adult‐type human AChRs, the patient's serum was positive. Thymectomy revealed a hyperplastic thymus. An intercostal muscle specimen revealed small miniature end‐plate potentials, 0.22 ± 0.02 mV instead of 0.56 ± 0.05 mV in controls. The number of 125I‐α‐bungarotoxin binding sites was normal. The decay time constant of end‐plate potentials was increased from 5.3 ± 0.6 msec in controls to 23 ± 3.6 msec in the patient. Ultrastructurally, there was no destruction of the end plate. Transfer of the patient's plasma to mice in vivo produced similar physiological changes in their diaphragms. We conclude that the patient has an immune‐mediated disorder, in which an antibody specific to the adult form of the AChRs alters the channel properties, reducing total current and slowing the closure. We propose the name “acquired slow‐channel syndrome” for this variant of myasthenia gravis.
Neonatal cytokines and coagulation factors in children with cerebral palsy
Authors: Nelson Karin B. , Dambrosia James M. , Grether Judith K. , Phillips Terry M.
Published: January 2005

We explored the association of inflammatory mediators and markers of autoimmune and coagulation disorders with cerebral palsy (CP), examinig 53 analytes in dried neonatal blood of 31 children with spastic CP, most born at term, and 65 control children. Ultramicroanalysis was performed by recycling immunoaffinity chromatography coupled with laser‐enhanced fluorescence and chemiluminescence detection. Reactive antibodies to lupus anticoagulant, anticardiolipin, antithrombin III, and the translational product of the factor V Leiden mutation were isolated by recycling immunoaffinity chromatography and measured by capillary electrophoresis with chemiluminescence‐enhanced immunoassay. Higher concentrations of interleukins (ILs) 1, 8, 9, tumor necrosis factor‐α, and RANTES were observed in these children with CP than in any control child. There were also substantial elevations of IL‐6, 11, 13, and other chemokines and colony‐stimulating factors in children with CP. Antiphospholipid antibody was present in a titer of 1:100 or greater in 4 children with CP and no control child. Using cuts empirically chosen by recursive partitioning, we found higher concentrations of antibody to antithrombin III, to a translational product of factor V Leiden mutation, and to proteins C and S in children with CP than in controls. We conclude that inflammation and these coagulation abnormalities, which have interacting pathways, are important in the etiology of CP.
α‐ketoglutarate dehydrogenase in alzheimer brains bearing the APP670/671 mutation
Authors: Gibson G. E. , Zhang H. , Sheu K. F. ‐R. , Bogdanovich N. , Lindsay J. G. , Lannfelt L. , Vestling M. , Cowburn R. F.
Published: January 2005

Alzheimer's disease (AD) is associated with a striking reduction in the activity of the α‐ketoglutarate dehydrogenase complex (KGDHC). The deficiency occurs in brains from AD patients of undefined etiology, and in fibroblasts from both sporadic and familial AD cases. To further assess the nature of the abnormality of KGDHC in AD, KGDHC activities and immunoreactivities were analyzed in brains from AD patients bearing the Swedish APP670/671 mutation. This gene defect causes overproduction of the amyloid β peptide. KGDHC activities were reduced by 55 to 57% compared with control values in the mutation‐bearing AD cases in the medial temporal and superior frontal cortices. The immunochemical levels of KGDHC subunits E1k (−51%) and E2k (−76%) declined, whereas E3 concentrations were unchanged. The results suggest that mitochondrial dysfunction is a part of the pathophysiological process in AD even when the primary pathogenic cause is nonmitochondrial.
Association between bleomycin hydrolase and Alzheimer's disease in caucasians
Authors: Farrer Lindsay A. , Abraham Carmela R. , Haines Jonathan L. , Rogaeva Ekaterina A. , Song Youqiang , McGraw Walker T. , Brindle Nicholas , Premkumar Smita , Scott William K. , Yamaoka Larry H. , Saunders Ann M. , Roses Allen D. , Auerbach Sanford A. , Sorbi Sandro , Duara Ranjan , Pericak‐Vance Margaret A. , St George‐Hyslop Peter H.
Published: January 2005

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with nondemented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.
Spinal muscular atrophy due to an isolated deletion of exon 8 of the telomeric survival motor neuron gene
Authors: Gambardella A. , Mazzei R. , Toscano A. , Annesi G. , Pasqua A. , Annesi F. , Quattrone F. , Oliveri R. I. , Valentino P. , Bono F. , Aguglia U. , Zappia M. , Vita G. , Quattrone A.
Published: January 2005

Patients with autosomal recessive spinal muscular atrophy (SMA) usually carry a homozygous deletion of exons 7 and 8 of the telomeric survival motor neuron (SMNT) gene, although an isolated deletion of SMN T exon 8 has never been found. We now report on 2 patients with the typical fetures of SMA types II and III, who carried a homozygous deletion of SMNT exon 8 but retained SMNT 7. Importantly, to exclude a sequence conversion event of telomeric exon 8, we amplified a fragment that spanned exons 7 and 8 of the SMN gene. The resulting 1,010‐base pair (bp) fragments were subjected to nested polymerase chain reaction (PCR) on exon 7. The subsequent restriction analysis failed to show any products of telomeric exon 7, as the site for primer 541 C1120 was lost in both alleles. These findings indicate a homozygous deletion of SMNT exon 8. Direct sequencing of the cloned 1,010‐bp fragment further confirmed that these 2 SMA patients did not possess telomeric exon 8. The present findings provide evidence that an isolated deletion of SMNT exon 8 is associated with the milder subtypes of SMA. Our data also demonstrate that the additional deletion of the NAIP gene exacerbates the severity of the disease.
Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the Parkin gene in affected individuals
Authors: Hattori Nobutaka , Kitada Tohru , Matsumine Hiroto , Asakawa Shuichi , Yamamura Yasuhiro , Yoshino Hiroyo , Kobayashi Tomonori , Yokochi Masayuki , Wang Mei , Yoritaka Asako , Kondo Tomoyoshi , Kuzuhara Shigeki , Nakamura Shigenobu , Shimizu Nobuyoshi , Mizuno Yoshikuni
Published: January 2005

Autosomal recessive juvenile parkinsonism (AR‐JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young‐onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR‐JP to chromosome 6q25.2–q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR‐JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR‐JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exo 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one‐base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one‐base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR‐JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.
Corticifugal fiber connections of the cortex of Macaca mullatta. The occipital region
Authors: Mettler Feed A.
Published: January 2005

Fibers from the upper opercular striate cortex pass to the following structures in the following order of abundance of association fibers: (a) Remainder of upper half of striate cortex including medially located portions. (b) Lower macular cortex. (c) Rest of striate cortex. (d) Posterior limb of the angular gyrus and middle annectant gyrus. (e) Caudal end of the posterior superior, parietal gyrus.
Thalamus of turtles and thalamic evolution
Authors: Papez James W.
Published: January 2005

The nuclear masses in the thalamus and the midbrain region of turtles are described are illustrated with sections of the brain of the green turtle, Chelone midas.
Electron microscopic study of the developing neuroblast of the dorsal root ganglion of the rabbit embryo
Authors: Tennyson Virginia M.
Published: January 2005

The differentiation of the neuroblast of the spinal ganglion of the embryonic rabbit has been studied by phase, light, and electron microscopy from the period of migration of the cells from the neural crest until their transformation into unipolar neurons. The relatively undifferentiated migratory neuroblast, which has single primitive neurite, contains fine filaments and large numbers of ribonucleoprotein particles, but very little membranous endoplasmic reticulum. The presence in the Golgi‐centriolar region of large numbers of neurotubules, which probably originate from the centriole, is one of the first signs of further maturation of the neuroblast. The neurotubles migrate into the neurite, where they become a prominent feature during development, particularly in the distal processes.

Elements of the immature Golgi complex appear to participate directly in the formation of the membranous portion of the primitive Nissl substance, which develops during the bipolar period.

A difference was noted in the fine structure of the processes of the transitional bipolar neuroblast; i.e., one neurite resembles an axon; whereas, the other contains granular endoplasmic reticulum typical of dendrites.

The findings of this study are in accord with the concept that the unipolar process arises by constriction and elongation of perikaryal cytoplasm. Two neural cell types, a small cell having randomly disposed organelles, and a larger cell having large clumps of endoplasmic reticulum at the periphery, can be distinguished. The application of the Cajal reduced silver technique to embryonic ganglia, which were subsequently examined with the electron microscope, resulted in a random distribution of silver deposit throughout neural perikarya.
Auerbach's plexus of the rat cecum in relation to the germfree state
Authors: Dupont Jean‐René , Jervis Helen Roland , Sprinz Helmuth
Published: January 2005

The cecum of germfree rats, after the second week of life, enlarges sixfold over that of conventional tank‐raised controls. Poor muscle tone as well as dietary factors have been incriminated. We have studied the myenteric plexus of the cecum in conventional and germfree rats, in an effort to find a neuronal explanation of the phenomenon and to test whether the neurovegetative periphery is capable of adapting to the changing size.

With routine and histochemical technics three salient features stood out: (1) The myenteric neurones in the cecum of the germfree rat on an average were three times larger than those of the controls (42 μ vs 16 μ). Some neurones of the germfree cecum attained giant size (over 150 μ). (2) They showed a lower DPNH diaphorase activity, unrelated to the increased cell size, (3) In the germfree rat cecum the meshes of the primary fiber plexus of Auerbach had increased in size along the antimesenteric border, while the network under the mesenteric attachment was smaller. The ratio between the network of the two sides was 1:12 in the germfree, 1:5 in the controls.

We have concluded that the neurones of Auerbach's plexus in the germfree cecum are indeed less active metabolically — a factor which may perpetuate the cycle of cecal distention in these animals. The neurovegetative periphery in the cecum has shown itself capable to responding to the increased cecal volume by neuronal hypertrophy.
The medial longitudinal fasciculus and disturbances of conjugate horizontal eye movements in the monkey
Authors: Carpenter Malcolm B. , Strominger Norman L.
Published: January 2005

In 16 monkeys attempts were made to produce localized unilateral and bilateral lesions in the medial longitudinal fasciculus (MLF) in the pons in order to study resulting disturbances of eye movements and fiber degeneration. Noteworthy physiological findings could be correlated with lesions and fiber degeneration in eight animals. Degeneration was studied by the Nauta technic.

Bilateral lesions of the MLF between the abducens nuclei impair all horizontal eye movements, except convergence. Unilateral lesions of the MLF rostral to the abducens nuclei produce: (1) paresis of ipsilateral ocular adduction on attempted lateral gaze and (2) monocular horizontal nystagmus in the contralateral abducting eye. Bilateral lesions in the latter location produce these disturbances bilaterally.

Paresis of ocular adduction resulting from lesions in the MLF is associated with ascending degeneration in the MLF projecting differentially upon cells of the ventral nucleus of the oculomotor complex, a cell group innervating the ipsilateral medial rectus muscle. Monocular horizontal nystagmus in the contralateral abducting eye appears to be a consequence of interruption of either: (1) descending fibers in the MLF, or (2) secondary vestibular fibers passing to the opposite abducens nucleus.

Unilateral lesions of the MLF rostral to the abducens nucleus produce degeneration ipsilaterally in: (1) the nuclei of the extraocular muscles, (2) the interstitial nucleus (Cajal), and (3) parts of the ventral posterior inferior, ventral posterior medial, parafascicular, centromedian, and recticular nuclei of the thalamus.
The auditory pathway of the epileptic waltzing mouse. II. Partially deaf mice
Authors: Ross Muriel D.
Published: January 2005

This study deals with degeneration occurring in the auditory pathway of the partially deaf epileptic waltzing mouse. Cellular changes include loss of Nissl material and swelling of the neurons. The fibers lose their myelin sheaths and ultimately disappear. These changes occur gradually and throughout the system, so that the animals slowly lose their hearing arid finally become deaf. Tests given to three of the four animals reported here show that the high tones are most affected, but the low tones are lost to a lesser extent. The specific locations of degenerative changes in the acoustic centers are described and related, as far as possible, to the tonotopic pattern in the auditory system as reported in the literature.

This comparison brings out a caudorostral relationship between the medial geniculate and the primary auditory cortex.
An electron microscopic study of degenerative changes in the cat cerebellum after intrinsic and extrinsic lesions
Authors: Smith Kenneth R. , Hudgens Richard W. , O'Leary James L.
Published: January 2005

Degenerative changes in the cerebellum of the cat have been observed electron microscopically 2 to 30 days after surgical lesions were placed in the inferior or middle cerebellar peduncles or after undercutting or isolating cerebellar folia. The changes were confined to the mossy fibers of the white matter and granular layer except when Purkinje cells were damaged buy undercutting. Mossy fiber terminals in the glomeruli underwent two kinds of change. Either the synaptic vesicles and mitochondria coalesced into dense clumps with loss of mitochondrial outer membranes and proliferation of cristae, or the vesicles and miotochondria disappeared leaving a swollen terminal containing only a few large pleomorphic vesicles and small dense polygonal bodies. Neurofilaments proliferated and filled a few terminals but most of the neurofilamentous hypertrophy and proliferation was confined to myelinated axons. Some phagocytosis of degenerated endings was observed and mild fibrous gliosis occurred in the glomeruli.

All of the changes observed in the present study have been reported in degenerating synapses and axons elsewhere in the central and peripheral nervous system, but there appeared to be more pleomorphism and less predictability of changes in the cerebellar cortex than have been noted in other single areas of the central nervous system.
Electron microscopic observations on vacuolated neurons in starved Rana esculenta
Authors: Srebro Zbigniew
Published: January 2005

An electron microscopic study of the brains of normal and starved individuals of Rana esculenta L. showed that some neurons from the posterior septal area of the telencephalon of the starved animals contain clear vacuoles, up to 3 μ in diameter. The electron micrographs show that the vacuoles derive from small ones present in the dense bodies/lysosomes/ by their enlargement and vacuolar transformation of the dense bodies. The vacuoles generally are membrane‐bound, but also membrane‐less ones can be found. In the latter case the shape of the vacuoles in irregular and they form villus‐like ramifications in the cytoplasm. These ramifications of the outer dense material appear to be dissolving in the cytoplasm or transforming into small vesicles.
The development of trigeminal nerve fibers to the oral mucosa, compared with their development to cutaneous surfaces, ,
Authors: Humphrey Tryphena
Published: January 2005

Small cutaneous branches of all three divisions of the trigeminal nerve pass toward epithelial surfaces in 14 mm human embryos. By 18 mm, such fibers are nearer the epithelium of the upper lip (14 μ., maxillary division) than the lower lip (31μ, mandibular division). At 20.5mm and 20.7mm, the age when Fitzgerald and Windle ('42) and Hooker ('52, '58) first found the perioral area sensitive to stimulation, the nerve fibers are about the same distance from the epithelium of both upper and lower lips (13–14 μ in rima oris area).

Maxillomandibular fibers of the trigeminal nerve reach the basement membrane of the oral cavity epithelium earlier in development than they touch the basement membrane of the cutaneous epithelium about the mouth. Nerve fibers also penetrate the basement membrane of oral mucosal surfaces earlier than that of perioral cutaneous surfaces and form crude Merkel's end discs in mucosal epithelium earlier in development (mucosal epithelium, ten weeks; cutaneous epithelium at 12 weeks according to Hogg, '41).

Ophthalmic fibers approach the upper eyelid epithelium later in development than the maxillomandibular fibers near perioral areas and touch the basement membrane of the eyelid epithelium a week later than they do that of the lips. Hooker did not observe reflexes from eyelid stimulation before ten weeks, when ophthalmic fibers reach the basement membrane, although reflexes from perioral stimulation were elicited when the nearest nerve fibers identified are still 13–14 μ from the basement membrane of the perioral epithelium. Additional correlations are made between the human fetal reflexes recorded by Hooker and the degree of development of the sensory peripheral nerve fibers.
Septal nuclei in primate phylogeny. A quantitative investigation
Authors: Andy Orlando J. , Stephan Heinz
Published: January 2005

Specific septal nuclei were quantitatively studied to determine their developmental changes during evolution. The animals utilized were three insectivores (Erinaceus europaeus, Crocidura russula and Sorex araneus), one prosimian (Galago demidovii) and two higher primates (Colobus badius and Cercopithecus ascanius). The primitive insectivores were used as basal forms of reference upon which developmental changes were determined for the progressively evolving primates. Septal nuclei were histologically identified and delineated on histologic photographs made from the serial histologic sections through the septum. The components of the septum were quantitatively compared to both the size of the total septum and to animal body size. The latter quantitative technique known as the allometric method provides measurements for change in absolute size. Increased growth rate occurred in all septal components except for nucleus septalis triangularis and the bed nucleus of the anterior commissure. The structures which underwent the greatest growth rate were the fimbria‐fornix complex, the bed nucleus of the stria terminalis and the nucleus septalis lateralis. The greatest single contributor to the enlargement of the septum in phylogeny was the nucleus of the diagonal band of Broca. Its growth rate was similar to that of the total septum (1.7 × basal forms) and it made up 30% of the septum volume. The nucleus septalis triangularis was the only one of the septal components to undergo an absolute reduction in size. The subfornical body, a structure lying along the ventro‐caudal surface of the ventral hippocampal commissure, underwent a marked increased size in higher forms, 4 × to 6 × that of basal forms.
The tecto‐thalamic connections in the brain of the rabbit,
Authors: Tarlov Edward C. , Moore Robert Y.
Published: January 2005

We have correlated the tectal connections and cytoarchitecture of regions in the rabbit's midbrain and caudal thalamus. The inferior colliculus projects ipsilaterally to the central gray, superior colliculus, and via the brachium of the inferior colliculus to its interstitial nucleus and the parabrachial region of the midbrain tegmentum. From the brachium, fibers fan out to the principal and internal divisions of the medial geniculate. A smaller contralateral pathway sweeps into the contralateral inferior colliculus and in its brachium to the interstitial nucleus, the parabrachial region, and the internal and principal divisions of the medial geniculate.

The superior collicular projection is mainly ipsilateral. Medially, fibers terminate in the central gray and pretectal area. Laterally, fibers ascend in the superior brachium to parabrachial region, suprageniculate pretectal nucleus, posterior complex, caudodorsal internal division of the medial geniculate, and to a discrete part of the ventral nucleus of later geniculate. A component of the commissure of Gudden originates in the rostral superior colliculus and terminates in the contralateral ventral lateral geniculate, posterior complex, pretectal area and midbrain tegmentum.

Interconnections between the colliculi and overlap of their projections in the parabrachial region, the central gray, and the internal division of the medial geniculate are described.
Evoked potential study of connections of avian archistriatum and caudal neostriatum
Authors: Phillips Richard E.
Published: January 2005

Evoked potential recording revealed that light but not auditory, tactile stimulation or sciatic nerve activated the archistriatum of urethane‐anesthetized chickens. Stimulation of the archistriatum evoked short latency responses throughout the distribution of tractus occipito‐mesencephalicus. Longer latency responses were recorded in other striate areas. Contralateral responses were much less widespread but were recorded from sites in archistriatum, septum, hypothalamus and optic tectum. The absence of multi‐sensory input coupled with the widespread projections of the archistriatum and the taming effect of lesions in tractus occipito‐mesencephalicus suggest that the structure serves as an activator in escape behavior. Reciprocal relations with tectal and/or neostriate regions demonstrated in the study are suggested as the sources for the necessary sensory information for this activating mechanism.
Lamination of the lateral geniculate nucleus in the squirrel monkey, Saimiri sciureus
Authors: Doty Robert William , Glickstein Mitchell , Calvin William Howard
Published: January 2005

The parvocellular portion of the lateral gesticulate nucleus (LGN) in the squirrel monkey (Saimiri sciureus) is a relatively unlaminated mass of cells. In order to determine whether a concealed laminar structure might exist, one eye was removed in each of three squirrel monkeys. Transneuronal degeneration did not appear prominent in the LGN of the animal which was allowed to survive for six months, but in the two animals which survived for one year six laminae were clearly present. There was transneuronal degeneration in layers 1, 4 and 6 contralateral to the enucleation, and 2, 3 and 5 ipsilaterally. Lack of interlaminar fiber masses probably accounts for the apparent absence of lamination in the normal parvocellular mass.