bluuebunny/crossref_metadata_2025 huggingface dataset:
Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease
Authors: Masliah E. , Hansen L. , Alford M. , Deteresa R. , Mallory M.
Published: January 2005

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D‐[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D‐ and L‐[3H]asparate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains AD brains displayed a 34% decrease in levels of D‐[3H]aspartate binding, a 30% decrease in L‐[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D‐[3H] and L‐[3H]aspartate binding, and decreased levels of synaptophysin immuno‐reactivity. Levels of L‐[3H]asparatate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activiyt in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.
Mutant GTP cyclohydrolase I mRNA levels contribute to dopa‐responsive dystonia onset
Authors: Hirano Makito , Tamaru Yoshiko , Ito Hidefumi , Matsumoto Sadayuki , Imai Terukuni , Ueno Satoshi
Published: January 2005

We present a new Japanese family with hereditary progressive dystonia with marked diurnal fluctuation/doparesponsive dystonia. The affected daughter and her asymptomatic father are heterozygous for a novel missense mutation that replaces His by Pro at codon 144 in the GTP cyclohydrolase I gene. Quantitative reverse transcription‐polymerase chain reaction revealed a higher ratio of mutant/normal mRNA encoding GTP cyclohydrolase I in the patient. These results demonstrate the importance of mutant mRNA levels for phenotypic variability among cases with the same mutation.
Search for retrovirus in patients with multiple sclerosis
Authors: Hackett John , Swanson Priscilla , Leahy David , Anderson Eve L. , Sato Shigeru , Roos Raymond P. , Decker Richard , Devare Sushil G.
Published: January 2005

Multiple sclerosis (MS) patient samples were screened for known or novel retroviruses using an ultrasensitive technique, IMx PERT, that detects the presence of reverse transcriptase (RT). This procedure has 105‐ to 107‐fold greater sensitivity than conventional RT assays and is capable of detecting 10 to 50 virions. Moreover, IMx PERT is at least as sensitive as polymerase chain reaction, and requires no previous knowledge of viral nucleotide sequence. The MS specimens analyzed in this study included 136 sera from 79 patients and 128 cerebrospinal fluid samples from 53 patients with relapsing or chronic progressive disease. In addition, peripheral blood mononuclear cells from 19 MS patients were cultured in an attempt to amplify or induce expression of low‐copy number or cell‐associated retrovirus. No evidence of retrovirus was found in any of the specimens obtained from MS patients.
Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies
Authors: Mirabella Massimiliano , Alvarez Renate B. , King Engel W. , Askanas Valerie , Weisgraber Karl H.
Published: January 2005

Sporadic inclusion body myositis and the hereditary inclusion body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired helical filaments. We immunostained muscle biopsy specimens from sporadic inclusion body myositis, hereditary inclusion body myopathy, disease control, and normal patients with several antibodies against apolipoprotein E (ApoE). Approximately 80 to 90% of the vacuolated muscle fibers of sporadic inclusion body myositis contained well‐defined, strongly immunoreactive ApoE inclusions, In hereditary inclusion body myopathy, only rare vacuolated fibers had immunoreactive inclusions, whereas most had diffuse cytoplasmic ApoE immunoreactivity. Ultrastructurally, ApoE immunoreactivity in sporadic myositis was localized mainly to the paired helical filaments. By contrast, in the hereditary form, ApoE immunoreactivity occurred on material in close proximity to the paired helical filaments, but never was on the paired helical filaments. In both muscle diseases, ApoE was also on the 6‐to 10‐nm filaments and amorphous material. In the sporadic form, ApoE‐immunoreactive deposits colocalized with Congo red‐positive deposits; however, in muscle fibers from patients with hereditary disease there was no congophilia. ApoE messenger RNA was not detectable in muscle fibers from patients with hereditary or sporadic disease but was expressed abundantly in muscle macrophages. In all control and inclusion body myositis or myopathy biopsy specimens, ApoE immunoreactivity was strong at the postsynaptic domain of neuromuscular junctions; nonjunctional regions of normal fibers were negative for ApoE. ApoE immunoreactivity occurred diffusely in regenerating muscle fibers, a subset of which had detectable ApoE messenger RNA.
A rapidly progressive adolescent‐onset oculopharyngeal somatic syndrome with rimmed vacuoles in two siblings
Authors: Rose Michael R. , Landon David N. , Papadimitriou Alex , Morgan‐Hughes John A.
Published: January 2005

We describe 2 Greek siblings who developed a rapidly progressive oculopharyngeal somatic syndrome, at the ages of 11 and 14 years, with muscle biopsies showing rimmed vacuoles and, in 1 case, cytoplasmic and intranuclear tubulofilamentous inclusions 25 nm in diameter. Although a similar pattern of muscle involvement with rimmed vacuoles is described in autosomal dominant oculopharyngeal muscular dystrophy, the age of onset, the rapid progression of the symptoms, and the nature of the tubulofilaments distinguish this as a separate entity.
The spectrum of hippocampal sclerosis: A quantitative magnetic resonance imaging study
Authors: Van Paesschen W. , Connelly A. , King M. D. , Jackson G. D. , Duncan J. S.
Published: January 2005

One hundred patients with intractable temporal lobe epilepsy and 22 control subjects were scanned on 1.5‐T Siemens SP63 Magnetom scanner. A combination of hippocampal T2 mapping, hippocampal volume measurement corrected for intracranial volume, and inspection of hippocampal morphology on a hippocampal volume distribution graph compared with a control graph revealed previously undetected forms of bilateral hippocampal sclerosis and four false‐positive diagnoses of hippocampal sclerosis made on visual inspection of the scans. A physiological asymmetry in the position of the hippocampi in 41% of control subjects and focal hippocampal atrophies in patients made measurement of the whole length of the hippocampus mandatory. The extent of hippocampal damage in patients with hippocampal sclerosis correlated with the number of secondary generalized seizures during a patient's lifetime. In contrast to patients with unilateral hippocampal sclerosis, patients with severe bilateral hippocampal sclerosis had no history of febrile convulsions. Twenty‐six patients with intractable temporal lobe epilepsy had normal hippocampal magnetic resonance imaging measures and as a group were significantly older at the onset of habitual epilepsy than were patiets with hippocampal sclerosis. In conclusion, a combination of quantitative magnetic resonance imaging techniques revealed a spectrum of hippocampal sclerosis and optimally defined boundaries of hippocampal normality. The spectrum of hippocampal sclerosis is related to the etiology, the number of secondary generalized seizures, and the age at onset of habitual epilepsy.
Reversible schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor
Authors: Winkler Jürgen , Ramirez Gilbert A. , Kuhn H. Georg , Peterson Daniel A. , Day‐Lollini Patricia A. , Stewart Gregory R. , Tuszynski Mark H. , Gage Fred H. , Thal Leon J.
Published: January 2005

Substantial dysfunction and loss of cholinergic neurons occur in Alzheimer's disease (AD). Nerve growth factor (NGF) is a potent neurotrophic factor for cholinergic basal forebrain neurons, and the use of NGF to stimulate residual dysfunctional cells in AD is being considered. To define the effects of NGF on other cell populations in the brain, NGF was continuously infused into the lateral ventricle of rats for 7 weeks. At the end of treatment, Schwann cell hyperplasia and abundant sensory and sympathetic neurite sprouting were observed in the subpial region of the medulla oblongata and the spinal cord. Following withdrawal of NGF, the Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites disappeared completely. These findings suggest that better temporal and spatial delivery systems for NGF must be explored to limit potential undesirable side effects while maintaining the survival and function of diseased basal forebrain cholinergic neurons.
Hereditary frontotemporal dementia is linked to chromosome 17q21—q22: A genetic and clinicopathological study of three dutch families
Authors: Heutink P. , Stevens M. , Rizzu P. , Bakker E. , Kros J. M. , Tibben A. , Niermeijer M. F. , Van Duijn C. M. , Oostra B. A. , Van Swieten J. C.
Published: January 2005

Hereditary frontotemporal dementia (HFTD) is a rare autosomal dominant form of presenile dementia characterized by behavioral changes and reduced speech. Three multigeneration kindreds with this condition, in the Netherlands, were investigated for clinicopathological comparison and linkage analysis. Frontotemporal atrophy on computed tomographic scanning and/or magnetic resonance imaging was usually present. Single‐photon emission computed tomography (SPECT) showed frontal hypoperfusion in the early phase of the disease. Brain tissue showed moderate to severe atrophy of frontal and temporal cortex with neuronal loss, gliosis, and spongiosis. Pick bodies were lacking in all cases of the 3 families. The mean age of onset varied significantly between families. We report here evidence for linkage to chromosome 17q21–q22 with a maximum lod score of 4.70 at Θ = 0.05 with the marker D17S946 and D17S791. Three other neurodenegenerative disorders with a strong clinical and pathological resemblance have recently been mapped to the same chromosomal region, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene.
Familial risk of migraine: A population‐based study
Authors: Stewart Walter F. , Staffa Judy , Lipton Richard B. , Ottman Ruth
Published: January 2005

Estimates of familial aggregation of migraine have varied considerably due, in part, to methodological differences among studies. We concluded a population‐based study of 73 clinically confirmed probands with migraine, 72 matched control probands, and 511 of their first‐degree relatives, all of whom were directly interviewed. The risk of migraine was 50% more likely in relatives of migraine probands than in relatives of controls. Migraine risk was considerably higher among relatives of probands with disabling migraine compared with relatives of probands with minimal disability. Moreover, for probands with minimal disability, no excess risk of migraine in female relatives was observed. Finally, in relatives risk of 4.04 was observed. No excess risk was observed among relatives of male probands who had migraine without aura. This study suggests that familial factors (environment related to the family or genetic factors) account for less than one‐half of all migaine cases in the population. Degree of disability in the proband appears to influence familial risk. These results suggest that the development of migraine is determined by complex gentic as well as environmental factors.
Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis
Authors: Cudkowicz M. E. , McKenna‐Yasek D. , Sapp P. E. , Chin W. , Geller B. , Hayden D. L. , Schoenfeld D. A. , Hosler B. A. , Horvitz H. R. , Brown R. H.
Published: January 2005

We registered 366 families in a study of dominantly inherited amyotrophic lateral sclerosis. Two hundred ninety families were screened for mutations in the gene encoding copper‐zinc cytosolic superoxide dismutase (SOD1). Mutations were detected in 68 families. The most common SOD1 mutation is an alanine for valine substitution in codon 4 (50%). We present clinical and genetic data concerning 112 families with 395 affected individuals. The clinical characteristics of patients with familial amyotrophic lateral sclerosis arising from SOD1 mutation are similar to those lacking SOD1 defects. Mean age at onset was earlier (Wilcoxon test,p= 0.004) in the SOD1 group (46.9 years [standard deviation, 12.5] vs 50.5 years [11.5] in the non‐SOD1 group). Bulbar onset was associated with a later onset age. The presence of either of two mutations, G37R and L38V, predicted an earlier age at onset. Kaplan‐Meier plots demonstrated shorter survival in the SOD1 group compared with the non‐SOD1 group at early survival times (Wilcoxon test,p= 0.0007). The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival. This information suggests it will be productive to investigate other genetic determinants in amyotrophic lateral sclerosis and to use epidemiological characteristics of the disease to help discern molecular mechanisms of motor neuron cell death.
Dopaminergic function in familial Parkinson's disease: A clinical and 18F‐dopa positron emission tomography study
Authors: Piccini P. , Morrish P. K. , Turjanski N. , Sawle G. V. , Burn D. J. , Weeks R. A. , Mark M. H. , Maraganore D. M. , Lees A. J. , Brooks D. J.
Published: January 2005

There is increasing evidence for familial aggregation in Parkinson's disease (PD). It is possible that some asymptomatic relatives of PD patients have subclinical nigral Lewy body pathology and their identification could help determine the true prevalence of the disease. We used 18F‐dopa positron emission tomography to investigate nigrostriatal dopaminergic terminal function in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism. Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen 18F‐dopa uptake (2.5 standard deviations below the normal mean). When discriminant function analysis was applied, all of these 8 subjects plus another 3 were classified with high probability as having PD. On neurological examination, 5 of the 32 relatives scanned had an isolated mild postural tremor and 2 of these 5 had reduced putamen uptake. Our findings provide further support for a role of inheritance in the etiology of PD and suggest that the penetrance for nigrostriatal dopaminergic dysfunction in familial clusters of PD is higher than the prevalence of clinical parkinsonism reported in epidemiological surveys.
Involvement of the ipsilateral motor cortex in finger movements of different complexities
Authors: Chen Robert , Gerloff Christian , Hallett Mark , Cohen Leonardo G.
Published: January 2005

Functional imaging and behavioral studies suggest involvement of the ipsilateral hemisphere in hand movements, particularly of the left hand. If this is so, transient disturbance of the motor cortex (M1) with repetitive transcranial magnetic stimulation (rTMS) may affect ipsilateral motor sequences, and the effects may differ on the two sides. We studied 15 right‐handed subjects who played a simple and a complex piano sequence for 8 seconds each. Two seconds after the beginning of each sequence, rTMS was delivered to the ipsilateral or contralateral M1, or directed away from the head (control trial). Ipsilateral M1 stimulation on either side induced timing errors in both sequences, and with the complex sequence induced more timing errors in the left hand than in the right hand. Errors of the right hand with both sequences occurred in the stimulation period only, but errors of the left hand with the complex sequence occurred in both the stimulation and poststimulation periods. We conclude that the ipsilateral M1 is involved in fine finger movements. The left hemisphere plays a greater role in timing ipsilateral complex sequences than the right hemisphere and may be more involved in the processing of complex motor programs.
Molecular analysis of cytochromec Oxidase deficiency in Leigh's syndrome
Authors: Adams Paula L. , Lightowlers Robert N. , Turnbull Douglass M.
Published: January 2005

Cytochrome c oxidase deficiency is the most common biochemical defect associated with Leigh's syndrome. The genetic defect responsible for this deficiency has not been identified in any patient with Leigh's syndrome. Given that this disorder appears to be inherited as an autosomal recessive trait, this would suggest prima facie that one of the nuclear DNA—encoded cytochrome c oxidase subunits is affected. We report the first detailed sequence analysis of all 10 cytochrome c oxidase nuclear complementary DNAs and the cytochrome c oxidase mitochondrial genes in a Leigh's syndrome patient with cytochrome c oxidase deficiency. No pathological mutations were identified in any of the cytochrome c oxidase structural genes.
Genetic evidence for the involvement of τ in progressive supranuclear palsy
Authors: Conrad Chris , Andreadis Athena , Trojanowski John Q. , Dickson Dennis W. , Kang David , Chen Xiaohua , Wiederholt Wigbert , Hansen Larry , Masliah Eliezer , Thal Leon J. , Katzman Robert , Xia Yu , Saitoh Tsunao
Published: January 2005

A dinucleotide repeat polymorphism in a τ intron was identified and used in a case‐control study to analyze the genetic association of τ with several neurodegenerative disease with τ pathology. Subjects with the homozygous τ AO alleles were excessively represented in the progressive supranuclear palsy (PSP) group, compared with the age‐matched healthy control group. Consequently, this allele is more frequently found in PSP than in a group of healthy subjects. This trend was not found in Alzheimer's disease or parkinsonism‐dementia complex of Guam, both of which are accompanied by major τ pathology. The result suggests τ possible involvement of τ in the pathogenesis of PSP.
Transthyretin amyloidosis: A new mutation associated with dementia
Authors: Petersen R. B. , Goren H. , Cohen M. , Richardson S. L. , Tresser N. , Lynn A. , Gali M. , Estes M. , Gambetti P.
Published: January 2005

Familial transthyretin (TTR) amyloidosis commonly presents with peripheral neuropathy and involvement of visceral organs. In contrast, signs of central nervous system (CNS) involvement are exceptional. We report that members of a kindred affected by a slowly progressive dementia, seizures, ataxia, hemiparesis, and decreased vision without neuropathy have TTR amyloid deposits in the leptomeninges, the brain parenchyma, and the eye. This condition, previously labeled oculoleptomeningeal amyloidosis, is linked to a mutation at codon 30 of TTR gene, resulting in the substitution of valine with glycine in this family, TTR amyloid deposits were present in the leptomeninges, especially the leptomeningeal vessels, and in the subependymal regions of the ventricular system where they disrupted the ependymal lining and resulted in amyloid‐glial formations protruding into and narrowing the ventricular system. Hydrocephalus and atrophy and infarction of cerebral and cerebellar cortexes were also present. Review of the literature shows that amyloid deposition in the leptomeninges is not uncommon in TTR amyloidoses clinically characterized by peripheral neuropathy and lack of CNS signs. The present kindred, which presented exclusively with signs of CNS involvement, expands the phenotype of TTR amyloidosis and raises questions concerning the mechanisms determining phenotypic expression in TTR familial amyloidosis.
Genetic predisposition to multiple sclerosis as revealed by immunoprinting
Authors: Epplen Cornelia , Jäckel Silke , Santos Eduardo J. M. , D'Souza Marcus , Poehlau Dieter , Dotzauer Bernd , Sindern Eckhart , Haupts Michael , Rüde Klaus‐Peter , Weber Frank , Stöver Jens , Poser Sigrid , Gehler Walter , Malin Jean‐Pierre , Przuntek Horst , Epplen Jörg T.
Published: January 2005

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty‐eight clinically well‐characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA‐DRB1*, T‐cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes. Altogether, approximately 17,000 genetic analyses were performed. Patients were grouped according to the course of MS—relapsing‐remitting or chronic progressive. Most of the genetic markers were not associated with increased risk or their exact contribution was not clear (e.g., tumor necrosis factor). The relative risks for HLA‐DRB1*15+ and DRB1*03+ individuals were 3.64 and 1.42, respectively. In both groups of patients, certain TCRB gene polymorphisms were risk factors. In DRB1*03+ individuals the relative risk was increased (>22) when a specific TCRBV6S3 allele was also inherited. Furthermore, distinct linkage disequilibria of TCRBV6S1/TCRBV6S3 elements in patients and control subjects strongly suggested an additional risk factor in the TCRBV region for DRB1*15+ individuals. These findings are discussed with respect to the pathogenesis and rational approaches to the therapy of MS.
A japanese family carrying a novel mutation in the emery‐dreifuss muscular dystrophy gene
Authors: Ichikawa Yaeko , Watanabe Masahiko , Kowa Hisatomo , Murayama Shigeo , Mizuno Takehiko , Komuro Issei , Ishiki Ryouji , Goto Jun , Kanazawa Ichiro
Published: January 2005

We report on a Japanese family affected by Emery‐Dreifuss muscular dystrophy carrying a novel mutation of the emerin (STA) gene. The cardinal clinical feature of the family was cardiac conduction block and mild myopathy. A deletion of 11 bp with a frameshift was identified in exon 6, causing truncation of the predicted protein. The relationship between mutation and phenotype is discussed.
Health‐related quality of life and seizure control in temporal lobe epilepsy
Authors: McLachlan Richard S. , Rose Kristopher J. , Derry Paul A. , Bonnar Casey , Blume Warren T. , Girvin John P.
Published: January 2005

We conducted a prospective study over 24 months to compare health‐related quality of life in surgically and medically treated patients with intractable temporal lobe epilepsy. Seizure frequency and health‐related quality of life were assessed in 81 patients before and 6, 12, and 24 months after treatment. Using the Epilepsy Surgery Inventory 55 (ESI‐55), we compared (1) different seizure outcome groups and (2) temporal lobectomy with continuing medical management. Follow‐up was satisfactory in 72 patients (89%), 51 treated with temporal lobectomy and 21 with no surgery. Pretreatment seizures and health‐related quality of life were comparable in the two groups. Seizure outcome was significantly better at 6, 12, and 24 months after surgery. At 24 months, seizure‐free patients and those with at least a 90% reduction in seizure frequency reported significant improvements in health‐related quality of life (on 5 of 10 subscales and overall Epilepsy Surgery Inventory 55 scale). Deterioration in quality of life occurred with less than 90% seizure reduction. Only one Epilepsy Surgery Inventory 55 subscale at 6 months and two subscales at 12 months showed a significant difference. Patients with good seizure outcome experience improved health‐related quality of life after treatment. Since temporal lobectomy results in considerably better seizure control than continued medical management, the findings support surgery as the preferred treatment, although changes in health‐related quality of life may not be evident until the second postoperative year.
Correlation of widespread preoperative magnetic resonance imaging changes with unsuccessful surgery for hippocampal sclerosis
Authors: Sisodiya S. M. , Moran N. , Free S. L. , Kitchen N. D. , Stevens J. M. , Harkness W. F. J. , Fish D. R. , Shorvon S. D.
Published: January 2005

Despite meticulous preoperative assessment, about 30% of patients with refractory partial epilepsy due to hippocampal sclerosis fail to become seizure free after appropriate temporal lobe surgery. Perioperative complications, hippocampal remnants, and bitemporal disease do not account for all failures; extrahippocampal epileptogenic tissue must persist in some patients. Such dual pathology is detected on routine visual inspection of magnetic resonance images in about 15% of patients with hippocampal sclerosis, but most such patients are excluded from surgery. We postulated that some patients have occult extrahippocampal cerebral structural abnormalities (i.e., subtle dual pathology) and that the presence of these abnormalities would be associated with a poor surgical outcome. Quantitative postprocessing of preoperative magnetic resonance images from 27 patients subsequently proved to have hippocampal sclerosis demonstrated extrahippocampal structural abnormalities in 14, 10 of whom did not become seizure free, while 11 of 13 patients without such changes did become seizure free (χ2, p < 0.005). Such structural information may supplement clinical decision making in some patients being evaluated for epilepsy surgery and help to explain the biological basis of poor outcome from such surgery.
Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: Dentatorubral‐pallidoluysian atrophy, machado‐joseph disease, and spinocerebellar ataxia type 1
Authors: Hashida Hideji , Goto Jun , Kurisaki Hiroshi , Mizusawa Hidehiro , Kanazawa Ichiro
Published: January 2005

Three autosomal dominant spinocerebellar ataxias, dentatorubral‐pallidoluysian atrophy (DRPLA), Machado‐Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult‐onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granularlayers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.
Cortical peptide changes in Huntington's disease may be independent of striatal degeneration
Authors: Mazurek Michael F. , Garside Sarah , Beal M. Flint
Published: January 2005

Patients with Huntington's disease (HD) develop pathological changes in cerebral cortex as well as in striatum. We studied levels of neuropeptide immunoreactivity in 13 areas of postmortem cerebral cortex dissected from 24 cases of HD and 12 controls. Concentrations of immunoreactive cholecystokinin (CCK‐LI) were consistently elevated 57 to 153% in HD cortex. Levels of vasoactive intestinal polypeptide (VIP‐LI) and neuropeptide Y (NPY‐LI) were significantly increased in 10 and 8 of the 13 cortical regions, respectively. Concentrations of somatostatin (SRIF‐LI) were increased in only 3 areas, while substance P (SP‐LI) was, for the most part, unchanged. Detailed analyses of the CCK‐LI and VIP‐LI data showed there to be no relationship between the increased cortical peptide levels and the degree of stiatal atrophy. We studied the same cortical peptides in rats with long‐standing stiatal lesions and found no significant changes of CCK‐LI, NPY‐LI, VIP‐LI, or SIRF‐LI in any of the 8 cortical regions that were examined. These results indicate that there are widespread and differential changes in cortical neuropeptide sysems in HD and that these changes occur independently of the striatal pathology that characterizes the illness.
The quest for unbiased research: Randomized clinical trials and the CONSORT reporting guidelines
Authors: Schulz Kenneth F.
Published: January 2005

The large and increasing number of randomized clinical trials in all of medicine has prompted the introduction of guidelines that are intended to improve the quality of the research and of the published papers derived from such investigations. These guidelines for reporting clinical trials, the Consolidated Standards of Reporting Trials (the CONSORT statement) were set forth by a group of journal editors, statisticians, biomedical investigators, and editors. The CONSORT statement has been published in several major medical journals and is likely to have a major impact on editorial policies as well as the design of such investigations. I have invited Dr Kenneth F. Schulz of the Centers for Disease Control and Prevention, a leading investigator in the evaluation of clinical trials and a participant in the design of the CONSORT guidelines, to prepare this brief summary for the Annals. The CONSORT statement is expected to have a substantial effect on the peer review of clinical trials, and it promises to elevate the quality of such investigations. Future submissions to the Annals will be evaluated in the context of these guidelines.
Endoglin gene polymorphism as a risk factor for sporadic intracerebral hemorrhage
Authors: Alberts M. J. , Davis J. P. , Graffagnino C. , McClenny C. , Delong D. , Granger C. , Herbstreith M. H. , Boteva K. , Marchuk D. A. , Roses A. D.
Published: January 2005

Intracerebral hemorrhage (ICH) is a common and serious type of stroke. Recent studies have shown that inherited factors that affect the devlopment of the vessel wall can increase the risk of ICH. We studied endoglin as a candidate gene in patients with sporadic ICH, since mutations in this gene can cause telangiectasia formation. One hundred three patients with sporadic ICH and 202 controls were studied. The polymerase chain reaction and single‐strand conformational polymorphism analysis were used to screen for mutations in exon 7 of the endoglin gene. No coding mutations in exon 7 were identified in the ICH patients or controls. A 6‐base intronic insertion was found 26 bases beyond the 3′ end of exon 7. The homozygous form of the insertion was present in 9 of 103 (8.7%) ICH patients compared with 4 of 202 (2.0%) controls, p = 0.012 (odds ratio 4.8 [95% confidence interval, 1.28, 21.60]). Analysis of the endoglin transcript around the insertion did not reveal any changes in the RNA sequence. There were no obvious clinical features that distinguished the ICH patients with the homozygous insertion from the other patients. The pathophysiologic mechanism underlying this association remains to be determined.
A subset of senile dementia with high incidence of the apolipoprotein E ϵ2 allele
Authors: Ikeda Kenji , Akiyama Haruhiko , Arai Tetsuaki , Sahara Naruhiko , Mori Hiroshi , Usami Mihoko , Sakata Masuhiro , Mizutani Toshio , Wakabayashi Koichi , Takahashi Hitoshi
Published: January 2005

There is a subset of very elderly patients with senile dementia in whom abundant neurofibrillary tangles are present, mainly in the hippocampal region, without a significant number of senile plaques. In a retrospective neuropathological examination of 239 dementia patients, 14 were found to have this type of senile dementia. The apolipoprotein E ϵ2, ϵ3, and ϵ4 allele frequencies in this patient group were 0.39, 0.50, and 0.11, respectively. Such a high frequency of the ϵ2 allele suggests that this type of dementia is distinct from Alzheimer's disease not only from a neuropathological but also from a genetic viewpoint.
Frontotemporal dementia and parkinsonism linked to chromosome 17: A consensus conference
Authors: Foster Norman L. , Wilhelmsen Kirk , Sima Anders A. F. , Jones Margaret Z. , D'Amato Constance J. , Gilman Sid ,   Conference Participants
Published: January 2005

We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous disorders, to agree on terminology, and to develop strategies for further research. The group identified 13 kindreds with sufficient evidence for linkage, finding in common to all a critical 2 cM between markers D17S791 and D17S800. There was agreement that (1) despite previous descriptions that have emphasized one or another clinical or neuropathological feature, the kindreds share clinical and neuropathological features; (2) until more specific information about the genetic defects becomes available, this disorder is best termed frontotemporal dementia and parkinsonism linked to chromosome 17; and (3) further research will be enhanced by identifying the gene responsible for this disorder, detecting additional cases within known families and, in new families, correlating mutations with phenotypes and more fully delineating the clinical, neuropsychological, and neuropathological characteristics of this disorder.
Clinical trial of plasma exchange and high‐dose intravenous immunoglobulin in myasthenia gravis
Authors: Gajdos Philippe , Chevret Sylvie , Clair Bernard , Tranchant Christine , Chastang Claude ,   for the Myasthenia Gravis Clinical Study Group
Published: January 2005

We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (IVIg) or plasma exchage (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of IVIg. Eighty‐seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or IVIg (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the IVIg group; p = 0.65). Similar efficacy, although slightly reduced in the 5‐day group was observed with both IVIg schedules. The tolerance of IVIg was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the IVIg group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for IVIg. IVIg is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with IVIg and to determine the optimal dosage of IVIg.
Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities
Authors: van der Knaap M. S. , Smit L. M. E. , Barth P. G. , Catsman‐Berrevoets C. E. , Brouwer O. F. , Begeer J. H. , de Coo I. F. M. , Valk J.
Published: January 2005

A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker‐Warburg syndrome (WWS), MRI showed hydrocephalus due to aqueduct stenosis, generalized cerebral cortical agyric or pachygyric polymicrogyria, diffuse cerebral hemispheric white matter abnormalities, and malformations of posterior fossa structures. In 4 patients with muscle–eye–brain disease, MRI showed cortical dysplasia, but less severe than in WWS. The cerebral white matter either was normal or contained multiple focal abnormalities. Malformations of posterior fossa structures were present. Eight patients, classified as having classic merosin‐deficient CMD (MD‐CMD), had diffuse cerebral hemispheric white matter abnormalities, no other abnormalities. One patient with MD‐CMD had only a few, focal white matter abnormalities. Three CMD patients had occipital agyria, otherwise normal gyration, multifocal or more diffuse cerebral white matter changes, and variable hypoplasia of pons and vermis. Two of the 3 patients had negative muscle merosin staining. The conclusion of the study is that MRI is an important adjunct in the classification of CMD patients. CMD with occipital agyria can be regarded as a newly recognized, separate CMD subtype.
Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas
Authors: Wienecke Ralf , Guha Abhijit , Maize John C. , Heideman Richard L. , DeClue Jeffrey E. , Gutmann David H.
Published: January 2005

Individuals affected with tuberous sclerosis complex (TSC) develop several benign and malignant tumors at increased frequency, including astrocytomas. Tuberin, the protein product of the tuberous sclerosis complex‐2 (TSC2) tumor suppressor gene, has been shown to directly inhibit cell growth and is expressed at high levels in normal central nervous system neurons and astrocytes. To determine whether TSC2 RNA and protein are reduced in astrocytomas from individuals without tuberous sclerosis, reverse transcriptase–polymerase chain reaction and immunoblotting analyses were performed on 49 adult astrocytomas, 10 pediatric astrocytomas, and 13 ependymomas. Eighteen of 40 (45%) high‐grade (World Health Organization [WHO] grade III/IV) astrocytomas and 4 of 8 (50%) adult low‐grade (WHO grade II) astrocytomas demonstrated reduced or absent TSC2 expression, including 1 gaint cell astrocytoma, whereas none of the 10 pediatric low‐grade astrocytomas anlayzed showed a reduction in TSC2 expression. Reduced or absent tuberin was observed in 2 of 6 (33%) ependymomas analyzed. These data demonstrate, for the first time, that reduced or absent TSC2 expression may represent one of the critical genetic events associated with the development of sporadic adult, but not pediatric, astrocytomas.
Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects
Authors: Shults Clifford W. , Haas Richard H. , Passov David , Beal M. Flint
Published: January 2005

The activities of complex I and complex II/III in platelet mitochondria are reduced in patients with early, untreated Parkinson's disease. Coenzyme Q 10 is the electron acceptor for complex I and complex II. We found that the level of coenzyme Q 10 was significantly lower in mitochondria from parkinsonian patients than in mitochondria from age‐ and sex‐matched control subjects and that the levels of coenzyme Q 10 and the activities of complex I and complex II/III were significantly correlated.
Frataxin gene of Friedreich's ataxia is targeted to mitochondria
Authors: Priller Josef , Scherzer Clemens R. , Faber Peter W. , MacDonald Marcy E. , Yong Anne B.
Published: January 2005

Friedriech's ataxia is caused by a triplet repeat expanison in intron 1, a noncoding region of the frataxin gene (X25). We have generated a chimeric gene composed of the frataxin gene fused with the green fluorescent protein (GFP) gene as a reporter. Transfection of the fusion construct into living COS cells revealed that the frataxin–GFP construct localizes to organelles that double‐label with 8–(4′‐chloromethyl) phenyl‐2,3,5,6,11,12,14,15‐octahydro‐1H,4H,10H‐13H‐diquinolizino‐8H‐xanthylium chloride (CMXRos), a novel mitochondrial dye. Thus, frataxin appears to be a nuclear‐encoded mitochondrial protein.
Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease
Authors: Limousin Patricia , Greene John , Pollak Pierre , Rothwell John , Benabid Alim‐Louis , Frackowiak Richard
Published: January 2005

High‐frequency electrical stimulation of the internal pallidum (GPi) or the subthalamic nucleus (STN) improves clinical symptoms of Parkinson's disease. In 12 parkinsonian patients, 6 with STN and 6 with GPi stimulators, we used H215O positron emission tomography to evaluate whether changes in movement performance were accompanied by change in regional cerebral blood flow (rCBF). Patients were scanned both at rest and while performing a free‐choice joystick movement, under conditions of effective and ineffective electrostimulation. During effective STN stimulation, movement‐related increases in rCBF were significantly higher in supplementary motor area, cingulate cortex, and dorsolateral prefrontal cortex (DLPFC) than during ineffective stimulation. No significant change was observed in any of these areas during GPi stimulation. The difference between the effect of STN and GPi stimulation on movement‐related activity was mainly localized to DLPFC. These results confirm the dominant role of nonprimary motor areas in the control of movement in parkinsonian patients and demonstraste the importance of STN input in the control of these areas.
Andersen's syndrome: A distinct periodic paralysis
Authors: Sansone V. , Griggs R. C. , Meola G. , Ptácek L. J. , Barohn R. , Iannaccone S. , Bryan W. , Baker N. , Janas S. J. , Scott W. , Ririe D. , Tawil R.
Published: January 2005

A previous study of 4 patients defined Andersen's syndrome (AS) as a triad of potassium‐sensitive periodic paralysis, ventricular dysrhythmias, and dysmorphic features. AS appears to be distinct in terms of its genetic defect from the α‐subunit of skeletal muscle sodium channel and the cardiac potassium channel responsible for most long QT syndromes (LQT1). We studied 11 additional patients with AS from 5 kindreds. Spontaneous attacks of paralysis were associated with hypokalemia, normokalemia, or hyperkalemia. All 11 patients had similar dysmorphic features. The QT interval was prolonged in all patients although only 4 were sympotomatic. Genetic linkage studies excluded linkage to the α‐subunit of the skeletal muscle sodium channel and to four distinct LQT loci. In addition, none of the common dihydropyridine receptor mutations responsible for hypokalemic periodic paralysis were present. We conclude that (1) AS is a genetically unique channelopathy affecting both cardiac and skeletal membrane excitability, (2) attacks of paralysis may be either hypokalemic or hyperkalemic, (3) a prolonged QT interval is an integral feature of this syndrome, and (4) a prolonged QT interval may be the only sign in an individual from an otherwise typical AS kindred. This may be confused with more common, potentially lethal LQT syndromes.
Functional and metabolic analysis of cerebral ischemia using magnetoencephalography and proton magnetic resonance spectroscopy
Authors: Kamada Kyousuke , Saguer Mark , Möller Martin , Wicklow Karsten , Katenhäuser Martin , Kober Helmut , Vieth Jürgen
Published: January 2005

The details of the relationship between brain function and metabolism in brain infarcts have not been studied. Using magnetoencephalography (MEG) and proton magnetic resonance spectroscopic imaging (1H MRSI), we localized sources of abnormal magnetic activities in ischemic brain regions and biochemical changes in suspected lesions showing pathological characteristics. Twelve patients with ischemic stroke were examined and the results of MEG and 1H MRSI were superimposed onto the corresponding MR images. The signal intensities of N‐acetyl (NA) and lactate (Lac) were measured in the lesions with highly concentrated dipoles of slow wave activity. Eleven of 12 cases had increased slow wave activity in the cortical areas adjacent to the infarcts; 1 case was excluded because the infarct was too small (<1 cm in diameter). The signal intensity of NA in the regions with the highest slow wave activity was significantly reduced and was well correlated with the dipole density of slow waves. Though Lac was mildly accumulated in the lesions, the Lac level had no correlation with slow wave magnetic activity. The remaining and metabolically active cortical tissue showing NA signal produced the abnormal slow wave activity. The remaining and metabolically active cortical tissue showing NA signal produced the abnormal slow wave activity under lactic acidosis (mils accumulation of Lac).
Central apnea and acute cardiac ischemia in a sheep model of epileptic sudden death
Authors: Johnston S. Claiborne , Siedenberg Ralf , Min Jeffrey K. , Jerome E. Heidi , Laxer Kenneth D.
Published: January 2005

The etiology of sudden death in patients with epilepsy remains unclear. Previous studies in a well‐established sheep model of status epilepticus showed that more than one‐third of the unsedated animals died within 5 minutes of seizure onset due to hypoventilation. The relative contributions of airway obstruction and central hypoventilation could not be determined because airway flow and respiratory effort were not monitored. In this study, status epilepticus was induced in unsedated sheep with tracheostomies monitored by electrocardiography, electroencephalography, arterial line, serial blood gases, and airway flowmeter. All 8 animals demonstrated central apnea and hypooventilation, which resulted in the death of 1 and contributed to the death of another. A third animal died of acute heart failure within 2 minutes of seizure onset, accompanied by a large septal myocardial hemorrhage, contraction bands, and signs of global cardiac ischemia. More subtle contraction bands, subendocardial hemorrhage, and signs of acute myocardial ischemia were seen in other animals as well, none of which died of cardiac causes. Malignant arhythmia was not seen in any of the sheep. Central hypoventilation and apnea accompany generalized status epilepticus and may be an important cause of sudden death in epileptics. Acute cardiac failure may also be a cause of epileptic sudden death.
Prospective study of neurological responses to treatment with macrophage‐targeted glucocerebrosidase in patients with type 3 Gaucher's disease
Authors: Schiffmann Raphael , Heyes Melvyn P. , Aerts J. M. , Dambrosia James M. , Patterson Marc C. , DeGraba Thomas , Parker Colette C. , Zirzow Gregory C. , Oliver Katherine , Tedeschi Gioacchino , Brady Roscoe O. , Barton Norman W.
Published: January 2005

We prospectively evaluated the clinical and biochemical responses to enzyme‐replacement therapy (ERT) with macrophage‐targeted glucocerebrosidase (Ceredase) infusions in 5 patients (age, 3.5–8.5 years) with type 3 Gaucher's disease. The patients were followed for up to 5 years. Enzyme dosage ranged from 120 to 480 U/kg of body weight/month. Systemic manifestations of the disease regressed in all patients. Neurological deficits remained stable in 3 patients and slightly improved in 1. One patient developed myoclonic encephalopathy. Cognitive deterioration occurred in 1 patient and electroencephalographic deterioration in 2. Sequential cerebrospinal fluid (CSF) samples were obtained during the first 3 years of treatment in 3 patients and were analyzed for biochemical markers of disease burden. Glucocerebroside and psychosine levels were not elevated in these specimens, whereas chitotriosidase and quinolinic acid were elevated in 2 patients. Progressive decrease in the CSF levels of these latter macrophage markers during 3 years of treatment implies a decreased number of Gaucher cells in the cerebral perivascular space. Similar changes were not observed in the patient who had a poor neurological outcome. In conclusion, ERT reverses systemic manifestations of type 3 Gaucher's disease and appears to reduce the burden of Gaucher cells in the brain–CSF compartment in some patients.