bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and machado‐joseph disease
Authors: Lopes‐Cendes Iscia , Maciel Patrícia , Kish Stephen , Gaspar Claudia , Silveira Isabel , Robitaille Yves , Clark H. Brent , Koeppen Arnulf H. , Nance Martha , Schut Lawrence , Coutinho Paula , Sequeiros Jorge , Rouleau Guy A. 
Published: January 2005

AbstractSpinocerebellar ataxia type 1 and Machado‐Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicims, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado‐Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocereballar ataxia type 1 and Machado‐Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra
Authors: Furlan Mauro , Marchal Gilles , Derlon Jean‐Michel , Baron Jean‐Claude , Viader Fausto 
Published: January 2005

AbstractWe prospectively tested the hypothesis that early recovery after ischemic stroke depends on the ultimate survival of functionally impaired, critically ischemic (i.e., “penumbral”) tissue. From a series of 26 consecutive patients studied with positron emission tomography within 18 hours of first‐ever stroke in the middle cerebral artery territory, all 11 survivors to the 2‐month end point who exhibited increased oxygen extraction fraction were declared eligible. The positron emission tomographic images were compared to ultimate infarction defined by computed tomography performed during the chronic stage. The penumbra (operationally defined by increased oxygen extraction fraction and divided outcome despite uniformly reduced cerebral blood flow) was individually detected in 10 of the 11 patients; cerebral blood flow ranged from 7 to 17 ml/100 gm·min, consistent with that found in monkey studies. The volume of the penumbra that escaped infarction was highly correlated with neurological recovery (p<0.04 to p<0.0001, depending on the scale used). This longitudinal study is the first to characterize the penumbra in humans and to document one mechanism strongly influencing recovery; the surviving penumbra may offer opportunities for secondary perifocal neuronal reorganization. Therapeutic measures to prevent infarction of the penumbra (up to 16 hours in this series) may have reduced residual neurological impairment. Mapping the extent of the penumbra, according to prospective criteria, may allow one to predict each patient's potential for recovery, and to select the most appropriate candidates for therapeutic trials.
Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy
Authors: Parano Enrico , Pavone Lorenzo , Falsaperla Raffaele , Trifiletti Rosario , Wang Ching 
Published: January 2005

AbstractWe report on a family with childhood‐onset spinal muscular atrophy with intrafamilial phenotypic variation. Typical of a large majority of such patients, both the child with spinal muscular atrophy type I and the child with type II were missing both copies of the survival motor neuron telomeric gene (SMNT). The more severely affected child, however, showed genotypic evidence consistent with the de novo loss of DNA sequence in addition to that inherited by both affected children. These data suggest that the intrafamilial phenotypic variation in this family results from a new mutation event in the more severely affected child. Examples of intrafamilial phenotypic variability are quite rare, but some reports exist in the spinal muscular atrophy literature. We present evidence that one explanation for this phenomenon is the occurrence of de novo deletion events at the highly unstable disease locus.
Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype
Authors: Korenke G. Christoph , Wilichowski Ekkehard , Hunneman Donald H. , Hanefeld Folker , Fuchs Sigrid , Krasemann Ernst , Doerr Helmuth G. 
Published: January 2005

AbstractWe report on monozygotic twins with different clinical phenotypes of X‐linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.
A point mutation associated with a severe phenotype of neurofibromatosis 2
Authors: MaCcollin M. , Davis Kevin , Braverman N. , Viskochil D. , Ruttledge M. , Ojemann R. , Gusella J. , Parry D. M. 
Published: January 2005

AbstractNeurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.
Inclusion body myositis: Clinical and pathological boundaries
Authors: Amato Anthony A. , Gronseth Gary S. , Jackson Carlayne E. , Wolfe Gil I. , Katz Jon S. , Bryan Wilson W. , Barohn Richard J. 
Published: January 2005

AbstractInclusion body myositis, polymyositis, and dermatomyositis are three distinct categories of inflammatory myopathy. Some authorities commented on the selective early weakness of the volar forearm muscles, quadriceps, and ankle dorsiflexors in inclusion body myositis. The most important feature distinguishing inclusion body myositis from the other two inflammatory myopathies is the lack of responsiveness to immunosuppressive treatment. Although most patients with inclusion body myosities have characteristic muscle biopsy findings, some cannot be distinguished histologically early from polymyositis. Presdicting responsiveness to mmunosuppressive medications, independent of muscle histology, would be valuable to clinicians. We retrospectively reviewed the pattern of weakness and other clinical features of 46 patients newly diagnosed with either inclusion body myositis, polymyositis, or dermatomyosities. Asymmetrical muscle weakness with prominent wrist flexor, finger flexor, and knee extensor involvement was specific for inclusion body myositis and unresponsive polymyositis. Male sex, lower creatine kinase levels, slower rate of progression, and peripheral neuropathy were also more common in inclusion body myositis and unresponsive polymyositis than in responsive polymyositis and dermatomyositis patients. Repeat muscle biopsy in 2 patients in teh unresponsive polymyositis group demonstrated histological features of inclusion body myositis. We suspect that patients with clinical features of inclusion body myositis but lacking histological confirmation may nonetheless have inclusion body myositis. Our study supports the recently proposed criteria for defintie and possible inclusion body myositis.
Origin and functional consequences of the complex I defect in Parkinson's disease
Authors: Swerdlow Russell H. , Parks Janice K. , Miller Scott W. , Davis Robert E. , Tuttle Jeremy B. , Trimmer Patricia A. , Sheehan Jason P. , Bennett James P. , Parker W. Davis 
Published: January 2005

AbstractThe mitochondrial electron transport enzyme NADH: ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1‐methyl‐4‐phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1‐methyl‐4‐phenyl pyridinium‐induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.
Apolipoprotein E and α1‐antichymotrypsin polymorphism in Alzheimer's disease
Authors: Nacmias Benedetta , Tedde Andrea , Latorraca Stefania , Piacentini Silvia , Bracco Laura , Amaducci Luigi , Sorbi Sandro , Guarnieri Bianca Maria , Petruzzi Concetta , Ortenzi Luigi 
Published: January 2005

AbstractA recent observation has shown that a common polymorphism in the α1‐antichymotrypsin (ACT) gene modifies the apolipoprotein E (ApoE) ε4‐associated Alzheimer's disease (AD) risk identifing the combination of the ACT/AA and ApoE ε4/ε4 genotypes as a potential susceptibility marker for AD. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE ε4/ε4 genotypes. The frequency of ApoE ε4/ε4 homozygosity in the AD sample resulted highest for the ACT/TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE ε4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.
Exclusion of the DYT1 locus in familial torticollis
Authors: Bressman S. B. , Greene P. E. , Raymond D. , Ford B. , de Leon D. , Fahn S. , Nygaard T. G. , Warner T. T. , Almasy L. , Uitti R. J. , Heiman G. A. , Kramer P. L. , Risch N. J. , Maraganore D. M. , Harding A. E. 
Published: January 2005

AbstractClinical‐genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb‐onset disease. The genetic basis of adult‐onset ITD is less well studied. In most multiplex adult‐onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non‐Jewish families with adult‐onset ITD limited to the cervical and brachial muscles and excluded the DYT1‐containing region. This study further restricts the role of DYT1 to childhood limb‐onset ITD and suggests that other genes are responsible for focal adult‐onset ITD.
Episodic ataxia and myokymia syndrome: A new mutation of potassium channel gene Kv1.1
Authors: Çomu Sinan , Narayanan Vinodh , Giuliani Michael 
Published: January 2005

AbstractEpisodic ataxia and myokymia syndrome is an autosomal dominant disorder characterized by persistent myokymia and attacks of unsteadiness, slurred speech, and tremulousness. This disease has been associated with point mutations in the potassium channel gene Kv1.1 (KCNA1), located at chromosome 12p13. Here, we describe a novel mutation within this gene in a newly diagnosed family.
Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures
Authors: McDonald John W. , Goldberg Mark P. , Gwag Byoung J. , Chi Shu‐Ing , Choi Dennis W. 
Published: January 2005

AbstractCyclosporine is used clinically as an immunosuppressant, but carries a risk of central nervous system toxicity due to undefined mechanisms. We examined the abiility of cyclosporine expsure to kill cultured mouse cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 μM cyclosporine for 24 to 48 hours developed concentration‐dependent neuronal death, with most neurons destroyed by 20 μM cyclosporine. This Neuronal death was characterized by cell body shrinkage and bleebbing, chromatin condenstation, and internucleosomal DNA fragmentation, consistent with apoptosis. Neuronal death was reduced by addition of cycloheximide, brain‐derived neurotrophic factor, or insulin‐like growth factor I but not N‐methyl‐D‐aspartate‐ or AMPA‐type glutamate receptor antagonists. Oligodendrocytes were more sensitive to cyclosporine‐induced damage than were neurons, but astrocytes were relatively resistant. Oligodendrocyte death was accompanied by positive TUNEL (terminal deoxynucleotidyl transferase‐mediated deoxyuridinetriphosphate‐biotin nick end‐labeling) staining and was attenuatd by application of ciliary neurotrophic factor or insulin‐like growth factor I but not glutamate receptro antagonists. Present observations raise the possibility that the central nervous system toxicity syndrome associated with cyclosporine may be caused by the drug‐induced death of oligodendrocytes and neurons.
Onset of dementia is associated with apolipoprotein E ε4 in Down's syndrome
Authors: Schupf Nicole , Lee Joseph H. , Kapell Deborah , Zigman Warren , Canto Basilisa , Tycko Benjamin , Mayeux Richard 
Published: January 2005

AbstractWe examined the influence of apolipoprotein E (apoE) genotype on risk of dementia in 82 adults with Down's syndrome (DS). Compared with those with an apoE 3/3 genotype, the group of adults with DS with apoE 2/4, 3/4, and 4/4 genotypes were 5 times more likely to become demented (RR = 4.7; 95% CI = 1.2, 17.9). We hypothesize that the increased risk of dementia may be mediated by exacerbation of β‐amyloid deposition.
Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging
Authors: Frey Kirk A. , Koeppe Robert A. , Kilbourn Michael R. , Vander Borght Thierry M. , Albin Roger L. , Gilman Sid , Kuhl David E. 
Published: January 2005

AbstractWe present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug‐or lesion‐compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood‐brain [11C]DTBZ transport (K1,) and VMAT2 binding site density (tissue‐to‐plasma DTBZ distribution volume, DV)from the cerebral and plasma DTBZ time courses her intravenous tracer injection. In controls, we found reductions of putamen DTBZ DV with advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (−61%) and in the caudate nucleus (−43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.
Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atrophy demonstrated with positron emission tomography
Authors: Gilman Sid , Junck Larry , Lohman Mary , Martorello Susan , Frey Kirk A. , Koeppe Robert A. , Vander Borght Thierry M. , Lee Lihsueh C. , Jewett Douglas M. , Kilbourn Michael R. , Little Roderick 
Published: January 2005

AbstractWe used [11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (VMAT2), with positron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.11).Mean blood‐to‐brain [11C]dihydrotetrabenazine transport (K1) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K1 was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal WT2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease.
Unusual clinical presentations of cortical‐basal ganglionic degeneration
Authors: Bergeron C. , Pollanen M. S. , Weyer L. , Black S. E. , Lang A. E. 
Published: January 2005

AbstractCortical‐basal ganglionic degeneration classically presents predominantly as a motor disorder with a unique constellation of histological alterations characterized by the presence of neuronal loss and gliosis in a selective distribution, swollen achromasic neurons, and extensive deposition of abnormal tau in neurons and glia. We now report 3 patients with this distinctive pathology who presented with cognitive changes and only mild or delayed motor symptoms. In 2 patients with severe dementia, pathological changes were extensive in the anterior frontal lobe, amygdala, and hippocampus. In a third patient who had an isolated speech disturbance for 5 years before developing the more typical motor features of cortical‐basal ganglionic degeneration, the most severe changes were observed in the left motor cortex and adjacent Broca's area. It is therefore apparent that the histological changes of cortical‐basal ganglionic degeneration result in a variety of clinical presentations depending on the topography of the lesions. On this basis we conclude that cortical‐ basal ganglionic degeneration should be considered in the differential diagnosis of language disturbances and dementia, particularly when the latter is accompanied by frontal lobe symptomatology, early speech alterations, or parkinsonism.
Muscular dystrophy associated with β‐dystroglycan deficiency
Authors: Salih Mustafa A. M. , Sunada Yoshihide , Al‐Nasser M. , Ozo C. O. , Al‐Turaiki M. H. S. , Akbar Maksood , Campbell Kevin P. 
Published: January 2005

Abstractβ‐Dystroglycan, a 43‐kd transmembrane dystrophinassociated glycoprotein, plays an important role in linking dystrophin to the laminin‐binding α‐dystroglycan. α‐/β‐Dystroglycan is encoded by a single gene on chromosome 3p21 and ubiquitously expressed in muscle and nonmuscle tissues. No known human diseases have been mapped to this locus. Here, we describe the selective deficiency of β‐dystroglycan in a 4‐year‐old Saudi boy with muscular dystrophy. The patient had a borderline elevation of serum creatine kinase level and early‐onset proximal symmetrical muscle weakness and wasting without calf hypertrophy. The milder phenotype may suggest a secondary deficiency of β‐dystroglycan; however, the unique immunofluorescence labeling suggests that the patient may present a novel form of muscular dystrophy.
Wide range in age of onset for chromosome 1‐related familial Alzheimer's disease
Authors: Bird Thomas D. , Levy‐Lahad Ephrat , Poorkaj Parvoneh , Sharma Vikram , Nemens Ellen , Lahad Amnon , Lampe Thomas H. , Schellenberg Gerard D. 
Published: January 2005

AbstractMutations in three different genes on chromosomes 1, 14, and 21 cause autosomal dominant forms of familial Alzheimer's disease (FAD). Most result in an early‐onset phenotype. However, several kindreds of Volga German ancestry have the same chromosome 1 gene mutation and demonstrate a relatively older mean age of onset and include individuals with late age of onset. In these families, the mean age of onset is 54.9 ± 8.4 years (range, 40–75 years), mean age at death is 65.9 ± 10.2 years (range, 43–88 years), and mean disease duration is 11.3 ± 4.6 years (range, 5–23 years). This contrasts with a group of 7 families with chromosome 14 mutations in which the mean age of onset is 44.8 ± 4.8 years (range, 30–55 years), mean age at death is 52.6 ± 5.7 years (range, 39–65 years), and mean disease duration is 7.6 ± 3.2 years (range, 2–17 years). (All means are significantly different in the 2 groups of families, p < 0.005.) In the chromo‐some 1 families, 7 persons (16%) had an age of onset at or older than 65 years and 22 (54%) survived to age 65 or older versus none in the chromosome 14 families. An example of probable nonpenetrance of disease at age 89 was also found in a chromosome 1 kindred. It is concluded that, unlike the chromosome 14 gene, mutations in the chromosome 1 FAD gene may result in individuals with a late age of onset overlapping with the more common sporadic form of the disease occurring in the general population. In light of the great variability in age of onset in persons with identical mutations, study of the genetic and environmental factors contributing to delayed onset of disease in chromosomal 1 FAD kindreds will be an important area for further investigation. Apolipoprotein E genotype may be one such factor that plays a partial role in this variability.