bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of the age at onset of Parkinson's disease by apolipoprotein E genotypes
Authors: Zareparsi Sepideh , Kaye Jeffrey , Camicioli Richard , Grimslid Holly , Oken Barry , Litt Michael , Nutt John , Bird Thomas , Schellenberg Gerard , Payami Haydeh
Published: January 2005

Parkinson's disease (PD) patients often develop dementia, and Alzheimer's disease (AD) patients frequently develop parkinsonian signs. The apolipoprotein E σ4 allele is associated with increased risk and earlier onset of AD. We studied 137 unrelated white PD patients. Those with σ4 had the earliest onset (52.7 · 9.8 years), σ3/σ3 patients had an intermediate onset (56.1 · 11.1 years), and those with σ2 had the latest onset (59.1 · 13.4 years). The age at onset distribution for σ4/σ – was significantly earlier than for σ3/σ3 and σ2/σ3. These preliminary results suggest that apolipoprotein E genotypes modulate the age at onset of PD.
Apolipoprotein E—associated risk for Alzheimer's disease in the African‐American population is genotype dependent
Authors: Sahota Amrik , Yang Min , Gao Sujuan , Hui Siu L. , Baiyewu Olusegun , Gureje Oyewusi , Oluwole Steven , Ogunniyi Adesola , Hall Kathleen S. , Hendrie Hugh C.
Published: January 2005

As a part of our ongoing study on Alzheimer's disease (AD) in elderly African Americans, we obtained clinical assessment and apolipoprotein E (ApoE) genotype data on 288 individuals (including 60 with AD). The ApoE σ4 allele frequency was significantly increased in AD patients compared with controls. The age‐adjusted odds ratio (OR) for AD in σ4 homozygotes was 4.83 (95% confidence interval [CI], 1.71–13.64) compared with the σ3/σ3 genotype, but the OR for AD with the σ3/σ4 genotype did not reach significance (1.20; 95% CI, 0.58–2.45). These findings suggest that the association between ApoE σ4 and AD is weaker in African Americans than in whites.
New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency
Authors: Dionisi‐Vici C. , Ruitenbeek W. , Fariello G. , Bentlage H. , Wanders R. J. A. , Schägger H. , Bosman C. , Piantadosi C. , Sabetta G. , Bertini E.
Published: January 2005

Two siblings presented with a new phenotype consisting of fatal progressive macrocephaly and hypertrophic cardiomyopathy. Onset of symptoms started in both patients at the end of the first month of life with massive brain swelling causing macrocephaly and evolving to extensive brain destruction. Light microscopy of the lesions showed extensive small‐vessel proliferation and gliosis. A distinct deficiency of complex I of mitochondrial respiratory chain was established in cultured fibroblasts, skeletal muscle, and heart muscle. Specific lack of complex I protein was demonstrated by two‐dimensional gel electrophoresis.
Differential distribution of the normal and mutated forms of huntingtin in the human brain
Authors: Gourfinkel‐An Isabelle , Cancel Géraldine , Trottier Yvon , Devys Didier , Tora Laszlo , Lutz Yves , Imbert Georges , Saudou Frédéric , Stevanin Giovanni , Agid Yves , Brice Alexis , Mandel Jean‐Louis , Hirsch Etienne C.
Published: January 2005

Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.
Effects of apomorphine on globus pallidus neurons in parkinsonian patients
Authors: Hutchison W. D. , Levy R. , Dostrovsky J. O. , Lozano A. M. , Lang A. E.
Published: January 2005

Current hypotheses of basal ganglia dysfunction in Parkinson's disease (PD) propose that neuronal hypoactivity in the globus pallidus externus (GPe), and hyperactivity in the output nuclei and the external and internal portions of the globus pallidus internus (GPi, e and GPi, i, respectively), result in the cardinal symptoms of PD. To test this theory, the nonselective D1‐ and D2‐dopamine receptor agonist apomorphine (30–100 μg/kg SC) was administered to 14 levodoparesponsive PD patients who were off medication (“of” state) while recording neurons in GP. For 15 neurons that were continuously monitored, apomorphine was found to increase the firing rate of 3 neurons in GPe, and decrease the rate of 12 in GPi. The mean firing rates of many different neurons were determined before (n = 285) and at various intervals after (n = 184) the injection of the drug. The mean rates before apomorphine were as follows: GPe, 45 Hz (SD 15, n = 85); GPi, e, 67 Hz (SD 14, n = 125); and GPi, i, 85 Hz (SD 19, n = 75). At 25 to 35 minutes after APO, the rate of GPe neurons had increased to 72 Hz (SD 18, n = 7), the rate of GPi, e neurons had decreased to 39 Hz (SD 15, n = 15), and in GPi, i the rate decreased to 34 Hz (SD 22, n = 18). Eighty minutes after apomorphine administration, the mean firing rates returned to preadministration values. This study supports current models of basal ganglia dysfunction in PD and suggests that the thereapeutic effect of apomorphine results from a normalization of the imbalance of neuronal activity in the direct and indirect pathways.
Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis: Analysis of 155 cases and identification of novel insertion mutation
Authors: Jackson Mandy , Al‐Chalabi Ammar , Enayat Zinat E. , Chioza Barry , Leigh Peter N. , Morrison Karen E.
Published: January 2005

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the brain and spinal cord and leading to death within 5 years of symptom onset. The great majority of ALS cases are sporadic, with the familial form (FALS) representing fewer than 10% of all cases. Mutations in the copper/zinc superoxide dismutase 1 (SOD‐1) gene have previously been identified as the underlying cause of approximately 20% of FALS cases. As the familial and sporadic forms of the disease are clinically similar, we have sought to determine whether such mutations in SOD‐1 underlie any sporadic ALS cases. We have screened 155 sporadic cases by single‐strand conformation polymorphism and have identified 4 sporadic cases that possess point mutations in exon 4 of the SOD‐1 gene. Two of these mutations are identical to those previously reported in FALS cases. One mutation is novel, resulting in a frameshift at Val118 due to the replacement of G (first base in the last codon of exon 4) by AAAAC. This mutation results in a truncated SOD‐1 protein due to the introduction of a stop codon three residues into exon 5.
A novel muscle sodium channel mutation causes painful congenital myotonia
Authors: Rosenfeld Jeffrey , Sloan‐Brown Karen , George Alfred L.
Published: January 2005

Mutations in the skeletal muscle voltage‐gated sodium channel α‐subunit gene (SCN4A) have been associated with a spectrum of inherited nondystrophic myotonias and periodic paralyses. Most disease‐associated SCN4A alleles occur in portions of the gene that encode the third and fourth repeat domains with the conspicuous absence of mutations in domain 1. Here we describe a family segregating an unusual autosomal dominant congenital myotonia associated with debilitating pain especially severe in the intercostal muscles. A novel SCN4A mutation causing the replacement of Val445 in the sixth transmembrane segment of domain 1 with methionine was discovered in all affected individuals and is the likely genetic basis for the syndrome. Myotonia was resistant to treatment; however, the most severely affected family member responded dramatically to the sodium channel blocking agent flecainide.
Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity
Authors: Ducros Anne , Joutel Anne , Cecillon Michaëlle , Tournier‐Lasserve Elisabeth , Vahedi Katayoun , Bousser Marie‐Germaine , Ferreira Antonio , Bernard Evelyne , Verier Albert , Echenne Bernard , De Munain Adolfo Lopez
Published: January 2005

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the α1 subunit of a P/Q‐type voltage‐dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Zmax: 3.33 at = 0.05) and D1S2705 (Zmax: 3.64 at = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21–q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1–linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.
Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes?
Authors: Schöls Ludger , Amoiridis Georgios , Büttner Thomas , Przuntek Horst , Epplen Jörg T. , Riess Olaf
Published: January 2005

Seventy‐seven families with autosomal dominant cerebellar ataxia were analyzed for the CAG repeat expansions causing spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22% of German ataxia families. Seven of 27 SCA6 patients had no family history of ataxia. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of one CAG unit on onset age was different for each SCA subtype. We compared clinical, electrophysiological, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome and patients often had onset after 55 years of age. SCAI was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. However, overlap between the four SCA subtypes was broad.
Neurobiology of Autism
Authors: Rapin Isabelle , Katzman Robert
Published: January 2005

Autism is a behaviorally defined, life‐long static developmental disorder of the brain that is poised for neurobiological investigation. It affects at least 1 or 2 in 1000 persons and has a broad range of severity. It has multiple causes, with genetics playing a major role. According to the DSM‐IV, defining features are impaired sociability, language and communication, and range of interests and activities. Mental deficiency is frequent but by no means universal. The cognitive profile is characterstic, occasionally with a superior but narrow talent. Perseveration, concreteness, affective blunting, and lack of insight into other persons' thinking may be conspicuous. The neurological basis of autism's many sensorimotor features, including stereotypies, is unknown. Attention and sleep are affected, and one third of individuals experience epilepsy by adulthood. Whether subclinical epilepsy plays a role in the developmental regression of the one third of the toddlers who lose their language skills and become autistic remains to be determined. Clinical neuroimaging and biochemical investigations are generally unremarkable. Fewer than 35 brains have been examined pathologically, none with modern techniques. The findings thus far suggest subtle prenatal neruonal maldevelopment in the cerebellum and certain limbic structures. Abnormalities in distributed networks involving serotonin and perhaps other neurotransmitters require further documentation.
Perfusion‐weighted imaging defects during spontaneous migrainous aura
Authors: Cutrer F. Michael , Sorensen A. Gregory , Weisskoff Robert M. , Østergaard Leif , Del Rio Margarita Sanchez , Lee E. John , Rosen Bruce R. , Moskowitz Michael A.
Published: January 2005

Perfusion‐and diffusion‐weighted magnetic resonance imaging was performed during spontaneous visual auras in four migraineurs. Alterations in relative cerebral blood flow (16–53% decrease), cerebral blood volume (6–33% decrease), and tissue mean transit time (10–54% increase) were observed in the gray matter of occipital cortex contralateral to the affected visual hemifield. No changes in the apparent diffusion coefficient were observed either while the patients were symptomatic or after resolution of the visual symptoms but before the onset of headache. Functional magnetic resonance imaging can be a useful noninvasive tool to study hemodynamic changes during spontaneous attacks of migraine with aura.
The medial temporal lobe in dementia with lewy bodies: A comparative study with Alzheimer's disease
Authors: Lippa C. F. , Johnson R. , Smith T. W.
Published: January 2005

The usefulness of determining medial temporal lobe (MTL) size in differentiating Alzheimer's disease (AD) from other dementia subtypes is unknown. We compared the cross‐sectional areas of the MTLs in histological sections from the brains of 18 patients with dementia with Lewy bodies (DLB) but lacking AD changes, 24 DLB patients with concurrent AD pathology, 20 pure AD cases, and 18 age‐matched control cases. Duration and severity of disease were comparable between groups. When data for cross‐sectional area were expressed as percentages of the average control area, DLB MTLs were significantly larger than either AD or DLB/AD MTLs at rostral levels (86 ± 16%, 54 ± 17%, and 66 ± 23% of control areas, respectively). At caudal levels, DLB MTLs were larger than AD MTLs (80 ± 20%, 59 ± 21%, and 77 ± 26% of control areas in DLB, AD, and DLB/AD, respectively). MTL cross‐sectional area often approaches normal in pure DLB, even when disease duration is prolonged and symptoms are end stage. In contrast, a greatly reduced MTL area mitigates against the diagnosis of DLB, unless there are concurrent AD changes.
Cytomegalovirus infection and schizencephaly: Case reports
Authors: Iannetti Paola , Nigro Giovanni , Spalice Alberto , Faiella Antonio , Boncinelli Edoardo
Published: January 2005

Two children with left open‐lip schizencephaly are reported. Cytomegalovirus (CMV) infection was demonstrated on the second day of life in Patient 1; in the other patient CMV infection was observed at the age of 4 years. Magnetic resonance imaging revealed polymicrogyric cortex lining the clefts. In Patient 2 polymicrogyria was also present in the corresponding area contralateral to the schizencephaly. Computed tomography revealed the presence of subependymal periventricular calcifications. Genetic analysis did not demonstrate the presence of EMX2 homeobox gene. The possible role of CMV infection in the complex multifactorial pathogenesis of schizencephaly is therefore suggested.
Opposite motor effects of pallidal stimulation in Parkinson's disease
Authors: Krack P. , Pollak P. , Limousin P. , Hoffmann D. , Benazzouz A. , Le Bas J. F. , Koudsie A. , Benabid A. L.
Published: January 2005

We studied the effects—on parkinsonian signs, on levodopa‐induced dyskinesias, and on levodopa response—of acute experimental high‐frequency stimulation of the internal pallidum (GPi) during off‐drug and on‐drug phases. Thirteen quadripolar electrodes were evaluated in 8 patients with Parkinson's disease (PD). Stimulation of the most ventral contacts, lying at the ventral margin of or just below the GPi, led to pronounced improvement in rigidity and a complete arrest of levodopa‐induced dyskinesias. The antiakinetic effect of levodopa was also blocked and the patients became severely akinetic. Stimulation of the most dorsal contacts, lying at the dorsal border of the GPi or inside the external pallidum, usually led to the moderate improvement of off‐drug akinesia and could also induce dyskinesias in some patients. When using an intermediate contact for chronic stimulation, a good compromise between these opposite effects was usually obtained, mimicking the effect of pallidotomy. We conclude that there are at least two different functional zones within the globus pallidus, at the basis of a different pathophysiology of the cardinal symptoms of PD. The opposite effects may explain the variable results of pallidal surgery reported in the literature and may also largely explain the paradox of PD surgery. A possible anatomical basis for these differential functional effects could be a functional somatotopy within the GPi, with the segregation of the pallidofugal fibers from the outer portion of the GPi, on one hand, forming the ventral ansa lenticularis and from the inner portion of the GPi, on the other hand, forming the dorsal lenticular fasciculus.
Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle
Authors: Brierley Elizabeth J. , Johnson Margaret A. , Lightowlers Robert N. , James Oliver F. W. , Turnbull Douglass M.
Published: January 2005

It has been proposed that one mechanism for nerve and muscle dysfunction with age involves the mitochondria. Mitochondria contain the only DNA outside the nucleus in mammalian cells. Mitochondrial DNA (mtDNA) has a high mutation rate, and low levels of pathogenic mutations have been found in tissues from elderly subjects. However, the role of these mutations in the aging process is uncertain unless a mechanism can be identified that would lead to a biochemical defect. In muscle tissue from normal elderly subjects we show that there are muscle fibers with very low activity of cytochrome c oxidase, suggestive of a mtDNA defect. In these cytochrome c oxidase‐deficient fibers we have found very high levels of mutant mtDNA. In addition, different mtDNA mutations are present in different fibers, which explains why there is a low overall incidence of an individual mutation in tissues from elderly subjects. These studies show a direct age‐related correlation between a biochemical and genetic defect in normal human tissues and that mtDNA abnormalities are involved in the aging process in human muscle.
Quantitative magnetic resonance imaging of brain development in premature and mature newborns
Authors: Hüppi Petra S. , Warfield Simon , Kikinis Ron , Barnes Patrick D. , Zientara Gary P. , Jolesz Ferenc A. , Tsuji Miles K. , Volpe Joseph J.
Published: January 2005

Definition in the living premature infant of the anatomical and temporal characteristics of development of critical brain structures is crucial for insight into the time of greatest vulnerability of such brain structures. We used three‐dimensional magnetic resonance imaging (3D MRI) and image‐processing algorithms to quantitate total brain volume and total volumes of cerebral gray matter (GM), unmyelinated white matter (WM), myelinated WM, and cerebrospinal fluid (CSF) in 78 premature and mature newborns (postconceptional age, 29–41 weeks). Total brain tissue volume was shown to increase linearly at a rate of 22 ml/wk. Total GM showed a linear increase in relative intracranial volume of approxi mately 1.4% or 15 ml in absolute volume per week. The pronounced increase in total GM reflected primarily a fourfold increase in cortical GM. Unmyelinated WM was found to be the most prominent brain tissue class in the preterm infant younger than 36 weeks of postconceptional age. Although minimal myelinated WM was present in the preterm infant at 29 weeks, between 35 and 41 weeks an abrupt fivefold increase in absolute volume of myelinated WM was documented. Extracerebral and intraventricular CSF was readily quantitated by this technique and found to change minimally. The application of 3D MRI and tissue segmentation to the study of human infant brain from 29 to 41 weeks of postconceptional age has provided new insights into cerebral cortical development and myelination and has for the first time provided means of quantitative assessment in vivo of early human brain development.
Effects of the nicotinic acetylcholine receptor agonist SIB‐1508Y on object retrieval performance in MPTP‐Treated monkeys: Comparison with levodopa treatment
Authors: Schneider J. S. , Van Velson M. , Menzaghi F. , Lloyd G. K.
Published: January 2005

This study assessed the relative potencies of levodopa/benserazide and the nicotinic acetylcholine receptor agonist SIB‐1508Y on reversal of cognitive and motor deficits in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–treated monkeys performing an object retrieval task. Monkeys previously taught to perform this task developed significant cognitive deficits after chronic low‐dose MPTP exposure. These monkeys then received additional MPTP treatment to superimpose a parkinsonian movement disorder on their preexisting cognitive deficits. Levodopa/benserazide treatment significantly improved motor aspects of object retrieval performance but did not significantly improve cognition. SIB‐1508Y (1 mg/kg) alone did not result in a statistically significant improvement in cognition or motor function in symptomatic MPTP‐lesioned animals with deficits in both of these areas. However, the combination of SIB‐1508Y and levodopa/benserazide caused significant improvements in both cognition and motor aspects of task performance, and did so at one third to one sixth of the levodopa dose necessary to improve only motor function. These results suggest the potential usefulness of SIB‐1508Y and levodopa as adjunctive therapies to improve at least some of the cognitive and motor deficits associated with Parkinson's disease.
Complex I Defect in muscle from patients with Huntington's disease
Authors: Arenas Joaquín , Campos Yolanda , Ribacoba René , Martín Miguel A. , Rubio Juan C. , Ablanedo Pilar , Cabello Ana
Published: January 2005

We found a variable defect of complex I of the mitochondrial respiratory chain, ranging in severity from 25% to 63% of control values, in muscle of patients with Huntington's disease (HD). The most severe defect was observed in the patient with the greatest expansion of CAG triplets. Muscle morphology showed myopathic changes such as moth‐eaten fibers, angulated fibers, increased subsarcolemmal oxidative activities, or an increased number of enlarged mitochondria with abnormal cristae. Multiple mitochondrial DNA deletions were found by polymerase chain reaction (PCR) analysis in muscle of the patient with the most severe defect of complex I. Our data further support the involvement of energetic defects and oxidative damage in muscle of patients with HD.
Cortical reflex myoclonus in rett syndrome
Authors: Guerrini Renzo , Bonanni Paolo , Parmeggiani Locio , Santucci Margherita , Parmeggiani Antonia , Sartucci Ferdinando
Published: January 2005

Rett syndrome (RS) is one of the most frequent causes of mental retardation in females. As there are no known biochemical, genetic, or morphological markers, diagnosis is based on clinical phenotype including severe dementia, autism, truncal ataxia/apraxia, loss of purposeful hand movements, breathing abnormalities, stereotypies, seizures, and extrapyramidal signs. Myoclonus, although reported in some series, has never been characterized. We studied 10 RS patients, age 3 to 20 years, and observed myoclonus in 9. Severity of myoclonus did not correlate with that of the other symptoms or with age. Multifocal, arrhythmic, and asynchronous jerks mainly involved distal limbs. Electromyographic bursts lasted 48 ± 12 msec. Burst‐locked electroencephalographic averaging generated a contralateral centroparietal premyclonus transient preceding the burst by 34 ± 7.2 msec. Motor evoked potentials showed normal latencies, indicating integrity of the corticospinal pathway. Somatosensory evoked potentials were enlarged. The C‐reflex was hyperexcitable and markedly prolonged (62 ± 4.3 msec), mainly due to increase in cortical relay time (28.4 ± 4.5 msec). We conclude that RS patients show a distinctive pattern of cortical reflex myoclonus with prolonged intracortical delay of the long‐loop reflex.
Quinidine sulfate therapy for the slow‐channel congenital myasthenic syndrome
Authors: Harper C. Michel , Engel Andrew G.
Published: January 2005

The slow‐channel congenital myasthenic syndrome (SCCMS) is caused by gain of function mutations in subunits of the end‐plate acetylcholine receptor (AChR). The mutations prolong the opening episodes of the AChR channel, leading to a depolarization block and an end‐plate myopathy. Because levels of quinidine sulfate attainable in clinical practice shorten the opening episodes of genetically engineered mutant SCCMS receptors in vitro, we tested the notion that the drug can be of benefit in SCCMS. We treated 6 SCCMS patients with quinidine sulfate in an open‐label trial, using objective clinical measures of muscle strength and repetitive stimulation studies as end points. One patient became allergic to quinidine after 7 days. The remaining patients tolerated the drug well and after 30 days of continuous therapy showed statistically significant improvement in muscle strength and in decrement of the compound muscle action potential elicited by repid rates of stimulation.
Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: Implications for ischemia and Huntington's disease
Authors: Calabresi Paolo , Centonze Diego , Pisani Antonio , Sancesario Giuseppe , Gubellini Paolo , Marfia Girolama A. , Bernardi Giorgio
Published: January 2005

Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether a different sensitivity to ionotropic glutamatergic agonists might account for this differential vulnerability. Intracellular recordings were obtained from morphologically identified striatal spiny neurons and LA cholinergic interneurons by using a rat brain slice preparation. The two striatal neuronal subtypes had strikingly different intrinsic membrane properties. Both subtypes responded to cortical stimulation with excitatory postsynaptic potentials: these potentials, however, had a different time course and pharmacology in the two classes of cells. Interestingly, membrane depolarizations and inward currents produced by exogenous glutamate receptor agonists (AMPA, kainate, and NMDA) were remarkably larger in spiny neurons than in LA interneurons. Moreover, concentrations of agonists producing reversible membrane changes in LA interneurons caused irreversible depolarizations in spiny cells. Our data suggest that the different physiological responses induced by the activation of ionotropic glutamate receptors may account for the cell type‐specific vulnerability of striatal neurons in ischemia and HD.
Neuropathology of preclinical and clinical lateonset Alzheimer's disease
Authors: Troncoso Juan C. , Cataldo Anne M. , Nixon Rallph A. , Barnett Jody L. , Lee Michael K. , Checler Frederic , Fowler David R. , Smialek John E. , Crain Barbara , Martin Lee J. , Kawas Claudia H.
Published: January 2005

We report on the neuropathological examinations of a 74‐year‐old woman with Alzheimer's disease (AD) and of her 47‐year‐old nondementd daughter. The brain of the mother showed fully developed pathological changes of AD. By contrast, the brain of the daughter revealed only perineuronal deposition of diffuse amyloid in cerebral cortex and striking abnormalities of the endosomallysosomal system, without neurofibrillary, glial, or microglial changes. These observations suggest that amyloid deposition and endosomal‐lysosomal changes are early events in late‐onset AD and that they may precede the onset of dementia of several decades.
Amyloid myopathy: An underdiagnosed entity
Authors: Spuler Simone , Emslie‐Smith Alison , Engel Andrew G.
Published: January 2005

Amyloidosis can involve multiple organs, including kidney, heart, peripheral nerve, skin, joints, and skeletal muscle, but rarely presents as a myopathy. We studied 13 adults with muscle weakness for between 3 months and 4 years in whom the diagnosis of systemic amyloidosis was unsuspected before or until just before the time of the muscle biopsy. All muscle specimens demonstrated congophilic deposits around blood vessels and muscle fibers, some necrotic and regenerating fibers, and signs of mild denervation. Immunostains in 10 patients revealed immunoglobulin amyloidosis in 7 and gelsolin amyloidosis in 1. Apolipoprotein E colocalized with the congophilic deposits in all 10, and a C‐terminal epitope of the β‐amyloid precursor protein was detected in 6. The frequency of the diagnosis of amyloid myopathy increased 10‐fold when we adopted the fluorescent Congo red stain as a routine procedure in assessing muscle biopsy specimens.
Temporal ictal electroencephalographic frequency correlates with hippocampal atrophy and sclerosis
Authors: Vossler David G. , Kraemer Dinna L. Abson , Knowlton Robert C. , Kjos Bent O. , Rostad Steve W. , Wyler Allen R. , Haltiner Alan M. , Hasegawa Hisanori , Wilkus Robert J.
Published: January 2005

We studied 328 complex partial seizures (CPS) in 63 consecutive patients with temporal lobe epilepsy who underwent scalp electroencephalography/video monitoring, magnetic resonance imaging (MRI), and surgery. The initial ictal discharge (IID), defined as the first sustained electrical seizure pattern localized to the surgical site, was determined. If the IID was rhythmic waves, the median frequency was measured. To determine if IID frequency correlates with hippocampal atrophy (HA) or sclerosis (HS), hippocampal volume ratios (HVRs) were measured (n = 52) or assessed visually (n = 11) on MRI, and mesial temporal histopathology specimens (n = 22) were graded for HS. Sixteen patients (25%) had no or mild HA (HVR = 0.78‐1.02), and 47 patients (75%) had moderate‐to‐marked unilateral (HVR = 0.33−0.76), or bilateral, HA. Theta frequency IIDs were significantly more commonly associated with moderate‐to‐marked HA than were delta IIDs. Theta frequency IIDs occurred in 19% of patients with mild or no HA, and 79% of patients with moderate‐to‐marked HA; delta IIDs occurred in 63% of patients with little to no HA, and 13% of those with moderate‐to‐marked HA. In addition, the median IId frequency inversely correlated with HVR and directly correlated with HS severity. In conclusion, faster frequency rhythmic IIDs during temporal lobe CPS correlate with greater degrees of ipsilateral HA on MRI, and higher grades of HS.
Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism
Authors: Kates Wendy R. , Mostofsky Stewart H. , Zimmerman Andrew W. , Mazzocco Michele M. M. , Landa Rebecca , Warsofsky Ilana S. , Kaufmann Walter E. , Reiss Allan L.
Published: January 2005

In this study, we investigated the neuroanatomical similarities and differences between a pair of monozygotic, 7.5‐year‐old twin boys discordant for strictly defined autism, to identify neuroanatomical pathways that are impaired in individuals with autism. Although the unaffected twin did not fulfill the traditional diagnostic criteria for autism, he displayed constrictions in social interaction and play that were consistent with the broader phenotype for autism that has been described in nonautistic co‐twins. Magnetic resonance imaging scans were obtained for each brother and compared with the scans of 5 age‐ and sex‐matched unaffected peers. Quantitative analysis of brain anatomy revealed that the affected twin had markedly smaller caudate, amygdaloid, and hippocampal volumes, and smaller cerebellar vermis lobules VI and VII, in comparison with his brother. Both twins evidenced disproportionately reduced volumes of the superior temporal gyrus and the frontal lobe relative to the comparison sample. The results suggest the dysfunction of two separate but overlapping neuroanatomical pathways, ie, one subcortical network differentiating the twins from each other that may underlie the traditional neurobehavioral phenotype for strictly defined autism, and a second cortical network differentiating the twins from the comparison sample that may lead to the broader phenotype for autism.
Longitudinal study of cerebrospinal fluid levels of tau, Aβ1–40, and Aβ1–42(43) in Alzheimer's disease: A study in Japan
Authors: Kanai M. , Matsubara E. , Isoe K. , Urakami K. , Nakashima K. , Arai H. , Sasaki H. , Abe K. , Iwatsubo T. , Kosaka T. , Watanabe M. , Tomidokoro Y. , Shizuka M. , Mizushima K. , Nakamura T. , Igeta Y. , Ikeda Y. , Amari M. , Kawarabayashi T. , Ishiguro K. , Harigaya Y. , Wakabayashi K. , Okamoto K. , Hirai S. , Shoji M.
Published: January 2005

To clarify the alterations of tau, amyloid β protein (Aβ) 1–40 and Aβ1–42(43) in the cerebrospinal fluid (CSF) that accompany normal aging and the progression of Alzheimer's disease (AD), CSF samples of 93 AD patients, 32 longitudinal subjects among these 93 AD patients, 33 patients with non‐AD dementia, 56 with other neurological diseases, and 54 normal control subjects from three independent institutes were analyzed by sensitive enzyme‐linked immunosorbent assays. Although the tau levels increased with aging, a significant elevation of tau and a correlation between the tau levels and the clinical progression were observed in the AD patients. A significant decrease of the Aβ1–42(43) levels and a significant increase of the ratio of Aβ1–40 to Aβ1–42(43) were observed in the AD patients. The longitudinal AD study showed continuous low Aβ1–42(43) levels and an increase of the ratio of Aβ1–40 to Aβ1–42(43) before the onset of AD. These findings suggest that CSF tau may increase with the clinical progression of dementia and that the alteration of the CSF level of Aβ1–42(43) and the ratio of Aβ1–40 to Aβ1–42(43) may start at early stages in AD. The assays of CSF tau, Aβ1–40, and Aβ1–42(43) provided efficient diagnostic sensitivity (71%) and specificity (83%) by using the production of tau levels and the ratio of Aβ1–40 to Aβ1–42(43), and an improvement in sensitivity (to 91%) was obtained in the longitudinal evaluation.
Small‐fiber sensory neuropathies: Clinical course and neuropathology of idiopathic cases
Authors: Holland Neil R. , Crawford Thomas O. , Hauer Peter , Cornblath David R. , Griffin John W. , McArthur Justin C.
Published: January 2005

We describe the clinical features, natural history, and neuropathology of 32 patients presenting with “burning feet”, for whom no specific cause was identified. All had neuropathic pain in the feet and morphological abnormalities of cutaneous innervation in skin obtained using punch biopsy. Most (29) had an abnormal sensory examination. All had normal strength, proprioception, tendon reflexes, and nerve conductions. Two clinical patterns were apparent, based on natural history and spatial distribution of cutaneous denervation. Most (28) patients presented with neuropathic pain initially restricted to the feet and toes but extending more proximally to involve the legs and hands with time. Intraepidermal nerve fiber (IENF) density was most severely reduced distally, with more normal IENF densities in skin from proximal sites. In contrast, a minority (4) presented with the abrupt onset of generalized cutaneous burning pain and hyperesthesia. In these patients, IENF densities were reduced in skin from both proximal and distal sites. Absolute IENF densities in calf skin were reduced below the lower limit of normal (5th percentile) in 26 (81%). Of the 6 who underwent sural nerve biopsy, 4 had selective loss of small myelinated and/or unmyelinated axons and 2 had normal histology and fiber densities despite reduced IENF densities in skin biopsy specimens. Punch skin biopsy from proximal and distal sites is a useful means of assessing these distinctive patients and may provide further insight into pathophysiology.
Frontotemporal dementia: Neuropil spheroids and presynaptic terminal degeneration
Authors: Zhou L. , Miller B. L. , McDaniel C. H. , Kelly L. , Kim O. J. , Miller C. A.
Published: January 2005

We compared the neuropathological changes of 6 patients with clinically diagnosed lobar dementia. In the 4 patients with histopathology consistent with frontotemporal dementia (FTD), moderate neuronal loss contrasted with marked cortical and subcortical gliosis. We found silver‐positive, carbohydrate‐rich, spheroidal enlargements of presynaptic terminals within the neuropil of specific central nervous system regions. The spheroids were immunopositive for the cytoskeletal proteins tau, the high molecular weight neurofilament subunit (NF‐H), and β‐tubulin. No abnormal tau phosphorylation and only rare ubiquitin immunoreactivity were detected in these structures. Carbohydrate modifications, including advanced glycation end products within the spheroid matrix, were confirmed by lectin binding, and by anti‐pentosidine immunoreactivity, and indicator of oxidative stress. Ultrastructurally, the spheroids consisted of unmyelinated, membrance‐enclosed structures filled with randomly arrayed pairs of filaments, approximately 8 to 10 nm in diameter, that were sparsely labeled with antibodies to unmodified tau (T14) and NF‐H. Despite clinical overlap, the central nervous systems of our FTD patients are distinguishable from those of other patients with other lobar dementias, including Pick's disease and corticobasal degeneration, by the absence of abnormally phosphorylated neuronal or glial tau inclusions. The neuropil spheroids are dystrophic changes of certain selectively vulnerable presynaptic terminals, suggesting a retrograde degenerative process in FTD.
Dopamine D2‐type agonists protect mesencephalic neurons from glutamate neurotoxicity: Mechanisms of neuroprotective treatment against oxidative stress
Authors: Sawada Hideyuki , Ibi Masakazu , Kihara Takeshi , Urushitani Makoto , Akaike Akinori , Kimura Jun , Shimohama Shun
Published: January 2005

Oxidative stress, a process in which neurotoxic oxygen free radicals cause dopaminergic neuronal degeneration, has been implicated in the degenerative process in Parkinson's disease. Glutamate‐induced neurotoxicity is a model of oxidative stress. We demonstrated that preincubation with D2‐type dopamine agonists bromocriptine and quinpirole provides neuroprotection against glutamate‐induced neurotoxicity in cultured rat mesencephalic neurons. Simultaneous administration of D2 agonists, however, did not provide neuroprotection. The protective effects were dependent on the duration of preincubation and were blocked by a D2 antagonist and a protein synthesis inhibitor. Furthermore, preincubation with D2 agonists provided neuroprotection against toxicity induced by calcium overload and exposure to superoxide anions. Confocal microscopic analysis, using 2,7‐dichlorofluorescin diacetate, revealed that bromocriptine preincubation suppressed the action of radicals on neurons. These findings indicate that dopamine D2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D2‐type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals.
Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease
Authors: Gu M. , Cooper J. M. , Taanman J. W. , Schapira A. H. V.
Published: January 2005

Several groups have identified mitochondrial complex I deficiency in Parkinson's disease (PD) substantia nigra and in platelets. A search for any mitochondrial DNA (mtDNA) mutation underlying this defect has not yet produced any consistent result. We have made use of a mtDNA‐less (μo) cell line to determine if the complex I deficiency follows the genomic transplantation of platelet mtDNA. From a preselected group of PD patients with low platelet complex I activity, 7 patients were used for detailed study. All 7 patients were used for mixed cybrid analysis and demonstrated a selective 25% deficiency of complex I activity. Individual clonal analysis of A549 μO/PD platelet fusion cybrids from 1 of the patients expressed combined complex I and IV deficiencies with 25% and 20% decreased activities in the PD clones, respectively. Histocytochemical, immunocytochemical, and cellular functional imaging studies of these clones showed the cells within the clones were heterogeneous with respect to cytochrome c oxidase (COX) function, COX I content, and mitochondrial respiratory chain activity. These results are in agreement with a previous study and support the proposition that an mtDNA abnormality may underlie the mitochondrial defect in at least a proportion of PD patients. This μo technology may serve as a means to identify the subgroup of PD patients in whom an mtDNA defect may contribute to development of the disease.
Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
Authors: Li Mei , Miwa Shigeru , Kobayashi Yasushi , Merry Diane E. , Yamamoto Masahiko , Tanaka Fumiaki , Doyu Manabu , Hashizum Yoshio , Fischbeck Kenneth H. , Sobue Gen
Published: January 2005

Spinal and bulbar muscular atrophy (SBMA) is an X‐linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR‐immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR‐bearing nuclear inclusions are present in SBMA.
Increased long‐term potentiation in the surround of experimentally induced focal cortical infarction
Authors: Hagemann Georg , Redecker Christoph , Neumann‐Haefelin Tobias , Freund Hans‐Joachim , Witte Otto W.
Published: January 2005

Functional recovery after stroke is partly due to cortical reorganization on a structural as well as a functional level. Recent investigations have shown that the excitability of brain areas surrounding cortical ischemic lesions is increased, probably due to a down‐regulation of γ‐aminobutyric acid–receptor activity. There is some evidence that these changes might increase the susceptibility of the lesioned brain for adaptive changes and recovery. Here, we investigated the propensity for the induction of long‐term potentiation (LTP) in the surround of experimentally induced focal cortical infarcts in rat somatosensory cortex in vitro. By using standard paradigms, LTP induction was found to be facilitated ipsilaterally in slices of lesioned animals 1 week after lesion induction. In homotopic contralateral areas, LTP was not different from control values. As LTP is commonly associated with plasticity and learning, the results provide further evidence for the lesion‐induced amplification of network plasticity, as it is required for the reshaping of cortical circuits by timely training procedures.
Ultrastructural connective tissue abnormalities in patients with spontaneous cervicocerebral artery dissections
Authors: Brandt Tobias , Hausser Ingrid , Orberk Erdem , Grau Armin , Hartschuh Wolfgang , Anton‐Lamprecht Ingrun , Hacke Werner
Published: January 2005

The cause of spontaneous cervicocerebral artery dissection is unknown. An underlying arteriopathy due to a connective tissue disorder has often been presumed. We studied 25 patients with proven nontraumatic dissections. The ultrastructural morphology of dermal connective tissue components was assessed by transmission electron microscopy of skin biopsies. Ultrastructural abnormalities were seen in 17 (68%) patients, resembling in some cases the aberrations found in Ehlers‐Danlos syndrome type II or III. These observations indicate a correlation of cervical artery dissections with connective tissue abnormalities. A structural abnormality in the extracellular matrix potentially caused by basic molecular defects is suggested and warrants further exploration.
Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]Dihydrotetrabenazine and positron emission tomography
Authors: Gilman Sid , Koeppe Robert A. , Adams Kenneth M. , Junck Larry , Kluin Karen J. , Johnson‐Greene Doug , Martorello Susan , Heumann Mary , Bandekar Rajesh
Published: January 2005

We used (+)[11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter, with positron emission tomography to study striatal monoaminergic presynaptic terminals in 7 male severe chronic alcoholic subjects without Wernicke–Korsakoff disease compared with 7 male normal controls of similar ages. We found reduced specific binding in the caudate nucleus and putamen in the alcoholic group, and the difference reached significance in the putamen. Specific binding was not decreased in the thalamus, which was examined as a reference structure. We also detected deficits in blood‐to‐brain transfer rate, K1, in the same regions of the alcoholic group, with a significant difference in the putamen. K1 was unchanged in the thalamus. The finding of reduced striatal VMAT2 in severe chronic alcoholic patients suggests that nigrostriatal monoaminergic terminals are reduced, with or without loss of neurons from the substantia nigra. The findings suggest that the damaging effects of severe chronic alcoholism on the central nervous system are more extensive than previously considered.