bluuebunny/crossref_metadata_2025 huggingface dataset:
Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography
Authors: Gilman Sid , Koeppe Robert A. , Junck Larry , Kluin Karen J. , Lohman Mary , St. Laurent Roy T.
Published: January 2005

We used positron emission tomography with [11C]flumazenil to study gamma‐aminobutyric acid type A/benzodiazepine receptor binding quantitatively in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem of 72 subjects, including 14 with multiple system atrophy of the ataxic (olivopontocerebellar atrophy) type, 5 with multiple system atrophy of the extrapyramidal/autonomic (Shy‐Drager syndrome) type, 18 with sporadic olivoponto‐cerebellar atrophy, 15 with dominantly inherited olivopontocerebellar atrophy, and 20 normal control subjects with similar age and sex distributions. In comparison with data obtained from the normal control subjects, we found significantly Decemberreased ligand influx in the cerebellum and brainstem of multiple system atrophy patients of the olivopontocerebellar atrophy type and in patients with sporadic olivopontocerebellar atrophy, but not in patients with multiple system atrophy of the Shy‐Drager syndrome type. Despite these differences in ligand influx, benzodiazepine binding was largely preserved in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem in patients with multiple system atrophy of both types as well as those with sporadic or dominantly inhierited olivoponto‐cerebellar atrophy as compared with normal control subjects. The finding of relative preservation of benzodiazepine receptors indicates that these sites are available for pharmacological therapy in these disorders.
An italian kindred with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Authors: Ragno Michele , Tournier‐Lasserve Elisabeth , Fiori Mario G. , Manca Antonio , Patrosso Maria Cristina , Ferlini Alessandra , Sirocchi Giovanna , Trojano Luigi , Chabriat Hugues , Salvi Fabrizio
Published: January 2005

Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle‐aged or even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which were affected by storke‐like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallMarchks of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic‐congophilic material that did not immunostain with antibodies against prion protein, β‐amyloid, cystatin C, transthyretin, or heat‐shock protein 70 and was similar to that described in the French families. Based on the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.
Increased sensitivity to ipsilateral cutaneous stimuli following transcranial magnetic stimulation of the parietal lobe
Authors: Seyal Masud , Ro Tony , Rafal Robert
Published: January 2005

Transcranial magnetic stimulation of the sensorimotor cortex results in Decemberreased sensitivity of threshold electrical stimuli to fingers of the contralateral hand. It has been suggested that one factor contributing to neglect contralateral to a unilateral parietal lesion is a release of the normal hemisphere from reciprocal interhemispheric inhibition by the damaged hemisphere. Consistent with this account, the current study demonstrated that transcranial magnetic stimulation over the parietal cortex results in increased sensitivity to cutaneous stimulation ipsilateral to the stimulation. The likely mechanism is a transcranial magnetic stimulation–induced transient dysfunction of the ipsilateral parietal cortex that then results in disinhibition of the contralateral parietal cortex.
Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin
Authors: Ljunggren Asa , Duggan David , McNally Elizabeth , Boylan Kevin B. , Gama Carlos H. , Kunkel Louis M. , Hoffman Eric P.
Published: January 2005

In our experience, more than half of muscular dystrophy patients show a primary dystrophinopathy. The underlying cause of muscular dystrophy in the vast majority of patients with normal dystrophin is unknown. Recently, a French family with 4 young siblings showing a muscular dystrophy of unknown progression was shown to have a primary deficiency of „adhalin,”︁ the 50‐kd dystrophin‐associated protein. Here we report the screening of the entire adhalin coding sequence in muscle biopsy specimens from 30 muscular dystrophy patients to (1) determine whether adhalin deficiency is restricted to the French population, (2) determine the incidence of adhalin deficiency in muscular dystrophy patients, and (3) characterize the clinical features and mutations in adhalin‐deficient patients. We identified a single African‐American girl with childhood‐onset muscular dystrophy and adhalin gene mutations. We found her to be a compound heterozygote for two different mutations of the same amino acid (Arg98Cys; Arg98His), one of which was previously identified in the French family. Our results suggest that primary adhalin deficiency in patients with muscular dystrophy but normal dystrophin is relatively infrequent, and that adhalin‐deficient patients are not restricted to the French population.
The subacute levodopa test for evaluating long‐duration response in parkinson's disease
Authors: Quattrone Aldo , Zappia Mario , Aguglia Umberto , Branca Damiano , Colao Rosanna , Montesanti Rita , Nicoletti Giuseppe , Palmieri Antonio , Parlato Giuseppe , Rizzo Milena
Published: January 2005

The clinical relevance of a long‐duration response (LDR) to levodopa therapy in Parkinson's disease (PD) has not been widely recognized. In 25 patients with moderate PD, we measured LDR on motor function after short periods of treatment with levodopa (subacute tests). Each subacute test lasted 15 days and consisted of the oral administration of levodopa at various interdose intervals (IDIs) of 48, 24, 12, 8, 6, and 5 hours. The goal for a subacute test was to achieve a satisfactory antiparkinsonian effect before the last levodopa dose (day 15), i.e., an LDR greater than 50% of the maximal response following an acute levodopa test (LDR‐endpoint). Twenty‐one patients (84%) reached the LDR‐endpoint. The IDI at which levodopa was administered clearly differentiated patients who were otherwise clinically indistinguishable when evaluated at baseline off medication or after an acute levodopa test. The IDI schedule that produced a satisfactory LDR was specific for each patient, since longer IDIs failed to produce the required LDR, and a shorter IDI schedule (resulting in larger cumulative dosage of levodopa) did not significantly enhance the response. Also, the LDR decay rate after discontinuation of treatment was individual for each patient and independent of the cumulative amount of levodopa administered. Both the IDI schedule and the LDR decay rate may reflect the ability of nigrostriatal neurons to store and to release dopamine formed from the exogenous precursor. The assessment of the LDR to levodopa by subacute tests is useful for establishing the appropriate dose of the drug, as well as for developing levodopa sparing strategies in PD patients.
Lack of an association between apolipoprotein E ϵ4 and Alzheimer's disease in elderly nigerians
Authors: Osuntokun B. O. , Sahota A. , Ogunniyi A. O. , Gureje O. , Baiyewu O. , Adeyinka A. , Oluwole S. O. , Komolafe O. , Hall K. S. , Unverzagt F. W. , Hui S. L. , Yang M. , Hendrie H. C.
Published: January 2005

As part of a community‐based study of Alzheimer's Disease (AD) in a Nigerian population aged 65 years and over, we have determined apolipoprotein E (APOE) genotypes on 56 subjects (39 controls and 17 subjects with dementia, including 12 with AD). The ϵ4 allele of APOE was not associated with AD or dementia in this community‐based sample. The ϵ4 allele frequency was 17.6% in demented patients and 16.7% in AD patients compared with 20.5% in the control subjects. These findings are in marked contrast to the strong association between the ϵ4 allele and AD in our previously reported study with African Americans.
Overexpression of DM20 messenger RNA in two brothers with pelizaeus‐merzbacher disease
Authors: Carango Paul , Funanage Vicky L. , Quirós Rubén E. , Debruyn Craig S. , Marks Harold G.
Published: January 2005

Pelizaeus‐Merzbacher disease is a rare, sex‐linked recessive, dysmyelinating disease of the central nervous system that has been associated with mutations in the myelin proteolipid protein (PLP) gene. Only 25% of patients studied with Pelizaeus‐Merzbacher disease have exonic mutations in this gene; the underlying cause of the disease in the remaining patients is unknown. The PLP gene encodes two major alternatively spliced transcripts called PLP and DM20. PLP messenger RNA is specifically expressed in central nervous system tissue, whereas DM20 messenger RNA is found in central nervous system, cardiac, and other tissues. We studied cultured skin fibroblasts from 2 brothers with Pelizaeus‐Merzbacher disease who exhibited no detectable exonic mutation of the PLP gene. Examination of RNA from these cells showed that the level of DM20 messenger RNA is elevated sixfold relative to male control skin fibroblasts. An unrelated female carrier, also with no detectable exonic mutation, showed a threefold increase in DM20 messenger RNA in cultured skin fibroblasts. Our findings suggest that in some patients, Pelizaeus‐Merzbacher disease is caused by overexpression of PLP gene transcripts, and that in these families a 50% increase of DM20 messenger RNA in females, relative to the increase in affected males, can identify a female carrier.
Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer's disease
Authors: Arai Hiroyuki , Terajima Masanori , Miura Masakazu , Higuchi Susumu , Muramatsu Taro , Machida Nobuo , Seiki Hisatomo , Takase Sadao , Clark Christopher M. , Lee Virginia M.‐Y. , Trojanowski John Q. , Sasaki Hidetada
Published: January 2005

Cerebrospinal fluid from 70 patients with Alzheimer's disease (AD) and 96 patients with non‐AD neurological diseases as well as 19 normal control subjects was surveyed by sandwich enzyme‐linked immunosorbent assay to quantitate levels of the microtubule‐associated protein tau in cerebrospinal fluid. The tau level was significantly increased in AD patients as compared with that in patients with non‐AD neurological diseases and control subjects. Increased tau levels were found irrespective of age at onset, apolipoprotein E genotype, and clinical stage. Western blots of AD cerebrospinal fluid proteins revealed two to three tau‐immunoreactive bands with an apparent molecular mass between 50 and 65 kd consistent with phosphorylated cerebrospinal fluid tau. Taken together, our results suggest that cerebrospinal fluid tau might reflect the progressive accumulation of altered tau due to the progressive death of neurons in the AD brain, and that the enzyme‐linked immunosorbent assay of cerebrospinal fluid tau may prove to be a reliable and early diagnostic test for AD.
Neutrophil inhibitory factor is neuroprotective after focal Ischemia in rats
Authors: Jiang Ning , Moyle Matthew , Soule Howard R. , Rote William E. , Chopp Michael
Published: January 2005

We tested the neuroprotective potential of neutrophil inhibitory factor (rNIF), a novel 41‐kd recombinant glycoprotein derived from a hookworm, in a model of focal cerebral ischemia in the rat. Male Wistar rats were assigned to treatment with rNIF and vehicle. Middle cerebral artery occlusion (MCAO) for 2 hours was induced by insertion of an intraluminal suture. Infusion of the drug was initiated at the onset of reperfusion. Infarct volume was determined 48 hours after reperfusion. Neutrophils were measured within the ischemic tissue by myeloperoxidase (MPO) staining. Treatment with rNIF resulted in a 48% reduction in cerebral infarction compared with control animals (p < 0.01). Neutrophil accumulation in the ischemic brains of rNIF‐treated rats was reduced significantly (p < 0.01) compared with control animals. The number of neutrophils within the infarcted tissue correlated positively with the size of the area of infarction (p < 0.001, r = 0.6) within representative cerebral coronal sections. We demonstrated a significant neuroprotective effect of rNIF with continuous treatment for 48 hours following 2 hours of MCAO. The neuroprotective effect was correlated with a reduced number of neutrophils within the ischemic tissue. These results demonstrate potential therapeutic properties of rNIF in the management of stroke.
Intractable partial epilepsy following low‐dose scalp irradiation in infancy
Authors: Reutens D. C. , Dubeau F. , Melanson D. , Remillard G. M. , Espinosa J. A. , King M. , Berkovic S. F. , Andermann F.
Published: January 2005

We report the development of intractable epilepsy in 3 patients treated with irradiation to „strawberry”︁ scalp nevi in infancy. Low‐dose radiation was used (12 and 13 Gy in 2 of the patients). The clinical evolution suggested a recognizable and distinctive postradiation syndrome. There was concordance between the site of radiation as shown by localized alopecia, the clinical features of the partial seizures, and electrographic abnormalities. The clinical picture was unlike delayed cerebral radiation necrosis of adulthood, which is not thought to occur at doses below 50 Gy, in 2‐Gy fractions. Neurological deficits were not progressive and in 2 patients there was no evidence of parenchymal injury on cranial magnetic resonance imaging scanning. These differences suggest pathogenetic differences to cerebral radiation injury of adulthood, probably relating to the interaction between nervous system development, individual susceptibility, and the low doses of radiation employed.
Intravenous γ‐globulin inhibits binding of anti‐GM1 to its taget antigen
Authors: Malik Ummekalsoom , Oleksowicz Leslie , Larov Normarl , Cardo Lisa J.
Published: January 2005

In this study, we preincubated the sera of 3 patients with neuropathies associated with elevated titers of IgM anti‐GM1 antibodies, with increasing concentrations of intra‐venous Ig (IVIg) and assayed the inhibitory effect of this mixture on antibody binding to immobilized GM, by an enzyme‐linked immunosorbent assay. Pharmacologic concentrations of IVIg, ranging from 0.1 μg/ml to 100 mg/ml, inhibited anti‐GM, binding to its target antigen from 26 ± 3 to 71 ± 7%, respectively, in a dose‐dependent manner. A similar inhibition of binding was also observed with IVIg F(ab′)2 fragments. These findings provide a possible mechanism for the clinical efficacy of IVI g in motor neuropathies.
Sporadic inclusion body myositis: Counts of different types of abnormal fibers
Authors: Pruitt J. Ned , Showalter Carol J. , Engel Andrew G.
Published: January 2005

Invasion of nonnecrotic muscle fibers by cytotoxic T cells, accumulation of congophilic amyloid inclusions in muscle fibers, and fiber necrosis are consistent histologic findings in sporadic inclusion body myositis (IBM). To evaluate the relative significance of these alterations, we quantitatively analyzed the frequency of these abnormalities in 31 electron microscopy proven cases of IBM (20 untreated and 11 immunosuppressed). Nonnecrotic muscle fibers invaded by T cells were severalfold more frequent than fibers displaying the other pathologic alterations. Comparison of muscle samples from treated and untreated patients revealed no significant differences in the respective frequencies of the three species of abnormal fibers. Moreover, there was no correlation of the frequency of any abnormality either with disease duration or length of treatment. The much higher Frequency of the invaded than Congo red‐positive fibers points to the importance of an immune‐mediated mechanism in the disease; but the basic cause of the disease remains undefined.
Clinical heterogeneity of adhalin deficiency
Authors: Morandi Lucia , Barresi Rita , Di Blasi Claudia , Jung Daniel , Sunada Yoshihide , Confalonieri Valeria , Dworzak Federica , Mantegazza Renato , Antozzi Carlo , Jarre Laura , Pini Antonella , Gobbi Giuseppe , Bianchi Carlo , Cornelio Ferdinando , Campbell Kevin P. , Mora Marina
Published: January 2005

We report adhalin deficiency in 8 patients with clinically diagnosed muscular dystrophy, dystrophic histopathological features, high plasma creatine kinase levels, normal expression of dystrophin, and marked variability of symptoms. Although the distribution of hyposthenia was similar in all 8 patients and predominantly involved muscles in the pelvic girdle, age at onset and rate of disease progression were highly variable: In 2 patients onset, at ages 24 and 25, was later than has been previously observed. We found no apparent relation between disease severity and the quantity of adhalin expressed. Two kinds of myopathy with adhalin deficiency have been reported: one caused by a mutation in the adhalin gene on chromosome 17 (primary adhalinopathy) and the other linked to chromosome 13. The product of the gene on chromosome 13 is probably associated with adhalin and its deficiency results in secondary adhalinopathy. The severity of clinical phenotypes in these adhalinopathies seems to relate more to the kind and site of the mutations than to the residual amount of the protein. We also detected a variable reduction in the laminin β1 subunit by immunohistochemistry in most patients, confirming that this is commonly associated with adhalin deficiency.
Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophc lateral sclerosis
Authors: Siklós László , Engelhardt József , Harati Yadollah , Smith R. Glenn , Joó Ferenc , Appel Stanley H.
Published: January 2005

Numerous studies of amyotrophic lateral sclerosis have suggested that increased intracellular calcium is a common denominator in motoneuron injury. In experimental models, IgG from patients with amyotrophic lateral sclerosis enhanced calcium entry and induced apoptotic cell death in vitro as well as increased intracellular calcium and induced ultrastructural alterations of the motor nerve terminals in mice in vivo. To determine whether similar increases in intracellular calcium and altered morphology are present in motor nerve terminals of amyotrophic lateral sclerosis patients in vivo, muscle biopsy specimens from 7 patients with amyotrophic lateral sclerosis, 10 nondenervating disease control subjects, and 5 patients with denervating neuropathies were analyzed with ultrastructural techniques, employing oxalate‐pyroantimonate fixation to preserve in situ calcium distribution. Motor nerve terminals from amyotrophic lateral sclerosis specimens contained significantly increased calcium, increased mitochondrial volume, and increased numbers of synaptic vesicles compared to any of the disease control groups, without exhibiting excess Schwann envelopment specific to denervating terminals. These results parallel the effect of amyotrophic lateral sclerosis IgG passively transferred to mice, and provide the first demonstration that neuronal calcium is, in fact, increased in amyotrophic lateral sclerosis in vivo.
Ultrastructural localization of adhalin in normal murine skeletal myofiber
Authors: Wakayama Yoshihiro , Inoue Masahiko , Murahashi Makoto , Shibuya Seiji , Jimi Takahiro , Kojima Hiroko , Oniki Hiroaki
Published: January 2005

The ultrastructural localization of adhalin and its relations to dystrophin, β‐dystroglycan, and β‐spectrin were studied in normal murine skeletal myofibers. The C‐terminal peptides of adhalin and β‐dystroglycan were synthesized based on their cDNAs, and the affinity‐purified antibodies against these peptides were produced. Single‐immunolabeling electron microscopy showed that the adhalin was located just inside the muscle plasma membrane or inside the myofiber a short distance from the plasma membrane. The adhalin signal was also noted at the sarcoplasmic side of plasmalemmd invaginations or at vesicular structures in subsarcolemmal areas. Double‐immunogold‐labeling electron microscopy disclosed a similar localization of dystrophin, β‐dystroglycan, and β‐spectrin. The close association of adhalin with dystrophin or β‐dystroglycan was demonstrated by formation of doublets by signals of antibodies of adhalin with those of dystrophin or β‐dystroglycan and was confirmed by statistical analyses. This study demonstrated that the location of adhalin is close to that of dystrophin and β‐dystroglycan at the muscle plasma membrane.
HLA Class II genes associated with REM sleep behavior disorder
Authors: Schenck Carlos H. , Garcia‐Rill Edgar , Segall Miriam , Noreen Harriet , Mahowald Mark W.
Published: January 2005

Twenty‐five white men with rapid eye movement (REM) sleep behavior disorder, but without narcolepsy, under‐went HLA class II antigen typing; 84% (N = 21) were DQw1 (DQB1*05,06) positive (28% [N = 7] were DR2 positive); DQB1*0501 (N = 9) and DQB1*0602 (N = 7) were the most common phenotypes. The 84% DQwl rate in men with REM sleep behavior disorder was significantly greater (p = 0.015) than the 56% DQwl rate found in a local white comparison group (N = 66), and was greater than the 39 to 66% DQw1 rates published for 12 white groups (N = 40–418/group). Thus, another disorder of REM sleep dysregulation (besides narcolepsy) appears to be strongly associated with specific HLA class I1 genes.
Magnetoencephalographic analysis of roland discharges in benign childhood epilepsy
Authors: Minami Taketsugu , Gondo Kenjiro , Yamamoto Tomoya , Yanai Shinji , Tasaki Kohsuke , Ueda Kohji
Published: January 2005

We report the detailed analysis of the generator and propagation of rolandic discharges in benign childhood epilepsy with centrotemporal spikes by means of 37‐channel magnetoencephalography with neuromagnetic three‐dimensional dipole localization. Equivalent current dipoles of prominent negative sharp waves of rolandic discharges appeared as tangential dipoles in the rolandic region, positive poles being situated anteriorly. These equivalent current dipoles showed a relatively limited localization and regular directions compared with other components. Equivalent current dipoles of preceding small positive waves, positive waves following negative sharp waves, and negative slow waves appeared in the vicinity of negative sharp waves. Equivalent current dipoles of rolandic discharges were located around the generator of somatosensory evoked magnetic fields stimulated at the lower lip. These findings suggest that rolandic discharges are generated through basically a mechanism similar to that for the middle‐latency components of somatosensory evoked responses.
Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease
Authors: Kushleika John , Checkoway Harvey , Woods James S. , Moon Jai‐Dong , Smith‐Weller Terri , Franklin Gary M. , Swanson Philip D.
Published: January 2005

Superoxide dismutases (SODs) are metalloenzymes that detoxify superoxide radicals, and occur in cytosolic (Cu,Zn‐SOD) and mitochondrial (Mn‐SOD) forms in multiple tissues, including brain. A neuroprotective effect against oxide stressor exposures may be provided by SOD, although excessive enzyme activity can produce cell injury by formation of hydroxyl radical from hydrogen peroxide. We measured Cu,Zn‐SOD and Mn‐SOD activities in peripheral lymphocytes of 43 newly diagnosed idiopathic Parkinsonapos;s disease (PD) cases and 62 age‐ and sex‐matched controls free of neurodegenerative disorders. Significant excesses of both SOD forms were found among PD cases compared with controls; however, the excesses were found exclusively among PD patients treated with the monoamine oxidase inhibitor selegiline (L‐deprenyl). Enzyme‐linked immunosorbent assays (ELI‐ SAs) confirmed that the activity excesses were due to in‐ creased protein rather than more highly reactive enzymes in lymphocytes of PD cases. Our findings clearly indicate the importance of selegiline on measured Cu,Zn‐SOD and Mn‐SOD activity in peripheral lymphocytes. Characterizing a possible therapeutic value of SOD will require longitudinal assessments of SOD in relation to PD progerssion.
Hypoplasia of the cerebellar vermis in neurogenetic syndromes
Authors: Schaefer G. Bradley , Thompson James N. , Bodensteiner John B. , McConnell James M. , Kimberling William J. , Gay Charles T. , Dutton William D. , Hutchings David C. , Gray Stanton B.
Published: January 2005

There are conflicting reports on the relationship between cerebellar vermal lobule hypoplasia and autism. Using quantitative magnetic resonance image analysis, we measured the cerebellar vermis in 125 normal individuals with a broad age range and 102 patients with a variety of neurogenetic abnormalities. We conclude that hypoplasia of cerebellar vermal lobules VI and VII is a nonspecific finding that even occurs in several conditions without autistic behavior. This suggests that it is not a specific neuroanatomical marker for autism, nor is cerebellar dys‐ genesis likely to be solely responsible for clinical autistic behaviors.
Hypersomnia following paramedian thalamic stroke: A report of 12 patients
Authors: Bassetti Claudio , Marhis Johannes , Gugger Matthias , Lovblad Karl O. , Hess Christian W.
Published: January 2005

Paramedian thalamic stroke (PTS) is a cause of organic hypersomnia, which in the absence of systematic sleep‐wake studies has been attributed to disruption of ascending activating impulses and considered a “earoused” state. However, an increasing amount of data suggests a role of the thalamus in sleep regulation and raises the possibility that a sleep disturbance contributes to hypersomnia in PTS. We evaluated 12 patients with magnetic resonance imaging‐proven isolated PTS and hypersomnia with 10 to >20 hours of sleep behavior per day. Nocturnal polysomnographic findings paralleled the severity of hypersomnia. All subjects had increased stage 1 NREM sleep, reduced stage 2 NREM sleep, and reduced numbers of sleep spindles. In patients with severe hypersomnia, slow‐wave (stages 3‐4) NREM sleep was often reduced, but there were no major REM sleep alterations. Daytime sleep behavior was associated mostly with stage 1 sleep by electroencephalogram; there was no correlation between hypersomnia and results of nap tests. We conclude that hypersomnia following PTS is accompanied by deficient arousal during the day and insufficient spindling and slow‐wave sleep production at night. These observations support the hypothesis of a dual role of the paramedian thalamus as “final common pathway” for both maintenance of wakefulness and promotion of NREM sleep.
Vestibular dysfunction in chronic inflammatory demyelinating Polyneuropathy
Authors: Frohman Elliot M. , Tusa Ronald , Mark Alexander S. , Cornblath David R.
Published: January 2005

Chronic inflammatory demyelinating polyneuropathy (CIDP) has occasionally been associated with clinical or laboratory evidence (magnetic resonance imaging, [MRI], visual evoked response, and brainstem auditory evoked response [BAER]) of cranial neuropathy. In most cases, the relationship of cranial nerve involvement to CIDP remains unclear. A 45‐year‐old woman noted foot numb‐ness, limb weakness, gait and postural instability, and oscillopsia. An IgG kappa monoclonal gammopathy of undetermined significance was found. Bilateral vestibulopathy was documented by clinical examination, bithermal calorics, rotary chair testing, BAERs, and dynamic posturography. MRI with gadolinium demonstrated enhancement of cranial nerve VIII bilaterally. Over the next 6 years, the patient's relapsing and remitting course of CIDP and vestibulopathy was assessed by quantitative muscle and vestibular function testing (clinically and neurophysiologically), and dynamic visual acuity. There was a striking synchronization between her CIDP and vestibulopathy with respect to clinical course including relapses and responses to immune therapy. The response to therapy, and evidence derived from clinical and laboratory investigations, suggest that the vestibular dysfunction was immune mediated.
Levodopa‐induced dyskinesias improved by a glutamate antagonist in parkinsonia monkeys
Authors: Papa Stella M. , Chase Thomas N.
Published: January 2005

Antagonists of the N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor have been reported to potentiate the antiparkinsonian action of levodopa and reverse levodopa‐induced motor fluctuations in animal models of Parkinson's disease. To evalute the effect of NMDA receptor blockade on dyskinesias complicating the response to long‐term levodopa therapy, we studied the selective antagonist LY235959 in six 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine‐lesioned monkeys. Drugs were administered subcutaneously, LY235959 at doses of 0.5, 1.0, 3.0, and 5.0 mg/kg and levodopa/benserazide at doses that produced moderate dyskinesias while almost totally reversing parkinsonian signs. Compared with vehicle control injections, LY235959 (3.0 mg/kg) abolished oral dyskinesias and diminished choreic dyskinesias by 68% (P < 0.01). Lower doses had smaller effects, although still significant, on oral dyskinesias (55% reduction at 1.0 mg/kg, P < 0.05). The highest LY235959 dose (5.0 mg/kg) prolonged oral dyskinesia suppression, but tended to increase dystonia severity. LY235959 had no effect on motor function when given alone and did not reduce the antiparkinsonian response to levodopa. These findings suggest that NMDA receptor blockade may ameliorate the dyskinetic complications of long‐term levodopa therapy, without diminishing the beneficial effects on parkinsonian signs.
Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex
Authors: Bristol Lynn A. , Rothstein Jeffrey D.
Published: January 2005

Glutamate transport is critical for synaptic inactivation of glutamate and prevention of excitotoxicity. The following four glutamate transporters have been identified in human brain: EAAT1, EAAT2, EAAT3, and EAAT4. Deficient glutamate transport has been identified in the motor cortex and the spinal cord of tissue from amyotrophic lateral sclerosis (ALS) patients. The defect appears to be due to a selective loss of the astroglial specific glutamate transporter protein EAAT2. In these studies we sought to extend our understanding of glutamate transporters in ALS by examining the mRNA for each transporter subtype in ALS motor cortex. All tissue was matched for age and postmortem delay. There was no quantitative change in mRNA for EAAT1, EAAT2, or EAAT3 in ALS motor cortex, even in patients with a large loss of EAAT2 protein (95% decrease compared with control) and decreased tissue glutamate transport (73% decrease compared with control). These studies suggest that the dramatic abnormalities in EAAT2 may be due to translational or post‐ translational processes.
The syndrome of posterior choroidal artery territory ifarction
Authors: Neau Jean‐Philippe , Bogousslavsky Julien
Published: January 2005

Posterior choroidal artery (PChA) territory infarcts remain the least well‐known type of thalamic infarcts. Our study of 10 personal cases, selected from 2,925 stroke patients admitted consecutively to a community‐based primary care center, and 10 published cases of unilateral PChA territory infarct suggests that they can often be differentiated clinically from other thalamic infarcts. Patients with PChA territory infarct associated with superficial posterior cerebral artery territory infarct or with another infarct were excluded. Damage was characteristically limited to the lateral geniculate body, pulvinar, posterior thalamus, hippocampus, and parahippocampal gyrus, without involvement of the upper midbrain and the anterior nucleus of thalamus. In lateral PChA territory infarct, the most common clinical manifestations included homonymous quadrantanopsia, with or without hemisensory loss and neuropsychological dysfunction (trans‐cortical aphasia, memory disturbances). A homonymous horizontal sectoranopsia is exceptional but particularly suggestive of the involvement of the lateral geniculate body in this territory. Medial PChA territory infarct was less frequent. Its neurologic picture was dominated by eye movement disorders not particularly suggestive of thalamic involvement. Late disability was usually absent or slight, being related to pain and delayed abnormal movements. The most common stroke etiology was presumed small‐vessel occlusive disease.
Analysis of chromosome 5q13 genes in amyotrophic lateral sclerosis: Homozygous naip deletion in a sporadic case
Authors: Jackson Mandy , Morrison Karen E. , Al‐Chalabi Ammar , Baldier Martijn , Leigh Peter N.
Published: January 2005

Although defects in the gene encoding the enzyme cytosolic copperlzinc superoxide dismutase (SODI) have been reported in 20% of familial amyotrophic lateral sclerosis (ALS) patients, the etiology of the remaining familial cases and the more common sporadic form of the disease remains unknown. Recently, deletions of the neuronal apoptosis inhibitory protein gene NAZP, of the survival motor neuron gene SMN, and of a further cDNA fragment, XS2G3, have been reported in childhood7‐onset proximal spinal muscular atrophy (SMA), another disorder with pathology restricted to the motor system. We have therefore investigated the possibility of alterations in SMN and NAIP in 154 patients with ALS (135 sporadic cases, 17 familial cases). None of these patients revealed mutations in SMN by single‐strand conformation polymorphism analysis. A single patient revealed a partial deletion of NAIP, with a homozygous absence of NAIP exon 5. While it is possible that this individual is one of the rare carriers of SMA who show NAIP deletions, a further explanation is that the NAIP deletion is in some way contributing to the ALS phenotype in this individual.
Deficiency of respiratory chain complex I is a common cause of leigh disease
Authors: Morris A. A. M. , Leonard J. V. , Brown G. K. , Bidouki S. K. , Bindoff L. A. , Turnbull D. M. , Woodward C. E. , Harding A. E. , Lake B. D. , Harding B. N. , Farrell M. A. , Bell J. E. , Mirakhur M.
Published: January 2005

We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.
Positron emission tomographic studies of cerebral benzodiazepine‐receptor binding in chronic alcoholics
Authors: Gilman Sid , Junck Larry , Martorello Susan , Lohman Mary , Koeppe Robert A. , Adams Kenneth , Johnson‐Greene Douglas , Kluin Karen J. , Brunberg James
Published: January 2005

Positron emission tomography was used with [11C] flumazenil (FMZ) and [18F] fluorodeoxyglucose to study GABA type A/benzodiazepine (GABA‐A/BDZ) receptors and cerebral metabolic rates for glucose (1CMRglc) in 17 male patients with severe chronic alcoholism (ALC), 8 with (ACD) and 9 without alcoholic cerebellar degeneration (non‐ACD). In comparison with male normal controls of similar ages, the ALC group had significantly reduced FMZ ligand influx (K1), FMZ distribution volume (DV), and 1CMRglc bilaterally in the medial frontal lobes, including superior frontal gyrus and rostral cingulate gyrus; the ACD group had significant reductions of K1, DV, and ICMRglc bilaterally in the same distribution, and also in the superior cerebellar vermis; and the non‐ACD group had significant reductions of K1, DV, and ICMRglc bilaterally in the same regions of the frontal lobes but not in the superior cerebellar vermis. When compared with the non‐ACD group, the ACD group had significant reductions of K1 and DV bilaterally in the superior cerebellar vermis. The results suggest that severe chronic alcoholism damages neurons containing GABA‐A/BDZ receptors in the superior medial apsects of the frontal lobes, and in patients with clinical signs of ACD, neurons containing GABA‐A/BDZ receptors in the superior cerebellar vermis.
Apolipoprotein E genotype in elderly nondemented subjects without senile changes in the brain
Authors: Yamada Masahito , Itoh Yoshinori , Otomo Eiichi , Suematsu Naomi , Matsushita Masaaki
Published: January 2005

Only a small minority of elderly subjects can survive with a brain free of senile changes (senile plaques, neurofibrillary tangles, and amyloid angiopathy) beyond the age of 80 years. We demonstrated that an increase of ε2 allele frequency and a decrease of ε4 allele frequency of the apolipoprotein E gene are associated with such brain aging without senile changes.
Functional MRI of lateral occipitotemporal cortex during pursuit and motion perception
Authors: Barton Jason J. S. , Simpson Trefford , Kiriakopoulos Elaine , Stewart Cindy , Crawley Adrian , Guthrie Bart , Wood Michael , Mikulis David
Published: January 2005

We performed functional imaging with a conventional 1.5‐T magnetic resonance scanner in 9 normal subjects. We used a gradient‐echo technique to examine changes in signal between periods when subjects viewed a stationary black‐and‐white grating, a moving grating, and when they followed a moving spot. We located image pixels with significant differences between the viewing conditions. In 7 subjects, these occurred in the lateral occipitotemporal cortex, a region previously identified as a putative human homologue of the motion‐sensitive middle temporal area (MT, or V5) of monkeys. Signal intensity was greater during pursuit of the moving dot than durin viewing of the moving grating with the eyes still, despite the fact that the moving grating generated more retinal image motion. In contrast, signal intensity in striate cortex was least during pursuit of the moving dot. These findings suggest that the lateral occipitotemporal cortex has extraretinal signals during pursuit. Such signals may include attentional input, corollary eye movement information, or even a pursuit command. Extraretinal signals suggest that the lateral occipitotemporal cortex may contain a human homologue not only of MT but also of other components of monkey V5 complex, such as the medical superior temporal area.
Cognitive deficits in Machado‐Josephs disease
Authors: Maruff P. , Tyler P. , Burt T. , Currie B. , Burns C. , Currie J.
Published: January 2005

Cognitive function was examined in 6 patients with genetically confirmed Machado‐Joseph disease (MJD) and 15 age‐and ethnically matched controls using a series of subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), a touch screen‐based testing system previously validated in a number of movement and neurodegenerative disorders. The MJD patients had deficits in visual attentional function that were characterized by a slowing of the processing of visual information when task demands were high and an inability to shift attention to previously irrelevant stimulus dimensions to discriminate between complex stimuli. Tests of learning and visual memory were normal. These results demonstrate that specific cognitive deficits occur in patients with MJD, independent of motor dysfunction, and these deficits may reflect disruption to frontosubcortical pathways.
Western versus asian types of multiple sclerosis: Immunogenetically and clinically distinct disorders
Authors: Yamasaki Kenji , Kira Jun‐Ichi , Kawano Yuji , Kobayashi Takuro , Kanai Takayuki , Nishimura Yasuhara , Matsushita Sho , Hasuo Kanehiro , Tobimatsu Shozo
Published: January 2005

The polymorphism of HLA‐DRBI, ‐DRB3, and ‐DRB5 genes as well as magnetic resonance images of the brain and spinal cord were studied in 57 Japanese patients with multiple sclerosis (MS). Twenty‐three patients clinically displayed selective involvement of the optic nerve and spinal cord and were classified as having Asian‐type MS. Patients with Asian‐type MS had fewer brain lesions shown gy magnetic resonance imaging, but more gadolinium‐enhanced spinal cord lesions than did patients with Western‐type MS (47% vs 17%). Fruthermore, the DR2‐associated DRBI1501 allele and DRB50101 allele were associated with Western‐type MS (41.2%), but not with either Asian‐type MS (0%) or healthy control subjects (14.2%). Heterogeneity inthe immunogenetic background and in the magnetic resonance imaging features between the two subtypes of MS thus suggests the presence of two etiologically distinct diseases in Asians.
Clinically distinct codon 69 mutations in major myelin protein zero in demyelinating neuropathies
Authors: Meijerink Peter H. S. , Zorn Ina , Baas Frank , de Visser Marianne , Bolhuis Pieter A. , Hoogendijk Jessica E. , Veldman Henk , Gabreëls‐Festen Anneke A. W. M.
Published: January 2005

Mutations in the major peripheral myelin protein zero (P0) gene on chromosome 1q21‐q23 have been found with the hereditary demyelinating polyneuropathy Charcot‐Marie‐Tooth type 1B. Here, we describe 2 patients with distinct neurological characteristics, carrying different substitutions at the same codon—Arg69His and Arg‐69Cys. The patients were heterozygous for the mutation, which in both appeared to be de novo. Histological examination of sural nerve biopsy specimens revealed defective myelin as well as marked differences, confirming the importance of P0 in the compaction of myelin.
Clinical and molecular genetic features of congenital spinal muscular atrophy
Authors: Devriendt Koenraad , Schollen Els , Cassiman Jean‐Jacques , Fryns Jean‐Pierre , Matthijs Gert , Lammens Martin , van Hole Chris , Devlieger Hugo , Dom René
Published: January 2005

A neonate presented with the fetal hypokinesia sequence and signs of spinal muscular atorphy (SMA). Severe pathological changes including ballooned neurons and neuronophagia were found not only in themotor nerve nuclei but also in the thalamic, cerebellar, and brainstem nuclei as well as in the dorsal root ganglia. Direct DNA analysis showed the presence of chimeric SMN gene, with a rearrangment occurring between exon 7 of the centromeric SMN gene and exon 8 of the telomeric SMN gene. Circumstantial evidence suggests that only a single copy of this gene is present, with transciriptional characeristics of a centromeric SMN gene. In addition, a homozygous deletion in the NAIP genes was demonstrated. This observation demonstrates that at least some cases with fetal hypokinesia and SMA may represent the severe end of a spectrum of disorders caused by deletions in the SMA locus on chromosome 5q13. In addition, these findigns are compatible with a modifying role for the centromeric SMN genes and the NAIP genes in the severitiy of the SMA phenotype.
End‐plate acetylcholine receptor deficiency due to nonsense mutations in the ε subunit
Authors: Engel Andrew G. , Ohno Kinji , Bouzat Cecilia , Sine Steven M. , Griggs Robert C.
Published: January 2005

We describe a congenital myasthenic syndrome associated with severe end‐plate (EP) acetylcholine receptor (AChR) deficiency not associated with an EP myopathy, and with evidence of immature AChR, containing the γ instead of the epsiv; subunit (γ‐AChR) at the EPs. Molecular genetic analysis of AChR‐subunit genes revealed two mutations in the ε‐subunit gene: insertion of a thymine after ε nucleotide 1101 (ε1101insT) that generates a nonsense condon directly, and insertionof a guanine after ε nucleotide 1293 (ε1293insG) that generates three missense codons followed by a nonsense codon. Each mutation predits truncation of the ε subunit at the level of the long cytoplasmic loop, between the third (M3) and fourth (M4) membrane spanning domains. The propositus' asymptomatic son carries ε1293G, indicating that the two mutations are heteroallelic. Expression of AChR harboring either mutation in human embryonic kidney (HEK) fibroblasts was markedly reduced. Single‐channel activit recorded from HEK cells cells expressin ε 1101insT‐AChR was infrequent but resembled activty of wild‐tpe AChR channels in amplitude and open duration. No channel activity could be recorded from HEK cells expressing ε 1293insG‐AChR. Expression of γAChR at the EPs may serve as the means of phenotypic rescue from potentially fatal nonsense mutations in the ε‐subunit gene.
X‐linked vacuolated myopathy: Membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma
Authors: Louboutin Jean‐Pierre , Villanova Marcello , Lucas‐Hérson Brigitte , Fardeau Michel
Published: January 2005

Cytochemical localization of calcium on muscle fibers from patients with X‐linked vocuolated myopathy demonstrated strong sarcolemmal or vacuolar calcium deposits in histologically abnormal muscle fibers. All membrane attack complex—positive fibers demonstrated such calcium accumulation. Total content of calcium was significantly elevated in muscles from patients with X‐linked vacuolated myopathy compared to control muscles. Taken together, these results suggest that calcium accumulation on sarcolemma could be probably secondary to membrane attack complex deposition on the cell surface.
Muscle—eye—brain disease: A neuropathological study
Authors: Haltia M. , Leivo I. , Somer H. , Pihko H. , Paetau A. , Kivelä T. , Tarkkanen A. , Tomé F. , Engvall E. , Santavuori P.
Published: January 2005

A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle—eye—brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker‐Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brain showed coarse gyri with an abnormally nodular surface („cobblestone cortex”︁). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortcal neurons formed irregular custers or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex—type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin α2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin α2 chain, reported to be severely deficient in WWS. These finding support nosological independence of MEB.