bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐speed memory scanning in Parkmson's disease: Adverse effects of levodopa
Authors: Poewe W. , Berger W. , Benke Th. , Schelosky L.
Published: January 2005

High‐speed memory scanning as assessed by the Sternberg paradigm was studied in 12 nondemented patients with fluctuating Parkinson's disease and 13 age‐matched healthy controls. Patients were first assesed before taking their morning dose of levodopa (“off”) and again after that dose had produced full clinical effect(“on”). Although motor components of the measured choice reaction time were slower in patients when off than in control subjects, memory scanning speed was not different. After levodopa (on), patients' motor time normalized, but cognitive processing speed became significantly slower when compared with previous performance in the off condition and with controls. Contrary to previous concepts of bradyphrenia in patients with Parkinson's diesase, these results indicate that dopaminergic stimulation can reduce cognitive processing speed.
Presence of the terminal complement complex (C5b‐9) precedes myelin degradation in immune‐mediated demyelination of the rat peripheral nervous system
Authors: Stoll Guido , Schmidt Beate , Jander Sebastian , Toyka Klaus V. , Hartung Hans‐Peter
Published: January 2005

In this study, the terminal complement complex c5b‐9 (TCC) was localized by immunocytochemistry at different clinical stages of experimental autoimmune neuritis. Deposits of TCC were found on the surface of Schwann cells and their myelin sheaths, and to some extent in the extracellular space at predilective sites of impending demyelination before onset of clinical signs and for a short period thereafter. Additionally, TCC was deposited on the surface of W3/13 positive leukocytes. No TCC immunoreactivity was seen in the distal stump of transected sciatic nerves 1 to 15 days after axotomy. The early and transient deposition of TCC on Schwann cells and myelin sheaths in experimental autoimmune neuritis before overt demyelination suggests that complement activation plays a pathogenic role in the initiation of immune‐mediated myelin damage. The lack of TCC immunoreactivity after nerve transection excludes a nonspecific activation process. The signals involved in local TCC formation in demyelinating peripheral nervous system disorders have yet to be explored.
Presence of HTLV‐I proviral DNA in central nervous system of patients with HTLV‐I–associated myelopathy
Authors: Kira Jun‐ichi , Itoyama Yasuto , Koyanagi Yoshio , Tateishi Jun , Kishikawa Masao , Akizuki Shin‐Ichiro , Kobayashi Itsuro , Toki Naoyuki , Sueishi Katsuo , Sato Hiroyuki , Sakaki Yoshiyuki , Yamamoto Naoki , Goto Ikuo
Published: January 2005

The polymerase chain reaction (PCR) method was used to determine the presence and amount of human T lymphotropic virus type I (HTLV‐I) proviral DNA in central nervous system (CNS) tissue obtained at autopsy from 6 patients with HTLV‐I–associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 1 patient with adult T‐cell leukemia (ATL) and CNS infiltration of leukemic cells, and 9 control subjects with other neurological disorders. HTLV‐I pX and env but not pol DNA were detected in CNS tissue from 5 of 6 patients with HAM/TSP. The ATL samples were positive for pX, env, and pol DNA by PCR. None of the control samples was consistently positive for HTLV‐I by PCR, but all showed positive bands on β‐globin PCR. Quantitative PCR combined with histological studies showed no correlation between HTLV‐I proviral DNA amounts and extent of perivascular mononuclear cell infiltration in the HAM/TSP CNS. Also, the amounts of pX and probably env DNA were greater in the HAM/TSP samples than in the ATL sample, although the extent of mononuclear cell infiltration was far less in the HAM/TSP samples than in the ATL sample. Therefore, in addition to infiltrating mononuclear cells, constituent cells of the CNS may harbor the HTLV‐I genome, at least in the pX and env regions, in patients with HAM/TSP.
A follow‐up study of isolated cases of suspected Huntington's disease
Authors: Bateman D. , Boughey A. M. , Scaravilli F. , Marsden C. D. , Harding A. E.
Published: January 2005

We reviewed 49 patients in whom a diagnosis of Huntington's disease (HD) seemed possible on clinical grounds, but who gave no history of definitely affected relatives. In 32 with the typical clinical features of HD (progressive chorea and dementia, postural instability, abnormal initiation of saccadic eye movements), the diagnosis was confirmed in 7 patients who had had autopsies, affected relatives were found in 5 others, and HD remained probable in a further 13 who were reexamined. In the 17 with a less typical clinical picture, a diagnosis of HD appeared most likely in 2; other causes for chorea such as cerebrovascular disease, neuroacanthocytosis, recrudescence of Sydenham's chorea, and drug‐induced tardive dyskinesia could be invoked in the remainder. We conclude that the likelihood of HD in a patient with the typical clinical features of this disorder but no history of affected relatives is at least 75%, which for practical purposes implies a risk to their children hardly less than in familial HD. The most plausible explanations for seemingly sporadic patients with HD are nonpaternity and mild, late‐onset disease that is overlooked by other family members.
Revised estimate of the prevalence of multiple sclerosis in the united states
Authors: Anderson D. W. , Ellenberg J. H. , Leventhal C. M. , Reingold S. C. , Rodriguez M. , Silberberg D. H.
Published: January 2005

Using three adjustments, we have revised a 1976 prevalence count for multiple sclerosis in the United States. The adjustments were made to data from a US national survey; they used 1990 population projections from the US Bureau of the Census, and results of investigations conducted in Weld and Larimer Counties, Colorado, and Olmsted County, Minnesota. It is estimated that approximately 250,000 to 350,000 persons in the United States in 1990 had physician‐diagnosed multiple sclerosis.
Familial amyloidotic polyneuropathy: Report of patients heterozygous for the transthyretin Gly42 gene
Authors: Murakami Tatsufumi , Yi Shigehiro , Yamamoto Kenji , Maruyama Shoichi , Araki Shukuro
Published: January 2005

We studied 2 patients from a Japanese family with familial amyloidotic polyneuropathy (FAP). Their clinical features are similar to type 1 FAP, and the proband's rectal tissue contained amyloid that stained with antihuman transthyretin (TTR) antiserum. Direct DNA sequencing of the proband's TTR gene revealed a guanine‐for‐adenine substitution in the second base of codon 42, producing a glycine for glutamate substitution in the plasma protein.
An abnormality of plasma amyloid protein precursor in Alzheimer's disease
Authors: Bush Ashley I. , Whyte Scott , Thomas Linda D. , Williamson Timothy G. , Van Tiggelen Cees J. , Currie Jon , Small David H. , Moir Robert D. , Li Qiao‐Xin , Rumble Baden , Mönning Ursula , Beyreuther Konrad , Masters Colin L.
Published: January 2005

βA4 amyloid deposition in the brain, which is characteristic of Alzheimer's disease(AD), may result from either overexpression of the amyloid protein precursor (APP) or failure of APP to be correctly processed. A blood marker reflecting this abnormal metabolism would be of diagnostic value and would provide a means of monitoring the efficacy of therapeutic interventions. We analyzed immunoblots of plasma APP enriched by heparin‐Sepharose chromatography from patients with moderate to severe AD dementia (n = 34) and control subjects (n = 77) and found an approximately 50% increase in the proportion of 130‐kd APP species in patients with AD (p < 0.001), no difference in the 110‐kd form, a 15 to 30% decrease in the 65‐kd form (p < 0.001), and a 20 to 35% decrease in the proportion of 42‐kd APP (p < 0.001). These species of APP were soluble, lacked the carboxyl terminus, and the 110‐and 42‐kd species were shown to be consistent with degradation products derived from the 130‐kd species. A comparison of levels of 130‐kd plasma APP from moderately to severely demented patients with AD and control subjects distinguished the two groups with a specificity of 87.0% and a sensitivity of 79.4%.
The first decade of molecular genetics in neurology: Changing clinical thought and practice
Authors: Rowland Lewis P.
Published: January 2005

Molecular genetics has had a powerful impact on clinical neurology. Definitions of disease are changing from clinical criteria to DNA analysis, resolving questions about the nature of clinically similar but not identical diseases. Genetic counseling is more reliable. Concepts of mendelian inheritance are being tested and new forms of mutation have been discovered to explain anticipation. Nonmendelian forms of inheritance have emerged; concepts of pathogenesis are on a more secure footing; and novel treatments are being explored.
Recurrent transverse myelitis, myasthenia gravis, and autoantibodies
Authors: Lindsey J. W. , Albers G. W. , Steinman L.
Published: January 2005

A 45‐year‐old man with a longstanding diagnosis of myasthenia gravis presented with four episodes of transverse myelitis in 5 years. Each episode improved after treatment with steroids. Laboratory studies revealed no evidence of multiple sclerosis or a structural spinal lesion. He had antinuclear and anti‐DNA antibodies and the HLA‐A1, B8, DR3 haplotype known to be associated with certain autoimmune diseases. We propose an autoimmune cause for the recurrent episodes of myelitis.
Extraocular muscles are spared in advanced duchenne dystrophy
Authors: Kaminski Henry J. , Al‐Hakim Mazen , Leigh R. John , Bashar M. Katirji , Ruff Robert L.
Published: January 2005

Fast‐twitch extremity muscle fibers are preferentially affected in Duchenne's and Becker' muscular dystrophy. Since saccades are thought to be mediated by fast‐twitch fibers, saccadic velocities would be expected to be decreased in these patients. Using infrared oculography, we found that the peak velocities of saccades in 3 patients with advanced Duchenne's or Becker's muscular dystrophy were normal. Clinical findings in 7 other patients with these forms of dystrophy were normal. This investigation is the first study of ocular motility in Duchenne's and Becker's muscular dystrophy. It demonstrates that extraocular muscle function is preserved and suggests that fast‐twitch fibers in extraocular muscles possess properties that protect against degeneration.
Low plasma apolipoprotein AII levels in human and mouse amyloidosis with mutant transthyretin (Met‐30) gene
Authors: Ando Yukio , Tanaka Yoshiya , Ueyama Hidetsugu , Sakashita Naomi , Yonehara Toshiro , Higuchi Keiichi , Araki Shukuro
Published: January 2005

We measured the serum apolipoprotein levels in patients with familial amyloidotic polyneuropathy (FAP). The serum apolipoprotein AII levels were much lower than those of the control subjects, while the levels in asymptomatic carriers of the FAP gene were normal. Other plasma apolipoprotein levels, such as apolipoproteins AI, B, CII, CIII, and E, were all within normal ranges. The decrease of apolipoprotein AII in the plasma of FAP patients correlated with the progression of the disease. In a transgenic mice model of FAP carrying human variant transthyretin gene (Met‐30), serum apolipoprotein AII levels were decreased in 1.5‐year‐old mice compared with control mice, while the 3‐month‐old mice had normal levels. These results suggest that apolipoprotein AII may play an important role in lipid metabolism or amyloid formation in patients with FAP.
Cloning and characterization of a lambert‐eaton myasthenic syndrome antigen
Authors: Rosenfeld Myrna R. , Wong Ellen , Dalmau Josep , Manley Geoff , Ponser Jerome B. , Sher Emanuele , Furneaux Henry M.
Published: January 2005

Lambert‐Eaton myasthenic syndrome is a paraneoplastic neuromuscular disorder in which an immune response directed against a small‐cell lung tumor crossreacts with antigens in the neuromuscular junction. To isolate and characterize the antigens, We screened a human fetal brain expression library with a high‐titer serum from a patient with Lambert‐Eaton myasthenic syndrome. This screening resulted in the isolation of a complementary DNA clone encoding an antigen we call myasthenic syndrome antigen B (MysB). Approximately 43% (3 of 7) of Lambert‐Eaton myasthenic syndrome sera specifically recognized MysB fusion protein, whereas none of 34 control sera did. The predicted amino acid sequence of this clone shows a high degree of homology to the b̃ subunit of calcium channel complexes. The MysB pre‐messenger RNA is alternatively spliced to yeild 3 forms of the protein differing in the domain between two highly conserved α‐helical segments.
Conjugal Alzheimer's disease: Is there an increased risk in offspring?
Authors: Bird T. D. , Nemens E. J. , Kukull W. A.
Published: January 2005

Thirty‐one couples in which both spouses had the clinical diagnosis of Alzheimer's disease (AD) (confirmed by autopsy in 12) were ascertained. The mean age of onset of dementia was 75.1 ± 7.4 years. These couples had 87 children, 63 still living. Seventeen (19.5%) of the children developed dementia, with a mean age of onset of 68.9 ± 8.3 years. Thirty of the children of the conjugal AD couples survived to age 65 or longer and 14 (47%) of them developed dementia. This prevalance of dementia in the children of affected couples is much greater than that in the children of two control groups consisting of 234 couples in which one spouse had AD and 192 couples in which neither spouse was demented. Twenty‐one of the conjugal AD couples had a family history of AD but the prevalence of dementia in their children was not greater than that in the children of conjugal AD couples without a family history of AD. These results represent additional evidence of an important genetic component in late‐onset AD and provide empirical risk data for the children of conjugal AD couples.
Anterior temporal language areas in patients with early onset of temporal lobe epilepsy
Authors: Devinsky Orrin , Perrine Kenneth , Llinas Rafael , Luciano Daniel J. , Dogali Michael
Published: January 2005

Eighteen consecutive patients undergoing dominant temporal lobectomy underwent preoperative cortical stimulation for language localization. Patients with naming deficits on anterior (4.5 cm from the temporal pole) temporal lobe stimulation had earlier seizure onset vs those without such deficits (5.8 yr vs 12.9 yr; p < 0.04). There was a similar trend for reading errors (6.3 yr vs 12.4 yr; p < 0.052). Resections always spared at least 1 cm anterior to any langauge area. There was no significant difference in postoperative neuropsychological tests between patients with and without anterior language representation. Early onset of dominant temporal lobe seizure foci leads to a more widespread or atypical distribution of language areas. Individual variability should be considered in epilepsy surgery to reduce postoperative language deficits.
Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination
Authors: French J. A. , Williamson P. D. , Thadani V. M. , Darcey T. M. , Mattson R. H. , Spencer S. S. , Spencer D. D.
Published: January 2005

In order to more precisely define a syndrome of medial temporal lobe epilepsy, histories and physical findings were evaluated in 67 patients studied with intracranial electrodes who had medial temporal seizure onset and became seizure free following temporal lobectomy. Patients with circumscribed, potentially epileptogenic mass lesions were excluded. Fifty‐four patients (81%) had histories of convulsions during early childhood or infancy, 52 of which were associated with fever. Complicated febrile seizures occurred in 33 (94%) of the 35 patients in whom detailed descriptions of the febrile seizures were available. Bacterial (5) or viral (2) central nervous system infections were present in 7 patients with seizures and fevers. Other less common, but probably significant, risk factors included head trauma (10%) and birth trauma (3%). Only 5 patients had no apparent risk factors. The mean age at habitual seizure onset was 9 years. All patients had complex partial seizures, with half having only complex partial seizures. The other half also had secondarily generalized tonic‐clonic seizures, but these were never the predominant seizure type. Only 3 patients had histories of convulsive status epilepticus and no patient had a history of nonconvulsive status epilepticus. All but 3 patients reported auras before some or all of their seizures, with an abdominal visceral sensation being by far the most common type of aura (61%). Of the 60 patients with identified risk factors, all but 2 had an interval between the presumed cerebral insult and the development of habitual seizures, with a mean seizure‐free interval of 7.5 years. Fifteen patients developed a seizure‐free interval following onset of habitual seizures, with a mean duration of 5.9 years. In 22 patients, the seizures had an evolutionary pattern, with seizures becoming progressively more elaborate over time. We conclude (1) there is a very strong relationship between complicated febrile seizures during early childhood or infancy and the later development of medial temporal lobe epilepsy; (2) habitual seizures in most patients from this population begin during, or shortly after, the first decade of life; (3) complex partial seizures are seen in all such patients; (4) generalized tonic‐clonic seizures are not a predominant seizure type in these patients, and convulsive status epilepticus in uncommon; (5) nonconvulsive status epilepticus rarely, if ever, occurs in these patients; (6) auras, particularly abdominal visceral sensations, are very common; and (7) medial temporal lobe epilepsy can be a progressive disease as evidenced by silent intervals and progressive elaboration of seizures.
Parvalbumin‐immunoreactive cortical neurons in Creutzfeldt‐Jakob disease
Authors: Ferrer Isidro , Casas Romi , Rivera Rosa
Published: January 2005

Massive abnormalities of parvalbumin‐immunoreactive cortical neurons were observed in the cerebral biopsy samples of 3 patients with Creutzfeldt‐Jakob disease. Immunoreactive cells had reduced and short, often fragmented, dendrites, and large numbers of dendritic varicosities were observed. Since parvalbumin‐immunoreactive neurons are the most important inhibitory cells in the cerebral cortex, the damage to these neurons may account, in part, for the impaired cortical function, and may play a role in the appearance of myoclonus and electroencephalographic patterns in patients with Creutzfeldt‐Jakob disease.
Mitochondrial myopathy with progressive decrease in mitochondrial tRNALeu(UUR) mutant genomes
Authors: Kawakami Yasuhiko , Sakuta Ryoichi , Hashimoto Kiyoshi , Fujino Osamu , Fujita Takehisa , Hida Masatoshi , Horai Satoshi , Goto Yu‐ichi , Nonaka Ikuya
Published: January 2005

A female patient with mitochondrial myopathy had a mitochondrial DNA mutation at nucleotide pair 3243, commonly seen in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), but unlike MELAS patients, she had no central nervous system symptoms. Muscle weakness, which was most severe when she was 7 years old, improved gradually with age. Comparison of two muscle biopsies obtained at an interval of 12.5 years (7 and 20 years of age, respectively), revealed that the number of ragged‐red fibers was markedly decreased and histochemical cytochrome c oxidase activity increased in parallel with the decrease in population of mutant genomes.
Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot‐Marie‐Tooth disease type 1A
Authors: Yoshikawa Hiroo , Nishimura Tomoya , Nakatsuji Yuji , Fujimura Harutoshi , Himoro Masato , Hayasaka Kiyoshi , Sakoda Saburo , Yanagihara Takehiko
Published: January 2005

The human peripheral myelin protein 22 (PMP‐22) gene has been mapped to chromosome 17p11.2 in the duplicated region associated with Charcot‐Marie‐Tooth disease type 1A. Southern blot analysis using PMP‐22 as a probe indicated that the PMP‐22 gene was duplicated in 5 patients from unrelated Japanese families with Charcot‐Marie‐Tooth disease type 1. In order to investigate whether or not an extra copy of PMP‐22 has an effect on its gene expression, we analyzed relative expression of messenger RNA for PMP‐22 and protein 0 (P0) against beta‐actin by Northern blotting in biopsied nerves of the patients with type 1A disease, and compared the results with those of patients having other demyelinating neuropathies and the autopsied nerves of patients without neuropathies. The relative expression of PMP‐22 messenger RNA in 5 patients with Charcot‐Marie‐Tooth disease type 1A was significantly higher than that in 5 patients with other demyelinating neuropathies (p < 0.05). There was no statistically significant difference in P0 expression between them. This study provided direct evidence for elevated expression of PMP‐22 in peripheral nerves of patients with Charcot‐Marie‐Tooth disease type 1A as the result of a gene dosage effect. However, the relation between elevated expression of PMP‐22 and the mechanism causing demyelination remains undetermined.
N‐acetylgalactosaminyl GD1a is a target molecule for serum antibody in Guillain‐Barré syndrome
Authors: Kusunoki Susumu , Chiba Atsuro , Kon Kazuo , Ando Susumu , Arisawa Kazuko , Tate Asako , Kanazawa Ichiro
Published: January 2005

Serum antibodies against such major glycolipids as GM1, GD1b, and LM1 have been reported in patients in the acute phase of Guillain‐Barré syndrome (GBS). Because minor unidentified glycolipids also may be targets of antibodies in GBS sera, we assayed serum antibody against a crude ganglioside fraction using thin‐layer chromatogram immunostaining. Antibody activity was detected against a band that migrated just below GD1a in 6 of the 50 patients with GBS tested. Antibody titer, as determined by enzyme‐linked immunosorbent assay, decreased during the course of the disease. All 6 patients had suffered gastrointestinal infection before the neurological onset of GBS and showed low amplitudes for the compound muscle action potentials and normal or only slightly decreased nerve conduction velocities. Thin‐layer chromatogram immunostaining did not show this antibody activity in any of the 16 normal and 119 disease controls. The unidentified glycolipid was isolated by DEAE–Sephadex A‐25 column chromatography, sialidase treatment, and Iatrobeads column chromatography. Fast atom bombardment‐mass spectra showed it to be N‐acetyl‐galactosaminyl GD1a.
Phenotype of chromosome 14–linked familial Alzheimer's disease in a large kindred
Authors: Lampe Thomas H. , Bird Thomas D. , Nochlin David , Nemens Ellen , Risse Steven C. , Sumi S. Mark , Koerker Richard , Leaird Brie , Wier Monna , Raskind Murray A.
Published: January 2005

We report the clinical and neuropathological features of chromosome 14–linked familial Alzheimer's disease (14qF AD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early‐appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q‐linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q‐linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each) (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q‐linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.
Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients
Authors: Tsujino Seiichi , Shanske Sara , Brownell A. Keith W. , Haller Ronald G. , DiMauro Salvatore
Published: January 2005

We identified two new mutations in 2 white patients with muscle lactate dehydrogenase deficiency. Both patients had exercise intolerance, cramps, and recurrent myoglobinuria. One patient was homozygous for a 2‐bp deletion in exon 5, resulting in a frameshift with premature termination of translation. The second patient was homozygous for a G → A substitution at the 3′ end of exon 2, leading to exon skipping and splicing of exon 1 to exon 3; the aberrantly spliced messenger RNA contains a frameshift, resulting in premature termination of translation. The present report provides evidence of molecular genetic heterogeneity in white patients with muscle lactate dehydrogenase deficiency.
Positron emission tomographic evidence for progression of human MPTP‐induced dopaminergic lesions
Authors: Vingerhoets F. J. G. , Snow B. J. , Tetrud J. W. , Langston J. W. , Schulzer M. , Calne D. B.
Published: January 2005

Transient exposure to the toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) produces a syndrome resembling idiopathic parkinsonism (IP). While IP inevitably progresses, the long‐term evolution of MPTP‐parkinsonism is unknown. Fluorodopa positron emission tomography (FD‐PET) is a reliable tool for assessing nigrostriatal dopaminergic function. We performed FD‐PET and clinical assessments on two occasions, 7 years apart, on 10 human subjects exposed to MPTP (age at the first scan, 32.7 ± 6.9 yr [mean ± SD], and on 10 normal individuals age, 53 ± 16 yr). At the time of their first scan, 5 of the subjects exposed to MPTP were clinically normal and 5 had limited signs of parkinsonism; 5 had new clinical deficits 7 years later. In the subjects exposed to MPTP, the PET index [(striatal – occipital)/occipital ratio] dropped by 2.3% per year from 0.70 ± 0.10 (mean ± SD) to 0.58 ± 0.10 (p < 0.001). This was significantly faster than normal aging (p < 0.01) and similar to the progression observed in IP (p = 0.06). The findings suggest that short‐term exposure to MPTP leads to a protracted decline in nigrostriatal dopaminergic function more rapid than occurs in normal aging and similar to IP progression. This is the first evidence that transient exposure to a toxin can cause progressive nigral pathology. At present, the mechanism leading to this progression is unknown. Our findings support the hypothesis that some neurodegenerative disorders may result from transient exposure to an environmental agent.
Amyloid β protein levels in cerebrospinal fluid are elevated in early‐onset Alzheimer's disease
Authors: Nakamura Tamiko , Shoji Mikio , Harigaya Yasuo , Watanabe Mitsunori , Hosoda Kenji , Cheung Tobun T. , Shaffer Lillian M. , Golde Todd E. , Younkin Linda H. , Younkin Steven G. , Hirai Shunsaku
Published: January 2005

The 4‐kd amyloid β prrotein (Aβ) deposited as amyloid in Alzheimer's disease (AD) is produced and released by normal proteolytic processing of the amyloid β protein precursor (βAPP) and is readily detected in cerebrospinal fluid (CSF). Here, we present the levels of Aβ in CSF from a total of 95 subjects, including 38 patients with AD, 14 with early‐onset AD and 24 with late‐onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The level of Aβ decreased with normal aging, and there was a significant elevation in the level of Aβ in the CSF of early‐onset AD patients (4.14 ±1.37 pmol/ml, p < 0.01). Neither Mini‐Mental State nor Functional Assessment Staging were correlated with the amount of Aβ in the CSF. The Aβ/secreted form of βAPP ration was elevated, but the level of α;1‐antichymotrypsin in the CSF did not correlate with the level of CSF Aβ in early‐onset AD patients. Thus, the level of Aβ in the CSF is elevated in early‐onset AD patients and is suggested to be correlated with the pathology in the brain that characterizes AD.
Pelizaeus‐Merzbacher disease presenting as spinal muscular atrophy: Clinical and molecular studies
Authors: Kaye Edward M. , Doll Rhonda F. , Natowicz Marvin R. , Smith Frances I.
Published: January 2005

Two brothers with profound neonatal hypotonia and hyporeflexia and electrodiagnostic testing consistent with lower motor neuron pathology were found to have a leukodystrophy. Using single‐strand conformational polymorphism analysis and direct sequencing, a mutation within exon 3 of the gene encoding proteolipid protein (Gly73 Arg substitution) was previously detected in both brothers and their mother, establishing the diagnosis of Pelizaeus‐Merzbacher disease. Despite reported sparing of the peripheral nervous system in Pelizaeus‐Merzbacher disease, we suggest that proteolipid protein gene products may influence the development of anterior horn cells or peripheral nervous system myelin and that some individuals affected with this disease may present with clinical and electromyographic features suggestive of neonatal spinal muscular atrophy.
Plasticity of nerve afferents to nigrostriatal neurons in parkinson's disease
Authors: Anglade Philippe , Javoy‐Agid France , AgidM Yves , Hirsch Etienne C. , Tsuji Shigeru
Published: January 2005

Clinical symptoms in Parkinson's disease do not appear until almost total depletion of dopamine has occurred in the striatum, suggesting the existence of compensatory mechanisms to offset the loss of nigrostriatal dopaminergic neurons. This compensation has been attributed mainly to an increased turnover of dopamine in the remaining dopaminergic neurons. Besides this biochemical phenomenon intrinsic to dopaminergic neurons, we tested whether morphological changes in the nerve afferents to the dopaminergic neurons could participate in these compensatory mechanisms. The afferents to the dendrites of dopaminergic neurons were analyzed ultrastructurally in the substantia nigra of parkinsonian patients and matched controls, using simultaneous histochemical detection of acetylcholine‐like cation and tyrosine hydroxylase. The size of acetycholine‐like cation‐containing terminals in contact with dopaminergic dendrites increased significantly by 38% in the substania nigra of parkinsonian patients; whereas their number per section of dopaminergic dendrite showed an increase of 60%, although not reaching statistical significance. The number of the terminals devoid of acetylcholine‐like cation per section of dopaminergic dendrite decreased significantly by 52% in the substantia nigra of parkinsonian patients. These results suggest (1) a plasticity of excitatory cholinergic neurons targeting nigral dopaminergic neurons and (2) an involution of noncholinergic nerve terminals, mostly originating from inhibitory nigral, pallidal, and striatal GABAergic neurons. The findings provide evidence of a capacity for neuronal plasticity in the elderly human brain, even in the presence of neurodegenerative disorders.
Neurotrophin‐3 reverses experimental cisplatin‐induced peripheral sensory neuropathy
Authors: Gao Wei‐Qiang , Dybdal Noel , Shinsky Natasha , Murnane Amy , Schmelzer Charles , Siegel Mark , Keller Gilbert , Hefti Franz , Phillips Heidi S. , Winslow John W.
Published: January 2005

Cisplatin, a widely used chemotherapeutic agent, induces a sensory neuropathy with selective loss of vibration sense and proprioception. Here we demonstrate that neurotrophin‐3 (NT‐3), a member of the nerve growth factor family of neurotrophic factors, restored to normal levels the reduced H‐reflex‐related sensory nerve conduction velocity induced by cisplatin in rats. NT‐3 treatment corrected an abnormal cytoplasmic distribution of neurofilament protein in large sensory neurons in dorsal root ganglia and the reduction in the numbers of myelinated fibers in sural nerves caused by cisplatin. The NT‐3–dependent reversal of cisplatin neurotoxicity thus suggests the possible use of NT‐3 in the treatment of peripheral sensory neuropathy.
Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives
Authors: Farrer Lindsay A. , Adrienne Cupples L. , Van Duijn Cornelia M. , Kurz Alexander , Zimmer Reinhilde , Müller Ulrich , Green Robert C. , Clarke Valerie , Shoffner John , Wallace Douglas C. , Chui Helena , Flanagan Steven D. , Duara Ranjan , George‐Hyslop Peter St. , Auerbach Sanford A. , Volicer Ladislav , Wells John M. , Van Broeckhoven Christine , Growdon John H. , Haines Jonathan L.
Published: January 2005

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the ϵ4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack ϵ4 and many persons having ϵ4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first‐degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of ϵ4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one ϵ4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of ϵ4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one ϵ4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex‐modification effect of the E4 isoform on disease susceptibility.
Striatal dopaminergic denervation in Pallidopyramidal disease demonstrated by positron emission tomography
Authors: Remy Philippe , Hosseini Hassan , Degos Jean‐Denis , Samson Yves , Agid Yves , Warter Jean‐Marie , Vidailhet Marie
Published: January 2005

Pallidopyramidal disease is a rare disease of young patients in which they manifest a parkinsonian syndrome and pyramidal signs. Pallidopyramidal disease has been attributed to a degeneration of the pallidum and the pyramidal tract, although only 1 patient has been studied postmortem. In the present report, [18F]fluorodopa positron emission tomography in 2 patients showed a marked dopaminergic denervation of the striatum, suggesting that this disease corresponds more to a nigropallidopyramidal dysfunction.
Nerve growth factor protects the neonatal brain against hypoxic–ischemic injury
Authors: Holtzman David M. , Sheldon R. Ann , Jaffe Wyatt , Cheng Yu , Ferriero Donna M.
Published: January 2005

Nerve growth factor (NGF) has been shown to protect specific neurons that express its signaling receptor, trkA, from a variety of insults. There are some data, in particular in the developing brain, indicating that NGF has neuroprotective actions that extend beyond cells expressing trkA. In this study, we asked whether NGF would protect against brain injury in a neonatal model of hypoxia–ischemia. Postnatal day (PD) 7 rat pups received a right carotid ligation and were then exposed to hypoxic conditions. Prior to carotid ligation and 48 hours later, pups received an intracerebroventricular injection of NGF or denatured NGF dissolved in vehicle or vehicle alone. Brains were then assessed at PD21. In vehicle‐ and denatured NGF‐treated animals, there was significant damage (30–40% volume loss) to both the striatum and cortex ipsilateral to the carotid ligation. In contrast, little damage (10% volume loss) was observed in most NGF‐treated animals. NGF injection studies revealed that NGF stimulated tyrosine phosphorylation of trkA in multiple brain regions. These results show that NGF appears globally neuroprotective to the developing brain in a neonatal model of hypoxia‐ischemia and that there may be novel mechanisms in vivo through which NGF exerts its protective actions.
Relationship between trinucliotide repeats and neuropathological changes in Huntington's diease
Authors: Furtado Sarah , Suchowersky Oksana , Rewcastle N. Barry , Graham Lisa , Klimek Mary Lou , Garber Anthony
Published: January 2005

The discovery of the Huntington's disease (HD) gene has provided the impetus to determine the association between the triplet repeat sequences and clinical manifestations of the disease. The present study is directed toward determining the relationship between the triplet repeat sequences and severity of the neurodegenerative process. Nineteen HD postmortem cases were evaluated for neuropathological changes as well as for the number of trinucleotide repeat sequences, each in a blinded fashion. Each case was assigned a gross grade according to the scale of Vonsattel and colleagues (1985); neuronal counts were then performed on both the caudate and the putamen. For 7 of the postmortem cases, blood had been collected prior to death and was analyzed for the HD gene. For the 12 remaining cases for which blood was unavailable, DNA from the frontal neocortex and striatum was extracted from frozen or formalin‐fixed paraffinized tissue and subsequently analyzed for the HD gene. When correlation was made for age at death, greater numbers of trinucleotide repeats were associated with greater neuronal loss, in both the caudate (r = 0.9641, p < 0.001) and the putamen (r = 0.9652, p < 0.001). When correction was made for disease duration, the correlation was again significant, for both the caudate (r = 0.6396, p < 0.01) and the putamen (r equals; 0.6710, p < 0.001). This suggests that in HD, longer trinucleotide repeat length is associated with a faster rate of deterioration and greater pathological severity. A comparison of trinucleotide repeat length in different brain regions in 4 of the HD postmortem cases associated with greater numbers of repeats consistently demonstrated fewer repeats in the cerebellum than in the frontal cortex, striatum or blood.
Developmental dyslexia: A motor‐articulatory feedback hypothesis
Authors: Heilman Kenneth M. , Voeller Kytja , Alexander Ann W.
Published: January 2005

Reading is mediated by parallel and widely distributed modular systems. There are, therefore, multiple loci in these systems where dysfunction may lead to developmental dyslexia. However, most normal children learn to read using the alphabetic system. Learning to use this system requires awareness that words are comprised of a series of speech sounds (phonological awareness) and the knowledge of how to conyert letters (graphemes) into these speech sounds (phonemes). Most dyslexic children have deficient phonological awareness and have difficulty converting graphemes into phonemes. Studies of patients with acquired lesions who are unable to convert graphemes into phonemes, as well as positron emission tomographic studies of normal subjects, suggest that the left inferior frontal lobe is important in phonologic reading. Phonetic gestures are represented in the brain as invariant motor commands that program the articulators. Phono‐ logic reading may activate the left inferior frontal lobe because grapheme‐to‐phoneme conversion requires activation of these motor‐articulatory gestures. Dyslexic children are unaware of the position of their articulators during speech. The inability to associate the position of their articulators with speech sounds may impair the development of phonological awareness and the ability to convert graphemes to phonemes. Unawareness of their articulators may be related to programming or feedback deficits.
Brain thiamine, its phosphate esters, and its metabolizing enzymes in alzheimer's disease
Authors: Mastrogiacomo Frank , Bettendorff Lucien , Grisar Thierry , Kish Stephen J.
Published: January 2005

Clinical data suggest that high‐dose thiamine (vitamin B,) may have a mild beneficial effect in some patients with Alzheimer's disease (AD). Since this action could be related to a brain thiamine deficiency, we measured directly levels of free (nonphosphorylated) thiamine and its phosphate esters, thiamine monophosphate and thiamine diphosphate (TDP), and activities of three TDP‐metabolizing enzymes (thiamine pyrophosphokinase, thiamine diphosphatase, and thiamine triphosphatase) in autopsied cerebral cortex of 18 patients with AD and 20 matched controls. In the AD group, mean levels of free thiamine and its monophosphate ester were normal, whereas levels of TDP were significantly reduced by 18 to 21% in all three cortical brain areas examined. Activities of the TDP‐metabolizing enzymes were normal in the AD group, suggesting that decreased TDP is not due to altered levels of these enzymes. The TDP decrease could be explained by a cerebral cortical deficiency in AD of ATP, which is needed for TDP synthesis. Although the magnitude of the TDP reduction is slight, a chronic subclinical TDP deficiency could contribute to impaired brain function in AD and might provide the basis for the modest improvement by thiamine in cognitive status of some patients with AD.
Trifunctional enzyme deficiency: Adult presentation of a usually fatal β‐oxidation defect
Authors: Schaefer Jochen , Jackson Sandra , Turnbull Douglass M. , Dick David J.
Published: January 2005

Disorders of mitochondrial fatty acid oxidation are a common cause of exercise‐induced rhabdomyolysis and myoglobinuria. We report three adult patients from a family with symptoms of recurrent exercise‐induced rhabdomylysis. This presentation closely resembles adult‐type carnitine palmitoyltransferase II deficiency except that these patients had an associated peripheral neuropathy. Investigation of fatty acid oxidation in the patients revealed a deficiencyof the mitochondrial trifunctional enzyme of β‐oxidation, a newly described fatty acid oxidation disorder with multiorgan involvement and a usually fatal outcome in early childhood. Our cases therefore represent a new phenotype of the disease, which is characterized by recurrent rhabdomyolysis and peripheral neuropathy, but without involvement of other organs, and which is associated with prolonged survival beyond the fourth decade. A low‐fat/high‐carbohydrate diet proved bneficial in one of the patients, drastically reducing the frequency of rhabdomyloytic episodes. Our findings suggest that mitochondrial trifnctional enzyme deficiency should be considered in patients with recurrent eipsodes of myoglobinuria and peripheral neuropathy presenting in later life.
Interferon beta induces interleukin‐10 expression: Relevance to multiple sclerosis
Authors: Rudick Richard A. , Ransohoff Richard M. , Peppler Richard , Medendorp Sharon Vanderbrug , Lehmann Paul , Alam John
Published: January 2005

Interferon‐β decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing‐remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon‐β may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon‐β‐1a on the expression of interleukin‐10, a cytokine that strongly inhibits cell‐mediated immune responses. Interferon‐β‐1a induced accumulation of interleukin‐10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon‐β‐1a increased serum levels of interleukin‐10 at 12 and 24 hours following the injection. Greater increases were induced with 12 × 106‐IU than 6 × 106‐IU injections. The effect of interferon‐β‐1a was relatively specific for interleukin‐10, as treatment with interferon‐β‐1a did not result in accumulation of transforming growth factor‐β messenger RNA. Upregulation of interleukin‐10 represents a possible mechanism of action of interferon‐β's therapeutic effect in relapsing‐remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.
Exercise fuel mobilization in mitochondrial myopathy: A metabolic dilemma
Authors: Vissing John , Galbo Henrik , Haller Ronald G.
Published: January 2005

In mitochondrial myopathy, severely impaired muscle oxidative capacity poses a dilemma for metabolic regulation in exercise. We inquired whether fuel mobilization during exercise in mitochondrial myopathy is adjusted to the reduced capacity to oxidize substrate, or if fuel is mobilized in excess of oxidative capacity. Hormonal and metabolic responses to 20 minutes of cycle exercise were studied in 4 patients with mitochondrial myopathy working at near maximal effort and in 4 healthy matched controls. On 2 separate days, controls were studied at the same absolute (A) workload (9 ± 3 W) and the same relative (R) workload (77 ± 9 W) as performed by the patients. During exercise, average glucose production was higher in patients (28 ± 5 μmol min−1 kg−1) than in controls at both workloads (A, 12 ± 1; R, 18 ± 2 μmol min−1 kg−1). Exercise‐induced increases in plasma glucose, growth hormone, epinephrine, norepinephrine, corticotropin, and lactate, and decreases in plasma insulin and pH were also larger in patients compared with findings in controls at both workloads. In conclusion, mitochondrial myopathies are associated with excessive neuroendocrine responses and mobilization of glucose during exercise. These responses augment ATP synthesis but result in proressive accumulation of nonoxidized substrates. Apparently, substrate mobilization and neuroendocrine responses in exercise are linked to oxidative demand rather than to oxidative capacity in working muscle.