bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral white matter changes in acquired immunodeficiency syndrome dementia: Alterations of the blood‐brain barrier
Authors: Power Christopher , Kong Pei‐Ann , Crawford Thomas O. , Wesselingh Steven , Glass Jonathan D. , McArthur Justin C. , Trapp Bruce D.
Published: January 2005

The cause of acquired immunodeficiency syndrome (AIDS) dementia, which is a frequent late manifestation of human immunodeficiency virus (HIV) infection, is unknown but radiological and pathological studies have implicated alterations in subcortical white matter. To investigate the pathological basis of these white matter abnormalities, we performed an immunocytochemical and histological analysis of subcortical white matter from AIDS patients with and without dementia, from pre‐AIDS patients (asymptomatic HIV‐seropositive patients), and from HIV‐seronegative control subjects. Reduced intensity of Luxol fast blue staining, designated “diffuse myelin pallor,” was detected in 8 of 15 AIDS dementia patients, 3 of 13 AIDS nondemented patients, and none of the pre‐AIDS patients (n = 2) or control subjects (n = 9). In contrast to Luxol fast blue staining, sections stained immunocytochemically for myelin proteins did not show decreased staining intensities in regions of diffuse myelin pallor. In addition, neither demyelinated axons nor active demyelination were detected in light and electron micrographs of subcortical white matter from brains of patients with AIDS dementia. An increase in the number of perivascular macrophages and hypertrophy of astrocytes and microglia occurred in brain sections from HIV‐infected patients. These changes were not specific to dementia or regions of diffuse myelin pallor and they occurred in both gray and white matter. In contrast to the lack of myelin pathology in AIDS dementia brains, significant accumulations of serum proteins in white matter glia were detected in the brains of 12 of 12 patients with AIDS dementia and 6 of 12 AIDS patients without dementia. Serum protein‐immunopositive cortical neurons were detected in the frontal cortex of 11 of 12 patients with AIDS dementia and 3 of 12 nondemented AIDS patients. Seronegative control subjects showed minimal serum protein immunoreactivity in both cortex and white matter. We conclude therefore that alterations in the blood‐brain barrier and not demyelination contribute to the development of AIDS dementia.
Cytochrome c oxidase reaction improves histopathological assessment of zidovudine myopathy
Authors: Chariot Patrick , Monnet Isabelle , Gherardi Romain
Published: January 2005

Zidovudine can induce a mitochondrial myopathy with ragged‐red fibers and partial cytochrome c oxidase deficency. In an attempt to improve histological assessment of zidovudine myopathy, we evaluated cytochorme c oxidase histochemical reaction in the muscle of 10 patients with biopsy‐proven zidovudine myopathy (Group 1), 10 myopathic immunodeficiency virus (HIV)‐infected patients not treated by zidovudine who had an immunohistological profile of HIV‐associated myopathy or other neuromuscular disorders (Group 3). Among zidovudine receivers, cytochrome c oxidase deficiency was found in 10 of 10 patients from Group 1 and 7 of 10 from Group 2. No cytochrome c oxidase deficiency was observed in patients not treated by zidovudine. When present, cytochrome c oxidase‐negative fibers accounted for 2 to 28% of fibers, and there was no difference for the number of cytchrome c oxidase‐negative fibers between Group 1 and Group 2. Most patients with cytochrome c oxidase deficiency that could be evaluated clinically after muscle biopsy improved after withdrawal of zidovudine (5 of 7 in Group 1,5 of 5 in Group 2). Patients who did not improve had an HIV‐associated myopathy concurrently with zidovudine myopathy. We conclude that cytochrome c oxidase reaction may be used as a reliable marker of zidovudine mitochondrial toxicity in HIV‐infected patients with muscular symptoms.
Side of onset of motor symptoms influences cognition in Parkinson's disease
Authors: Tomer Rachel , Levin Bonnie E. , Weiner William J.
Published: January 2005

Studies attempting to relate cognitive impairment to asymmetry of motor symptoms in Parkinson's disease (PD) have found contradictory results. We examined 88 patients with unilateral onset of idiopathic PD who underwent a comprehensive neuropsychological assessment, including language, visuosptial abilities, abstraction and reasoning, attention and mental tracking, set shifting, and memory. Patients whose motor signs began on the left side of the body consistently performed more poorly on the battery of cognitive measures than did patients with right‐side onset. Significant differences were found on immediate and delayed verbal recall, word retrieval, semantic verbal fluency, visuospatial analysis, abstract reasoning, attention span, and mental tracking. These differences could not be attributed to differences in the overall severity of motor symptoms at the time of cognitive assessment, or the current pattern of motor asymmetry. This finding suggests that damage to right‐hemisphere dopamine systems plays a disproportionately greater role in PD‐related cognitive decline than a presumably comparable left‐hemisphere dopamine depletion.
Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity
Authors: Przedborski Serge , Jackson‐Lewis Vernice , Muthane Uday , Jiang Hong , Ferreira Mayra , Naini Ali B. , Fahn Stanley
Published: January 2005

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa‐induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose‐ and time‐ dependent manner. In contrast, other compounds such as homovanillic acid, 3,4‐dihydroxyphenylacetic acid, and 3‐O‐methyl‐dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine. In agreement with a critical role of monoamine oxidase in this effect in vitro, we observed that noncatecholamine substrates of this enzyme such as serotonin and β‐phenylethylamine were potent inhibitors of complex I. However, autoxidation may also be involved in this process because the effect of levodopa, 6‐hydroxydopa, and 6‐hydroxydopamine on complex I activity was only partially suppressed by monoamine oxidase inhibitors. These observations demonstrate that the chronic administration of levodopa can cause alterations in mitochondrial respiratory chain activity in rats that are most likely related to an oxidative stress provoked by the increase in dopamine turnover. We suggest that this mechanism may exaggerate a mitochondrial defect already present in the brains of PD patients and thus may play a role in the progression of PD.
The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome
Authors: Santorelli Filippo M. , Shanske Sara , Macaya Alfons , DeVivo Darryl C. , DiMauro Salvatore
Published: January 2005

Twelve patients with Leigh's syndrome from 10 families harbored a T > G point mutation at nt 8993 of mtDNA. This mutation, initially associated with neurogenic weakness, ataxia, and retinitis pigmentosa, was later found to result in the Leigh phenotype when present in a high percentage. In our patients, the mutation was heteroplasmic, maternally inherited, and appeared to segregate rapidly within the pedigrees. Quantitative analysis revealed a good correlation between percentage of mutant mitochondrial genomes and severity of the clinical phenotype. The mutation was not found in > 200 patients with other mitochondrial encephalomyopathies or in controls. Mitochondrial enzyme activities were normal in all but 1 patient, and there were no ragged‐red fibers in the muscle biopsy. Lactic acidosis was present in 92% of patients. Our findings suggest that the mtDNA nt 8993 mutation is a relatively common cause of Leigh's syndrome.
Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: Experience in 23 patients
Authors: So Yuen T. , Olney Richard K.
Published: January 2005

We reviewed our experience in 23 patients with acquired immunodeficiency syndrome (AIDS) who had acute lumbosacral polyradiculopathy. The patients developed a distinctive syndrome of rapidly progressive flaccid paraparesis and areflexia that was frequently associated with sphincter disturbances. Persuasive laboratory evidence of a cytomegalovirus polyradiculopathy (polymorphonuclear pleocytosis or confirmatory cerebrospinal fluid culture) was found in 15 of the 23 patients. Treatment with ganciclovir in these patients led to clinical stabilization, although worsening during the first 2 weeks of treatment was common. Most patients with cytomegalovirus polyradiculopathy had severe residual deficits. Metastasis from systemic lymphoma accounted for the polyradiculopathy in 2 other patients. A more benign syndrome was identified in the remaining 6 patients. They generally had slower clinical progression and less severe neurological deficits at their nadir than did patients with cytomegalovirus polyradiculopathy. Unlike patients with cytomegalovirus infection, their cerebrospinal fluid showed a predominantly mononuclear pleocytosis. Moreover, spontaneous improvement without treatment was common. Our experience together with the published experience of others suggests that the acute lumbosacral polyradiculopathy in AIDS is a clinical syndrome with different etiologies and variable clinical outcome. Recognition of this heterogeneity is necessary for the management of individual patients, as well as the interpretation of treatment results.
Congenital Horner's syndrome does not alter Lisch nodule formation
Authors: Mindel Joel S. , Rubenstein Allan E. , Wallace Sibylle , Aron Alan M. , Halperin Jane
Published: January 2005

A 21‐year‐old woman with neurofibromatosis type 1 (NF‐1) had a unilateral congenital Horner's syndrome with resultant hypopigmentation of the affected iris. Lisch nodules, which are melanocytic hamartomas, were similar in number, size, and pigmentation in both eyes. The present findings suggest that the formation of Lisch nodules is not influenced by the presence or absence of sympathetic innervation of the iris.
Organ‐specific autoantigens induce transforming growth factor‐β mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis
Authors: Link Joanne , Fredrikson Sten , Söderström Mats , Olsson Tomas , Höjeberg Bo , Ljungdahl Åke , Link Hans
Published: January 2005

Multiple sclerosis (MS) is characterized by patchy accumulations of inflammatory cells combined with demyelination. There are mononuclear cells in blood and cerebrospinal fluid of patients with MS that produce interferon‐γ and interleukin‐4 in response to myelin basic protein (MBP) and proteolipid protein (PLP). Here we describe autoantigen‐induced production of transforming growth factor‐β (TGF‐β). This multifunctional cytokine has inhibitory effects on the growth, differentiation, and effector functions of activated T cells. Blood and cerebrospinal fluid cells were exposed in short‐term cultures to MBP and PLP and, after hybridization with complementary DNA oligonucleotide probes, they were evaluated for TGF‐β mRNA expression. Patients with MS had higher numbers of MBP‐ and PLP‐responsive TGF‐β mRNA expressing cells in blood compared with control patients with other neurological diseases or myasthenia gravis and a five‐ and threefold further increment in their cerebrospinal fluid. In blood of patients with myasthenia gravis, where the acetylcholine receptor (AChR) is a target for autoaggressive immunity, there were increased levels of AChR‐responsive TGF‐β mRNA expressing cells. Thymectomized myasthenia gravis patients showed higher levels of TGF‐β mRNA expressing cells compared with patients not thymectomized. Numbers of cells responding to AChR in MS and MBP in myasthenia gravis did not differ from numbers found in absence of antigen. Patients with other neurological diseases showed infrequent and low responses to MBP, PLP, and AChR. Diseases with presumed autoimmune pathogenesis are associated with organ‐specific autoantigen‐induced TGF‐β production, which is increased after thymectomy.
Botulinum toxin‐A improves the rigidity of progressive supranuclear palsy
Authors: Polo Kathleen B. , Jabbari Bahman
Published: January 2005

Botulinum toxin‐A (botox) can improve spasticity and decrease painful spasms in the affected limbs of patients with multiple sclerosis. We report significant improvement of muscle rigidity in the upper limbs after focal administration of botulinum toxin A to 2 patients with progressive supranuclear palsy.
Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa‐responsive dystonia
Authors: Takahashi Hirohide , Levine Robert A. , Galloway Matthew P. , Snow Barry J. , Calne Donald B. , Nygaard Torbjoern G.
Published: January 2005

We report cerebrospinal fluid monoamine metabolite analyses and 6‐[18F]fluoro‐1‐dopa positron emission tomography (FD‐PET) from an asymptomatic carrier of the gene for dopa‐responsive dystonia. Cerebrospinal fluid homovanillic acid, tetrahydrobiopterin, and neuropeterin concentrations were reduced in this man and in his affected children. His FD‐PET was normal, as we have previously found in dopa‐responsive dystonia. Neurological function and FD‐PET may be normal despite marked abnormality in dopamine metabolism.
Dopa‐responsive dystonia: Pathological and biochemical observations in a case
Authors: Rajput A. H. , Gibb W. R. G. , Zhong X. H. , Shannak K. S. , Kish S. , Chang L. G. , Hornykiewicz O.
Published: January 2005

We report the first neuropathological and neurochemical study of a patient with dopa‐responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa‐responsive dystonia.
Eye movements in parkinsonian syndromes
Authors: Vidailhet Marie , Rivaud Sophie , Gouider‐Khouja Neziha , Pillon Bernard , Bonnet Anne‐Marie , Gaymard Bertrand , Agid Yves , Pierrot‐Deseilligny Charles
Published: January 2005

Eye movements were recorded in 14 patients with Parkinson's disease (PD) in the “off” condition, 14 patients with striatonigral degeneration (SND), 10 patients with corticobasal degeneration (CBD), and 10 patients with progressive supranuclear palsy (PSP), with comparison with 12 control subjects. Vertical saccade paralysis was not observed in the PD, SND, and CBD groups but was present in 9 patients of 10 in the PSP group. In the PD and SND groups, horizontal reflexive visually guided saccade latency and accuracy were similar, and differed only slightly from those of controls. In the CBD group, saccade latency was significantly increased and correlated to an “apraxia score”; whereas, in the PSP group, saccade amplitude was significantly decreased. Thus, the abnormalities of both horizontal saccade parameters in the PSP group contrasted with those observed in the CBD group. The percentage of errors in the antisaccade task, an index of prefrontal dysfunction, was markedly increased only in the PSP group. The smooth pursuit gain was decreased in all groups but more severely in the PSP group. It may be concluded that saccade abnormalities are clearly different in SND, CBD, and PSP, and might help in early differential diagnosis in individual patients, but that SND cannot be differentiated from PD on the simple basis of eye movement abnormalities.
Human spongiform encephalopathy: The national institutes of health series of 300 cases of experimentally transmitted disease
Authors: Brown Paul , Gibbs C. J. , Rodgers‐Johnson Pamela , Asher David M. , Sulima Michael P. , Bacote Alfred , Goldfarb Lev G. , Gajdusek D. Carleton
Published: January 2005

We present a synthesis of clinical, neuropathological, and biological details of the National Institutes of Health series of 300 experimentally transmitted cases of spongiform encephalopathy from among more than 1,000 cases of various neurological disorders inoculated into nonhuman primates during the past 30 years. The series comprises 278 subjects with Creutzfeldt‐Jakob disease, of whom 234 had sporadic, 36 familial, and 8 iatrogenic disease; 18 patients with kuru; and 4 patients with Gerstmann‐Sträussler‐Scheinker syndrome. Sporadic Creutzfeldt‐Jakob disease, numerically by far the most important representative, showed an average age at onset of 60 years, with the freqauent early appearance of cerebellar and visual/oculomotor signs, and a broad spectrum of clinical features during the subsequent course of illness, which was usually fatal in less than 6 months. Characteristic spongiform neuropathology was present in all but 2 subjects. Microscopically visible kuru‐type amyloid plaques were found in 5% of patients with Creutzfeldt‐Jakob disease, 75% of those with kuru, and 100% of those with Gerstmann‐Sträussler‐Scheinker syndrome; brain biopsy was diagnostic in 95% of cases later confirmed at autopsy, and proteinase‐resistant amyloid protein was identified in Western blots of brain extracts from 88% of tested subjects. Experimental transmission rates were highest for iatrogenic Creutzfeldt‐Jakob disease (100%), kuru (95%), and sporadic Creutzfeldt‐Jakob disease (90%), and considerably lower for most familial forms of disease (68%). Incubation periods as well as the durations and character of illness showed great variability, even in animals receiving the same inoculum, mirroring the spectrum of clinical profiles seen in human disease. Infectivity reached average levels of nearly 105 median lethal doses/gm of brain tissue, but was only irregularly present (and at much lower levels) in tissues outside the brain, and except for cerebrospinal fluid, was never detected in bodily secretions or excretions.
Transgenic mouse brain histopathology resembles early Alzheimer's disease
Authors: Higgins L. S. , Holtzman D. M. , Rabin J. , Mobley W. C. , Cordell B.
Published: January 2005

Transgenic mice expressing the 751–amino acid form of the human amyloid precursor protein develop extracellular β‐amyloid protein (Aβ)–immunoreactive deposits that increase in frequency with age. Here we show that the appearance and histological profile of deposits in the transgenic mice closely resemble those of preamyloid deposits in the brains of young adults with Down's syndrome, who presumably have the pathology of early‐stage Alzheimer's disease. Specific monoclonal antibodies reveal that material in the deposits has the free carboxyl terminus of Aβ 1‐42, and that the deposits contain material which, by immunohistochemical analysis, apparently originates from the human β‐amyloid precursor protein (βPP) transgene. In rare cases, the transgenic mouse brains contain several different histopathological characteristics of Alzheimer lesions. These features include dense Aβ immunoreactivity which co‐localizes with gliosis and with Alz50‐immunoreactive structures resembling swollen boutons of dystrophic neurites. These observations demonstrate that the murine brain is capable of reproducing several typical features of Alzheimer histopathology.
Methylmercury poisoning: Long‐term clinical, radiological, toxicological, and pathological studies of an affected family
Authors: Davis Larry E. , Kornfeld Mario , Mooney Herbert S. , Fiedler Kurt J. , Haaland Kathleen Y. , Orrison William W. , Cernichiari Elsa , Clarkson Thomas W.
Published: January 2005

For 3 months in 1969 a family in the United States that included a pregnant mother consumed pork containing methylmercury. Children, aged 20, 13, and 8 years and a neonate, developed severe neurological signs. Twenty‐two years later, the 2 oldest had cortical blindness or constricted visual fields, diminished hand proprioception, choreoathetosis, and atentional deficits. Magnetic resonance images showed tissue loss in the calcarine and parietal cortices and cerebellar folia. The youngest had quadriplegia, blindness, and severe mental retradation until their deaths. The brain of the 8‐year‐old who died at age 30 showed cortical atrophy, neuronal loss, and gliosis, most pronounced in the paracentral and parietooccipital regions. The total mercury level in formalin‐fixed, left occipital cortex was 1,974 ng/gm as measured by atomic absorption. Regional brain mercury levels correlated with extent of brain damage. A control patient had 38.5 ng of mercury/gm in the occipital cortex. Systemic organs in the patient and a control subject had comparable mercury levels. In mercury‐intoxicated rats, we found that only 5 to 10% of total brain mercury was lost by formalin fixation. Brain inorganic mercury in the patient ranged from 82 to 100%. Since inorganic mercury crosses the blood‐brain barrier poorly, biotransformation of methyl to inorganic mercury may have occurred after methylmercury crossed the blood‐brain barrier, accounting for its persistence in brain and causing part of the brain damage.
MRI detects acute degeneration of the nigrostriatal dopamine system after MPTP exposure in hemiparkinsonian monkeys
Authors: Miletich R. S. , Bankiewicz K. S. , Quarantelli M. , Plunkett R. J. , Frank J. , Kopin I. J. , Di Chiro G.
Published: January 2005

Exposure to 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP) can cause an acute chemical toxicity resulting in a parkinsonian state in humans and nonhuman primates. We wished to assess whether the toxicity from MPTP is associated with changes on magnetic resonance images of brain structures containing dopamine neuronal processes or with disrupture of the blood‐brain barrier. Normal rhesus monkeys and monkeys at various times after being subjected to unilateral intracarotid injection of MPTP (0.4 mg/kg) were studied with magnetic resonance imaging using T1‐and T2‐weighted spin‐echo and gradient‐echo sequences. Disrupture of the blood‐brain barrier was assessed also with magnetic resonance imaging after administration of gadolinium‐diethylenetriamine pentaacetic acid. Parkinsonian symptoms contralateral to the infused carotid usually appeared within 1 day after MPTP exposure, reaching their peak severity by 7 days, when all monkeys showed clear clinical abnormalities. Magnetic resonance imaging changes developed in concomitance with the clinical signs and were characterized by increased signal intensity on T2‐weighted images as well as decreased intensity on T1‐weighted images of the ipsilateral caudate and putamen. T2 hyperintensity was also present just dorsal to the pars compacta of the substantia nigra, in the region of the proximal nigrostriatal tract. All magnetic resonance imaging changes in the next 2 weeks. There were no abnormalities at any time in the globus pallidus, nucleus accumbens, and other structures innervated by the mesocorticolimbic dopamine system. After MPTP exposure, there was no evidence of blood‐brain barrier disrupture, suggesting that vasogenic edema was an unlikely factor in the production of the observed abnormalities. The signal intensity changes on magnetic resonance images are most probably asociated with cytotoxic edema caused by the acute MPTP‐induced degeneration of nigrostriatal dopamine nerve terminals and axons. Follow‐up by magnetic resonance imaging, to 3 years after MPTP infusion, failed to reveal any residual abnormalities.
The relationship of essential tremor to other movement disorders: Report on 678 patients
Authors: Koller William C. , Busenbark Karen , Miner Kevin ,   The Essential Tremor Study Group
Published: January 2005

We examined 678 essential tremor patients in specialty, university, and private practice clinics. The mean age of patients was 65.2 years with a similar number of men and women. Six percent of patients were left‐handed. A positive family history of tremor was reported in more than 60% of patients. Alcohol ingestion was reported to decrease tremor in 74% of patients who were cognizant of the effect of alcohol on tremor. Mean age at tremor onset was 45.3 years. An earlier onset of tremor was observed in those patients having a positive family history of tremor. Tremor affected the hands in 90% of patients, head in 50%, voice in 30%, and legs and chin in 15%. Functional disability was common and impairment at work occurred in 18% Propranolol and primidone were the most frequently used drugs and were effective in 40% of patients. Six and one‐tenth percent of essential tremor patients had concomitant Parkinson's disease, 6.9% had a coexisting dystonia, and 1.8% had myoclonus. It is concluded that the frequency of Parkinson's disease in essential tremor is more than would be reported in the general population and that other movement disorders are infrequently observed in essential tremor.
Chromosomal fragility associated with familial Alzheimer's disease
Authors: Ettinger Susan , Weksler Marc E. , Zhou Xianting , Blass John , Szabo Paul
Published: January 2005

To test whether chromosomal instability is associated with familial Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for analyzing DNA breakage because of its numerous markers and ease of selection in rodent‐human hybrid cells. Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X‐linked glucose‐6‐phosphate dehydrogenase (G6PD) gene with the selected HPRT gene in hybrid cells, indicating breakage between the markers. Lower cotransfer of the more distant X‐linked gene, MIC‐2, was statistically significant in this kindred, but not in other patients with familial Alzheimer's disease. The distance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a “hot spot” for breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease. The somatic cell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced by the Alzheimer defect. A hypothesis implicating a candidate gene, C1‐THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.
Vestibular syndromes in the roll plane: Topographic diagnosis from brainstem to cortex
Authors: Brandt Thomas , Dieterich Marianne
Published: January 2005

Central vestibular syndromes may be classified according to the three major planes of action of the vestibuloocular reflex, secondary to a lesional tone imbalance in either the horizontal yaw plane or the vertical pitch or roll plane. The clinical signs, both perceptual and motor, of a vestibular tone imbalance in the roll plane are ocular tilt reaction (OTR), ocular torsion, skew deviation and tilts of the perceived visual vertical (SVV). Either complete OTR or skew torsion without head tilt indicates a unilateral peripheral deficit of otolith input or a unilateral lesion of graviceptive brainstem pathways from the vestibular nuclei (crossing midline at the pontine level) to the interstitial nucleus of Cajal (INC) in the rostral midbrain. SVV tilts are the most sensitive sign of a vestibular tone imbalance in roll and occur with peripheral or central vestibular lesions from the labyrinth to the vestibular cortex. All tilt effects, perceptual, ocular motor and postural, are ipsiversive (ipsilateral eye undermost) with unilateral peripheral or pontomedullary lesions below the crossing of the graviceptive pathways. All tilt effects are contraversive (contralateral eye undermost) with unilateral pontomesencephalic brainstem lesions and indicate involvement of the medial longitudinal fasciculus or the rostral midbrain (INC). Unilateral lesions of vestibular structures rostral to the INC typically manifest with deviations of perceived vertical without concurrent eye–head tilt. OTR in unilateral paramedian thalamic infarctions indicates simultaneous ischemia of the paramedian rostral midbrain including the INC. Unilateral lesions of the posterolateral thalamus can cause thalamic astasia and moderate ipsiversive or contraversive SVV tilts, thereby indicating involvement of the vestibular thalamic subnuclei. Unilateral lesions of the parietoinsular vestibular cortex cause moderate, mostly contraversive SVV tilts. An SVV tilt found with monocular but not with binocular viewing is typical for a trochlear or oculomotor palsy rather than a supranuclear graviceptive brainstem lesion.
Chromosome 14–encoded Alzheimer's disease: Genetic and clinicopathological description
Authors: Haltia Matti , Viitanen Matti , Sulkava Raimo , Ala‐Hurula Veli , Poyhonen Minna , Goldfarb Lev , Brown Paul , Levy Efrat , Houlde Henry , Crook Richard , Goate Alison , Clark Robert , Korenblat Kevin , Pandit Sunil , Keller Helen Donis , Llius Lena , Liu Li , Axelman Karin , Forsell Lotta , Winblad Bengt , Lannfelt Lars , Hardy John
Published: January 2005

A family of Finnish descent with very‐early‐onset Alzheimer's disease has been identified. Genetic analysis of this family eliminated the amyloid precursor protein gene as the pathogenic locus, but strongly implicated a locus on chromosome 14q23.4 between D14S52 and D14S55. The early age at onset of the disease (average, 36 years; range, 35–39 years), the rapid progression, and the early and prominent myoclonus, while they appear to be frequent findings in the chromosome 14–encoded form of Alzheimer's disease, raised the clinical suspicion of prion disease. However, sequencing the prion gene–coding region of 2 affected members of the pedigree failed to show any abnormality. Apart from the presence of modest cortical vacuolar change, the pathological features of our index patient appeared typical of Alzheimer's disease with abundant senile plaques immunoreactive with beta‐amyloid, but not with prion protein antibodies.
The apolipoprotein E ε4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations
Authors: Haan Joost , Van Broeckhoven Christine , Van Duijn Cornelia M. , Voorhoeve Els , van Harskamp Frans , van Swieten John C. , Maat‐Schieman Marion L. C. , Roos Raymund A. C. , Bakker Egbert
Published: January 2005

In 31 symptomatic and 5 asymptomatic carriers of the amyloid precursor protein (APP) gene codon 693 mutation, 10 family members without mutation, and 5 carriers of the APP gene codon 692 mutation (3 with early‐onset Alzheimer dementia, 2 with cerebral hemorrhage), a high frequency of the apolipoprotein E ϵ4 allele was found. Age at onset, age at death, occurrence of dementia, and number of strokes did not differ between APP gene mutation carriers with or without ϵ4 allele, showing that the clinical expression of these APP mutations is not influenced by the apolipoprotein E gene.
Neurological complications of organ transplantation
Authors: Patchell Roy A.
Published: January 2005

Over the last thirty years, organ transplantation has become a practical treatment option for many otherwise fatal diseases. New immunosuppressive agents, advances in tissue matching, and improvements in surgical technique have increased both the number and type of transplants performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end‐stage disease. However, these advances have come at a price. Transplant recipients are subject to numerous complications, many of which involve the nervous system. Depending on the type of organ transplanted, 30 to 60% of transplant recipients experience neurological problems. Most neurological complications, especially those related to immunosuppression, are common to all transplant types; other complications are associated predominantly with specific transplant types. This report reviews the general categories of neurological complications as well as the specific problems associated with each kind of transplant.
The shoulder–hand syndrome after stroke: A prospective clinical trial
Authors: Braus Dieter F. , Krauss Joachim K. , Strobel Jörg
Published: January 2005

Shoulder‐hand syndrome developed in 36 (27%) of 132 hemiplegic patients in a prospective study. Subluxation, paresis of the shoulder girdle, moderate spasticity, and deficits in confrontation visual field testing were the major risk factors. In a placebo‐controlled, nonblinded trial, 31 of the 36 patients became almost symptom free within 10 days' treatment with low doses of oral corticosteroids. Shoulder joint capsules taken at autopsy of 7 patients showed signs of previous trauma of the affected shoulder. In the second part of this study on another 86 patients, early awareness of potential injuries to shoulder joint structures reduced the frequency of shoulder‐hand syndrome from 27 to 8%. These clinical findings suggest that shoulder‐hand syndrome in hemiplegia is initiated by peripheral lesions. A self‐perpetuating vicious cycle may be established, followed by the clinical picture of a “reflex sympathetic dystrophy.” In the majortity of stroke patients, this clinical phenomenon seems to be preventable by avoiding shoulder trauma.
Myelin basic protein peptide specificity and T‐cell receptor gene usage of HPRT mutant T‐cell clones in patients with multiple sclerosis
Authors: Lodge Patricia A. , Allegretta Mark , Steinman Lawrence , Sriram Subramaniam
Published: January 2005

Characterization of T cells responding to autoantigens is central to understanding autoimmune disease. We have used somatic mutation at the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene as an index of T‐cell amplification in vivo. With this strategy we previously showed that myelin basic protein–reactive T cells can be isolated only from the HPRT mutant T‐cell population cultured from the peripheral blood of multiple sclerosis patients and not from normal individuals. In this study, 165 HPRT mutant and 104 wild‐type clones were examined for their reactivity to myelin basic protein and overlapping peptides of myelin basic protein. Five HPRT mutant clones that recognized myelin basic protein and myelin basic protein peptides along with three clones that responded to myelin basic protein peptide alone were isolated. All but one of the eight clones recognized peptides derived from the carboxy terminus of myelin basic protein (p84‐168). Sequence analysis showed heterogeneous expression of T‐cell receptor Vα and Vβ genes and CDR3s. These studies showed that in vivo amplified autoimmune T cells from patients with long‐standing disease use diverse T‐cell receptor elements in the recognition of C‐terminal myelin basic protein peptides.
Chronic relapsing axonal neuropathy: A first case report
Authors: Chroni Elisabeth , Hall Susan M. , Hughes Richard A. C.
Published: January 2005

A relapsing and remitting axonal polyneuropathy developed in a woman at age 47. Serial electrophysiological studies showed that the amplitudes of compound muscle action potentials and sensory action potentials were reduced but conduction velocities were only midly slowed. F wave latencies were normal and there was no evidence of conduction block. Two sural nerve biopsy specimens showed changes supportive of axonal neuropathy. Repeated responses to prednisolone alone and later prednisolone and azathioprine suggested that inflammatory, possibly autoimmune, processes were important in this case of chronic relapsing axonal neuropathy.
Apolipoprotein E genotypes in Parkinson's disease with and without dementia
Authors: Koller William C. , Glatt Sander L. , Hubble Jean P. , Paolo Anthony , Tröster Alexander I. , Schmidt Karen , Karst Annette , Handler Michael S. , Horvat Rebecca T. , Martin Coleman , Wijsman Ellen M. , Yu Chang‐En , Schellenberg Gerard D.
Published: January 2005

The apolipoprotein E gene (Apo E) type 4 allele is a genetic risk factor influencing the development and age of onset of Alzheimer's disease. Because Parkinson's disease shares many characteristics of Alzheimer's disease, we studied the frequencies of Apo E genotypes in a cohort of 52 Parkinson's disease patients with dementia and 61 patients without dementia. Dementia was determined per National Institute of Neurological and Communicative Disorders and Stroke criteria and Mattis Dementia Rating Scale (DRS) < 126. Normal cognition was defined as DRS > 132. Apo E genotype and allele frequencies did not differ between demented and nondemented parkinsonian patients. Neither group's genotype and allele frequencies differed from that of a nondemented population of 78 controls. We conclude that the Apo E ε4 allele influences neither the development of Parkinson's disease nor the dementia associated with Parkinson's disease nor the dementia associated with Parkinson's disease.
Damage to dopamine systems differs between parkinson's disease and alzheimer's disease with parkinsonism
Authors: Murray Angela M. , Weihmueller Fredric B. , Marshall John F. , Hurtig Howard I. , Gottleib Gary L. , Joyce Jeffrey N.
Published: January 2005

Parkinsonism occurs in approximately 35 to 40% of patients with Alzheimer's disease (AD) even with little or no neuronal degeneration in the substantia nigra, which in idiopathic Parkinson's disease (PD) results in the severe loss of striatal dopamine transporter sites. It is not known if there is a loss of striatal dopamine transporter sites in AD with coexistent parkinsonism (AD/parkinsonism). We quantified the pattern of these sites in the striatum and midbrain of patients with the clinical diagnosis of PD, AD, and AD/parkinsonism in comparison with a group of age‐matched control subjects. We also quantified the number of D2 receptors and the levels of tyrosine hydroxylase in the substantia nigra and ventral tegmental area of same groups. The results showed that in AD the loss of dopamine transporter sites was restricted to the nucleus accumbens. The loss of these sites in the AD/parkinsonism group was more extensive than in the AD group, with the most severe losses in the rostral caudate and putamen and least in the caudal caudate and putamen. While the PD group showed an equally severe reduction in numbers of sites, the caudal to rostral gradient of loss differed from that in the AD/parkinsonism group. The PD group also showed a marked loss of dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors (located on dopamine neurons) in the substantia nigra and ventral tegmental area. In contrast, no reductions in dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors were observed in the substantia nigra and ventral tegmental area of the AD or AD/parkinsonism groups. Thus, the loss of striatal dopamine transporter sites in AD/parkinsonism may be related to the clinical parkinsonian symptoms. However, the loss is not simply the result of neuronal degeneration in the substantia nigra, but must derive from other processes.
Detection of silent cerebellar lesions by increasing the inertial load of the moving hand
Authors: Manto M. , Godaux E. , Jacquy J.
Published: January 2005

In a previous study, we analyzed the hypermetria of wrist flexion movements in patients with a cerebellar syndrome. We found that hypermetria augmented when the inertial load of the moving hand was artificially increased. In the present study, we applied the same protocol to patients with an apparently normal neurological examination, in spite of a cerebellar lesion documented by magnetic resonance imaging. In all of these patients, the addition of a mass to the moving hand caused the appearance of a hypermetria. This lack of adaptation of fast and accurate movements to an increased inertia thus appears as a new diagnostic tool enabling the detection of silent cerebellar lesions.
Cerebral oxygen supply and utilization during infant cardiac surgery
Authors: Plessis Adre J. Du , Newburger Jane , Jonas Richard A. , Hickey Paul , Naruse Hiroo , Tsuji Miles , Walsh Amy , Walter Gene , Wypij David , Volpe Joseph J.
Published: January 2005

The survival of infants with congenital heart disease has improved dramatically. However, the incidence of neurological injury in infants surviving cardiac surgery remains considerable. These neurological sequelae are attributable at least in part to hypoxia‐ischemia/reperfusion, which inevitably accompanies infant heart surgery with deep hypothermia, cardiopulmonary bypass, and circulatory arrest. To begin to identify mechanisms of brain injury during infant cardiac surgery, we used near‐infrared spectroscopy to study the relationship between cerebral intravascular (hemoglobin) and mitochondrial (cytochrome aa3) oxygenation in 63 infants (aged 1 day to 9 months) undergoing deep hypothermic repair of congenital heart defects, throughout the intraoperative period. Moreover, we assessed the effect of postnatal age on these changes. The cerebral concentration of oxidized cytochrome aa3 decreased from the onset of deep hypothermic cardiopulmonary bypass, despite apparent abundant intravascular oxygenation manifested by a simultaneous increase in the cerebral concentration of oxyhemoglobin. During this interval infants older than 2 weeks had a greater decrease in oxidized cytochrome aa3 than did infants 2 weeks old or younger. During deep hypothermic circulatory arrest, cerebral levels of oxidized cytochrome aa3 remained depressed while those of oxyhemoglobin declined. With reperfusion following circulatory arrest, the recovery of oxidized cytochrome aa3 was delayed, despite a rapid recovery of intravascular oxygenation (HbO2). After rewarming and 60 minutes of reperfusion, only 46% of infants recovered to the baseline level of cerebral oxidized cytochrome aa3. These findings demonstrate a paradoxical dissociation of changes in intravascular and mitochondrial oxygenation during hypothermic cardiopulmonary bypass; a pronounced decrease of mitochondrial oxygenation is established during induction of hypothermia and a delay in recovery of mitochondrial oxygenation occurs following circulatory arrest. These effects were more pronounced in infants older than 2 weeks than in younger infants. The data suggest potentially deleterious impairments of intrinsic mitochondrial function or of delivery of intravascular oxygen to the mitochondrion or both, effects previously undetected and apparently influenced by cerebral maturation.
Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: A new model for multiple sclerosis
Authors: Massacesi Luca , Genain Claude P. , Lee‐Parritz David , Letvin Norman L. , Canfield Donald , Hauser Stephen L.
Published: January 2005

A chronic relapsing‐remitting form of experimental autoimmune encephalomyelitis was induced in the common marmoset Callithrix jacchus following a single immunization with human white matter. Individual animals in this species are born as natural bone marrow chimeras, allowing transfer of functional T‐cell populations between genetically distinct siblings. The acute disease was characterized clinically by mild neurological signs. Pathologically, the disease was characterized by perivascular mononuclear cell infiltrates, large foci of primary demyelination, and reactive astrogliosis. No animal displayed hemorrhagic‐necrotic lesions or polymorphonuclear cell infiltrates characteristic of other acute forms of primate experimental autoimmune encephalomyelitis. A late spontaneous relapse occurred in each of 2 animals followed for 3 to 12 months subsequent to recovery from the acute attack. In these animals, chronic lesions consisted of mononuclear cell infiltrates within large sharply defined areas of demyelination and astrogliosis, and resembled active plaques of chronic multiple sclerosis. Proliferative responses to myelin basic protein but not to myelin proteolipid protein were present in peripheral blood lymphocytes of immunized animals. Furthermore, myelin basic protein–reactive T‐cell lines derived from immunized donors induced clinical signs of experimental autoimmune encephalomyelitis when adoptively transferred into a sibling, indicating that myelin basic protein–reactive T cells can induce disease in this species. Because of its clinical and pathological similarity to human multiple sclerosis and the ability to adoptively transfer experimental autoimmune encephalomyelitis, this model system should prove useful in the analysis of the immunological mechanisms responsible for autoimmune demyelination in outbred primates.
The role of hypoventilation in a sheep model of epileptic sudden death
Authors: Johnston S. Claiborne , Horn Jan K. , Valente John , Simon Roger P.
Published: January 2005

Unexpected sudden death is a common event in otherwise healthy epileptics, though its etiology has remained unclear. Many authors have suggested cardiac arrhythmias as the cause, and limited data in humans and animal studies have supported this. However, autopsy series in humans have shown pulmonary edema, a phenomenon not compatible with a sudden arrhythmic death, as a possible cause. We developed a model of status epilepticus in unanesthetized, chronically instrumented sheep in which sudden death and pulmonary edema occur. Catecholamine levels and seizure type and duration did not differ between animals dying suddenly and those surviving. Benign arrhythmias were generated in all animals; in no case did an arrhythmia account for the death of an animal. Striking hypoventilation was demonstrated in the sudden death group but not in the surviving animals. Differences in peak left atrial and pulmonary artery pressures, and in extravascular lung water were also demonstrated; pulmonary edema did not account for the demise of the sudden death animals. Thus, our model of epileptic sudden death supports a role of central hypoventilation in the etiology of sudden unexpected death and confirms the association with pulmonary edema. The importance of arrhythmia in its pathogenesis is not confirmed.