25: Muscle Nerve. 2006 May;33(5):701-6.
Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation
mimicking a myopathy.
Stewart HG, Mackenzie IR, Eisen A, Brannstrom T, Marklund SL, Andersen PM.
Department of Clinical Neurosciences, Umea University, SE-90785 Umea, Sweden.
heather.stewart@neuro.umu.se
A 71-year-old woman with a family history of amyotrophic lateral sclerosis (ALS)
was investigated for symmetrical, proximal limb and abdominal muscle weakness.
Initial examination showed mild proximal muscle weakness in the arms and legs,
slightly elevated serum creatine kinase (CK) level, and normal electromyographic
(EMG) findings. A myopathy was the presumed diagnosis. Over the next year,
weakness became severe and tendon reflexes became unelicitable; no upper motor
signs were present. EMG then showed acute and chronic denervation and a muscle
biopsy showed target fibers and grouped atrophy. DNA analysis revealed a G72C
CuZn-superoxide dismutase (SOD1) mutation. Fasciculations were absent throughout
the disease. The patient died 53 months after symptom onset and autopsy revealed
loss of lower motor neurons (LMN) and SOD1-positive inclusions. This case
expands the phenotypic spectrum of ALS associated with SOD1 mutations to include
presenting features that mimic a myopathy.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 16435343 [PubMed - indexed for MEDLINE]
24: J Physiol Paris. 2006 Mar-May;99(2-3):211-20. Epub 2006 Jan 30.
Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis.
Durand J, Amendola J, Bories C, Lamotte d'Incamps B.
CNRS UMR 6196, Plasticite et Physiopathologie de la Motricite, Universite de la
Mediterranee, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
durand@dpm.cnrs-mrs.fr
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative and fatal human
disorder characterized by progressive loss of motor neurons. Transgenic mouse
models of ALS are very useful to study the initial mechanisms underlying this
neurodegenerative disease. We will focus here on the earlier abnormalities
observed in superoxide dismutase 1 (SOD1) mutant mice. Several hypotheses have
been advanced to explain the selective loss of motor neurons such as apoptosis,
neurofilament disorganisation, oxidative stress, mitochondrial dysfunction,
astrogliosis and excitotoxicity. Although disease onset appears at adulthood,
recent studies have detected abnormalities during embryonic and postnatal
maturation in animal models of ALS. We reported that SOD1(G85R) mutant mice
exhibit specific delays in acquiring sensory-motor skills during the first week
after birth. In addition, physiological measurements on in vitro spinal cord
preparations reveal defects in evoking rhythmic activity with
N-methyl-DL-aspartate and serotonin at lumbar, but not sacral roots. This is
potentially significant, as functions involving sacral roots are spared at late
stages of the disease. Moreover, electrical properties of SOD1 lumbar
motoneurons are altered as early as the second postnatal week when mice begin to
walk. Alterations concern the input resistance and the gain of SOD1 motoneurons
which are lower than in control motoneurons. Whether or not the early changes in
discharge firing are responsible for the uncoupling between motor axon terminals
and muscles is still an open question. A link between these early electrical
abnormalities and the late degeneration of motoneurons is proposed in this short
review. Our data suggest that ALS, as other neurodegenerative diseases, could be
a consequence of an abnormal development of neurons and network properties. We
hypothesize that the SOD1 mutation could induce early changes during the period
of maturation of motor systems and that compensatory mechanisms-linked to
developmental spinal plasticity-might explain the late onset of the disease.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16448809 [PubMed - indexed for MEDLINE]
23: J Neurol Sci. 2006 May 15;244(1-2):41-58. Epub 2006 Feb 17.
Widespread loss of neuronal populations in the spinal ventral horn in sporadic
motor neuron disease. A morphometric study.
Stephens B, Guiloff RJ, Navarrete R, Newman P, Nikhar N, Lewis P.
Neuromuscular Unit, West London Neurosciences Centre, Imperial College London,
UK.
The cytopathology and loss of neurons was studied in 7670 neurons from the
ventral horn of the third lumbar segment of the spinal cord of six sporadic
motor neuron disease (MND) patients compared with 7568 neurons in seven age
matched control subjects. A modified Tomlinson et al. [Tomlinson BE, Irving D,
Rebeiz JJ. Total numbers of limb motor neurones in the human lumbosacral cord
and an analysis of the accuracy of various sampling procedures. J Neurol Sci
1973;20:313-27] sampling procedure was used for neuronal counts. The ventral
horn was divided in quadrants. Neuronal populations were also classified by the
maximum cell diameter through the nucleolus. There was widespread loss of
neurons in all quadrants of the ventral horn in MND. Size distribution
histograms showed similar neuron loss across all populations of neurons. The
dorsomedial quadrant contains almost exclusively interneurons and the
ventrolateral quadrant mostly motor neurons. The cytopathology of neurons in the
dorsomedial quadrant and of large motorneurons in the ventrolateral quadrant MND
was similar. In the dorsomedial quadrant, neuron loss (56.7%) was similar to the
loss of large motor neurons in the ventrolateral quadrant (64.4%). The loss of
presumed motor neurons and interneurons increased with increased disease
duration. There was no evidence that loss of presumed interneurons occurred
prior, or subsequent, to loss of motor neurons. We conclude that, in sporadic
MND, all neuronal populations in the ventral horn are affected and that
interneurons are involved to a similar extent and in parallel with motor
neurons, as reported in the G86R transgenic mouse model of familial MND. The
increasing evidence of loss of neurons other than motor neurons in MND suggests
the need for revising the concept of selective motor neuron vulnerability.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16487542 [PubMed - indexed for MEDLINE]
22: Neurosci Lett. 2006 May 15;399(1-2):157-61. Epub 2006 Feb 20.
Differential expression of the NMDA NR2B receptor subunit in motoneuron
populations susceptible and resistant to amyotrophic lateral sclerosis.
Fuller PI, Reddrop C, Rodger J, Bellingham MC, Phillips JK.
Division of Health Sciences, Murdoch University, South St, Murdoch, Perth 6150,
WA, Australia.
We have compared the expression pattern of NMDA receptor subunits (NR1 and
NR2A-D) and NR1 splice variants (NR1-1a/1b,-2a/2b,-3a/3b,-4a/4b) in motor neuron
populations from adult Wistar rats that are vulnerable (hypoglossal, XII) or
resistant (oculomotor, III) to death in amyotrophic lateral sclerosis (ALS). The
major finding was higher levels of expression of the NR2B subunit in the
hypoglossal nucleus. Quantitative real-time PCR showed that NR1 was expressed at
a greater level than any of the NR2 subunits (>15 fold greater, P<or=0.05, n =
11 animals), while conventional RT-PCR showed no difference in NR1 splice
variant expression (with all variants except NR1-3 detected in both nuclei; n =
6 animals). Within III, the NR2B subunit was expressed 1.7 to 2.6-fold lower
than the other NR2 subunits (P<or=0.05), while in XII all NR2 subunits were
expressed at equal levels. When comparing levels between the 2 nuclei, mRNA for
the NR2B subunit was expressed 2.1-fold higher in XII compared to III
(P<or=0.05), while their was no difference in mRNA expression for the other
subunits. Immunohistochemical analysis confirmed greater NR2B protein levels
within individual hypoglossal neurons compared to oculomotor neurons (1.8-fold
greater, P<or=0.05, n = 5 animals). Lower expression of the NMDA NR2B subunit
may constitute one factor conferring protection to oculomotor neurons in ALS.
PMID: 16490316 [PubMed - indexed for MEDLINE]
21: Neurosci Lett. 2006 May 22;399(3):186-90. Epub 2006 Feb 21.
Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS
patients.
Cova E, Cereda C, Galli A, Curti D, Finotti C, Di Poto C, Corato M, Mazzini G,
Ceroni M.
Laboratory of Experimental Neurobiology, IRCCS, Foundation C. Mondino Institute
of Neurology, via Mondino, 2, 27100 Pavia, Italy. emanuela.cova@mondino.it
Markers of oxidative stress have been found in spinal cord, cortex,
cerebrospinal fluid, and plasma of SALS patients. Mitochondrial and calcium
metabolism dysfunction were also found in peripheral lymphocytes from SALS
patients. In this study, we demonstrate that lymphocytes from SALS patients are
more prone to undergo alteration of cell membrane integrity both in basal
conditions and following oxidative stress induced by H2O2 treatment. The
expression of the antioxidant proteins, Bcl-2, SOD1 and catalase in basal
conditions, was significantly lower in lymphocytes from SALS patients than in
lymphocytes from age and sex matched controls. Exposure to H2O2 induced a
time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Conversely,
the levels of these proteins remained unchanged in SALS lymphocytes even after
18 h stress. Catalase expression was not significantly modified by oxidative
stress. Our results demonstrate that two factors involved in the genesis and/or
progression of the familial form of the disease with SOD1 mutation are altered
also in the sporadic form of ALS and suggest that the oxidative stress
protection pathway is deregulated in lymphocytes from ALS patients.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16495003 [PubMed - indexed for MEDLINE]
20: Muscle Nerve. 2006 May;33(5):677-90.
Cortical versus spinal dysfunction in amyotrophic lateral sclerosis.
Attarian S, Vedel JP, Pouget J, Schmied A.
Department of Neurology and Neuromuscular Diseases, CHU La Timone, 264 rue
Saint-Pierre, 13385 Marseille, France. sattarian@@ap-hm.fr
Little is known about the possible link between cortical and spinal motor neuron
dysfunction in amyotrophic lateral sclerosis (ALS). We correlated the
characteristics of the responses to transcranial magnetic stimulation (TMS) with
the electromechanical properties and firing pattern of single motor units (MUs)
tested in nine ALS patients, three patients with Kennedy's disease, and 15
healthy subjects. In Kennedy's disease, 19 of 22 MUs were markedly enlarged with
good electromechanical coupling and discharged with great variability. Their
excitatory responses increased with MU size. In ALS, 17 of 34 MUs with
excitatory responses behaved as in Kennedy's disease. By contrast, 28 MUs with
nonsignificant responses showed poor electromechanical coupling and high firing
rates, whereas 28 MUs with inhibitory responses showed moderate functional
alterations. This result indicates that in ALS as in Kennedy's disease,
sprouting of corticospinal axons may occur on surviving motoneurons. A clear
relationship exists between the responsiveness of MUs to TMS and their
functional state.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16506152 [PubMed - indexed for MEDLINE]
19: Biochem Biophys Res Commun. 2006 May 12;343(3):719-30. Epub 2006 Mar 9.
Alteration of familial ALS-linked mutant SOD1 solubility with disease
progression: its modulation by the proteasome and Hsp70.
Koyama S, Arawaka S, Chang-Hong R, Wada M, Kawanami T, Kurita K, Kato M, Nagai
M, Aoki M, Itoyama Y, Sobue G, Chan PH, Kato T.
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology,
Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585,
Japan.
Accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) occurs in patients
with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify
the conversion of SOD1 from a normally soluble form to insoluble aggregates, we
investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1
transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were
sequentially separated into Triton X-100-insoluble/sodium dodecyl sulfate
(SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords,
the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble
dimers were significantly elevated before motor dysfunction onset. In COS-7
cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated
the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16563356 [PubMed - indexed for MEDLINE]
18: Biochem Biophys Res Commun. 2006 May 12;343(3):793-8. Epub 2006 Mar 10.
Colivelin prolongs survival of an ALS model mouse.
Chiba T, Yamada M, Sasabe J, Terashita K, Aiso S, Matsuoka M, Nishimoto I.
Department of Pharmacology, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku-ku, Tokyo 160-8582, Japan.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease for
which there is no sufficiently effective therapy. We have reported in our earlier study that intracerebroventricular (i.c.v.) injection of activity-dependent neurotrophic factor (ADNF) improves motor performance of G93A-SOD1 transgenic mice without significant prolongation in survival. Here, we found that i.c.v. injection of a synthetic hybrid peptide named Colivelin composed of ADNF and AGA-(C8R)HNG17, a potent derivative of Humanin that is a bioactive peptide with anti-Alzheimer's disease activity, dose-dependently improved motor performance and prolonged survival of ALS mice. Histological analysis, performed at the age of 120 days, demonstrated increased motoneuronal survival in spinal cords of Colivelin-treated mice as compared with saline- or ADNF-treated mice, indicating that Colivelin is a promising neurotrophic peptide
for treatment of ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16564029 [PubMed - indexed for MEDLINE]
17: J Biol Chem. 2006 May 19;281(20):14076-84. Epub 2006 Mar 27.
Caspase-3 cleaves and inactivates the glutamate transporter EAAT2.
Boston-Howes W, Gibb SL, Williams EO, Pasinelli P, Brown RH Jr, Trotti D.
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease,
Harvard Medical School, Charlestown, Massachusetts 02129, USA.
EAAT2 is a high affinity, Na+-dependent glutamate transporter with predominant
astroglial localization. It accounts for the clearance of the bulk of glutamate
released at central nervous system synapses and therefore has a crucial role in
shaping glutamatergic neurotransmission and limiting excitotoxicity. Caspase-3
activation and impairment in expression and activity of EAAT2 are two distinct
molecular mechanisms occurring in human amyotrophic lateral sclerosis (ALS) and
in the transgenic rodent model of the disease. Excitotoxicity caused by
down-regulation of EAAT2 is thought to be a contributing factor to motor neuron
death in ALS. In this study, we report the novel evidence that caspase-3 cleaves
EAAT2 at a unique site located in the cytosolic C-terminal domain of the
transporter, a finding that links excitotoxicity and activation of caspase-3 as
converging mechanisms in the pathogenesis of ALS. Caspase-3 cleavage of EAAT2
leads to a drastic and selective inhibition of this transporter. Heterologous
expression of mutant SOD1 proteins linked to the familial form of ALS leads to
inhibition of EAAT2 through a mechanism that largely involves activation of
caspase-3 and cleavage of the transporter. In addition, we found evidence in
spinal cord homogenates of mutant SOD1 ALS mice of a truncated form of EAAT2,
likely deriving from caspase-3-mediated proteolytic cleavage, which appeared
concurrently to the loss of EAAT2 immunoreactivity and to increased expression
of activated caspase-3. Taken together, our findings suggest that caspase-3
cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate
uptake in mutant SOD1-linked ALS.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16567804 [PubMed - indexed for MEDLINE]
16: FASEB J. 2006 May;20(7):1003-5. Epub 2006 Mar 29.
Increasing cannabinoid levels by pharmacological and genetic manipulation delay
disease progression in SOD1 mice.
Bilsland LG, Dick JR, Pryce G, Petrosino S, Di Marzo V, Baker D, Greensmith L.
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of
Neurology, University College London, Queen Square, London, WC1N 3BG, United
Kingdom.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder
characterized by the selective loss of motoneurons in the spinal cord, brain
stem, and motor cortex. However, despite intensive research, an effective
treatment for this disease remains elusive. In this study we show that treatment
of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid,
WIN55,212-2, significantly delays disease progression. Furthermore, genetic
ablation of the Faah enzyme, which results in raised levels of the
endocannabinoid anandamide, prevented the appearance of disease signs in
90-day-old SOD1G93A mice. Surprisingly, elevation of cannabinoid levels with
either WIN55,212-2 or Faah ablation had no effect on life span. Ablation of the
CB1 receptor, in contrast, had no effect on disease onset in SOD1(G93A) mice but
significantly extended life span. Together these results show that cannabinoids
have significant neuroprotective effects in this model of ALS and suggest that
these beneficial effects may be mediated by non-CB1 receptor mechanisms.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16571781 [PubMed - indexed for MEDLINE]
15: J Clin Epidemiol. 2006 May;59(5):541-3. Epub 2006 Mar 14.
Dimensional structure of the SF-36 in neurological patients.
Dallmeijer AJ, Dekker J, Knol DL, Kalmijn S, Schepers VP, de Groot V, Lindeman
E, Beelen A, Lankhorst GJ; on behalf of the FuPro study group.
Department of Rehabilitation Medicine, VU University Medical Center, P.O. Box
7057, Amsterdam 1007 MB, The Netherlands. A.Dallmeijer@vumc.nl
Publication Types:
Research Support, Non-U.S. Gov't
Validation Studies
PMID: 16632144 [PubMed - indexed for MEDLINE]
14: J Anesth. 2006;20(2):109-12.
Effects of lumbar sympathetic ganglion block for a patient with amyotrophic lateral sclerosis (ALS).
Kitoh T, Kobayashi K, Ina H, Ofusa Y, Otagiri T, Tanaka S, Ono K.
Department of Anesthesiology and Resuscitology, Shinshu University School of
Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
A 59-year-old man with amyotrophic lateral sclerosis (ALS) received lumbar epidural and sympathetic ganglion blocks to increase regional blood flow and improve his clinical symptoms. After a lumbar epidural block (0.5% mepivacaine), the skin temperature of his affected lower extremities rose by 7.0 degrees C and became close to that of the intact side, and the distance he was able to walk with his cane increased from 2 to 8 m. The clinical effects produced by the lumbar sympathetic ganglion block (99.5% alcohol) were sustained for approximately 8 weeks after the first block and for approximately 6 weeks after the second block. There were no particular adverse effects or complications
associated with these nerve block procedures. Epidural and sympathetic ganglion
blocks for an ALS patient, albeit their effects are of a transient nature, may improve related clinical symptoms, and were thought to play a contributory role in improving our patient's quality of life.
Publication Types:
Case Reports
PMID: 16633768 [PubMed - indexed for MEDLINE]
13: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7148-53. Epub 2006 Apr 24.
Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.
Furukawa Y, Fu R, Deng HX, Siddique T, O'Halloran TV.
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston,
IL 60208, USA.
Point mutations in Cu, Zn-superoxide dismutase (SOD1) cause a familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Aggregates of mutant SOD1 proteins are observed in histopathology and are invoked in several proposed mechanisms for motor neuronal death; however, the significant stability and activity of the mature mutant proteins are not readily explained in such models. Recent biochemical studies suggest that it is the immature disulfide-reduced forms of the familial ALS mutant SOD1 proteins that play a critical role; these forms tend to misfold, oligomerize, and readily undergo incorrect disulfide formation upon mild oxidative stress in vitro. Here we provide physiological support for this mechanism of aggregate formation and show that a significant fraction of the insoluble SOD1 aggregates in spinal cord of the ALS-model transgenic mice contain multimers cross-linked via intermolecular disulfide bonds. These insoluble disulfide-linked SOD1 multimers are found only in the spinal cord of symptomatic transgenic animals, are not observed in unafflicted tissue such as brain cortex and liver, and can incorporate WT SOD1 protein. The findings provide a biochemical basis for a pathological hallmark of this disease; namely, incorrect disulfide cross-linking of the immature, misfolded mutant proteins leads to insoluble aggregates.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16636274 [PubMed - indexed for MEDLINE]
12: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7142-7. Epub 2006 Apr 24.
Conversion to the amyotrophic lateral sclerosis phenotype is associated with
intermolecular linked insoluble aggregates of SOD1 in mitochondria.
Deng HX, Shi Y, Furukawa Y, Zhai H, Fu R, Liu E, Gorrie GH, Khan MS, Hung WY,
Bigio EH, Lukas T, Dal Canto MC, O'Halloran TV, Siddique T.
Davee Department of Neurology and Clinical Neurosciences, Northwestern
University Feinberg School of Medicine, Tarry Building, Room 13-715, 303 East
Chicago Avenue, Chicago, IL 60611, USA. h-deng@northwestern.edu
Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in
double-transgenic mice. This conversion, observed in the mitochondrial fraction
of the spinal cord, involved formation of insoluble SOD1 dimers and multimers
that are crosslinked through intermolecular disulfide bonds via oxidation of
cysteine residues in SOD1. Our data thus show a molecular mechanism by which
SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16636275 [PubMed - indexed for MEDLINE]
11: Brain Res Bull. 2006 May 15;69(5):489-94. Epub 2006 Mar 27.
Subcortical motor plasticity in patients with sporadic ALS: An fMRI study.
Tessitore A, Esposito F, Monsurro MR, Graziano S, Panza D, Russo A, Migliaccio
R, Conforti FL, Morrone R, Quattrone A, Di Salle F, Tedeschi G.
Second Division of Neurology, Second University of Naples, Piazza Miraglia, 2,
Naples 80131, Italy.
OBJECTIVE: To address the potential contribution of subcortical brain regions in
the functional reorganization of the motor system in patients with sporadic ALS
(sALS) and to investigate whether functional changes in brain activity are different in sALS patients with predominant upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction. METHODS: We studied 16 patients with sALS and 13 healthy controls, using BOLD-fMRI, while they performed a simple visually paced motor task. Seven patients had definite clinical UMN signs while nine patients had prevalent clinical and electrophysiological LMN involvement. fMRI data were analyzed with Brain Voyager QX. RESULTS: Task-related functional changes were identified in motor cortical regions in both patients and healthy controls. Direct group comparisons revealed relatively decreased BOLD fMRI responses in left sensorimotor cortex, lateral premotor area, supplementary motor area and right posterior parietal cortex (p < 0.05 corrected) and relatively increased responses in the left anterior putamen (p < 0.001 uncorrected) in sALS patients. Additional analyses between the two patients subgroups demonstrated significant BOLD fMRI response differences in the anterior cingulate cortex and right
caudate nucleus (p < 0.001 uncorrected) with more robust activation of these areas in patients with greater UMN burden. Importantly, there were no significant differences in performance of the motor task between sALS patients and controls as well as between sALS patient subgroups. CONCLUSIONS: Our data demonstrate a different BOLD fMRI pattern between our sALS patients and healthy controls even during simple motor behavior. Furthermore, patients with sALS and greater UMN involvement show a different reorganization of the motor system compared to sALS patients with greater LMN dysfunction.
PMID: 16647577 [PubMed - indexed for MEDLINE]
10: Clin Chem Lab Med. 2006;44(5):589-93.
Alterations in anti-oxidative defence enzymes in erythrocytes from sporadic amyotrophic lateral sclerosis (SALS) and familial ALS patients.
Nikolic-Kokic A, Stevic Z, Blagojevic D, Davidovic B, Jones DR, Spasic MB.
Department of Physiology, Institute for Biological Research Sinisa Stankovic, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia and Montenegro.
san@ibiss.bg.ac.yu
BACKGROUND: Overproduction of nitric oxide (NO) and hydrogen peroxide (H(2)O(2))
may be an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS). Owing to their ability to permeate through biological membranes, excess NO and H(2)O(2) may be present in the media surrounding motor neurones. Anti-oxidative defence enzymes (ADEs) in erythrocytes are capable of detoxifying reactive oxygen species (produced endogenously or exogenously), but may also be structurally modified and inactivated by reactive oxygen and nitrogen species. Both balanced and coordinated ADE activities are of utmost importance for their correct physiological function. METHODS: We determined activity of the following ADEs: copper-zinc superoxide dismutase (CuZn SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) in erythrocytes from sporadic ALS patients [SALS (-/+)], familial ALS patients with the Leu144Phe mutation in the SOD1 gene [FALS (+/+)], asymptomatic carriers with the Leu144Phe mutation in the SOD1 gene (+/-), and control subjects (-/-). We also examined the in vitro effect of diethyldithiocarbamate (DDC) on CuZn SOD activity in erythrocytes from
FALS patients, SALS patients and control subjects. RESULTS: The influence of the
Leu144Phe mutation and/or disease was apparent for ADE activities measured in
all three patient groups. The SOD1 gene mutation decreased CuZn SOD and GSH-Px
activity (two-way ANOVA, significant mutation effect). We noted that the disease also contributed to decreased CuZn SOD activity in SALS patients in comparison with the control group (two-way ANOVA, mutation and disease effect). The disease also influenced CAT and GR activity. CAT activity was decreased in both SALS and FALS patients. In all three patient groups, GR activity was higher than in the control group. Finally, DDC inhibited CuZn SOD activity in erythrocytes from control subjects, FALS (Leu144Phe) patients and SALS patients; however, its effect was more pronounced and significant in FALS patients. CONCLUSIONS: Changes in erythrocyte ADE activities suggest that oxidative stress, involved in the motor neurone pathogenesis of SALS and FALS, also has systemic effects. Differences in ADE systems between the study groups revealed the presence of different types of oxidative pressure, indicating the potential additional benefit of individually designed anti-oxidant cocktail therapies.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16681429 [PubMed - indexed for MEDLINE]
9: Neurol Clin. 2006 May;24(2):233-65.
Neuromuscular disorders in clinical practice: case studies.
Bhatt JR, Pascuzzi RM.
Department of Neurology, Indiana University School of Medicine, 1120 South
Drive, Indianapolis, IN 46202, USA.
Neuromuscular disorders represent a large group of highly varied and interesting
clinical disorders, many of which have major general medical manifestations.
These disorders can be diagnosed largely based on the patient's history and
physical examination with a little help from modern technology. Despite the
outdated belief that neurologic conditions are diagnosed but rarely treatable,
all cases discussed herein represent disorders for which there are extensive
options and opportunities for meaningful management. These 16 brief case
overviews challenge and refresh diagnostic skills and provide the framework for
selected comments regarding management options.
Publication Types:
Case Reports
PMID: 16684631 [PubMed - indexed for MEDLINE]
8: Chest. 2006 May;129(5):1322-9.
Supramaximal inflation improves lung compliance in subjects with amyotrophic lateral sclerosis.
Lechtzin N, Shade D, Clawson L, Wiener CM.
Department of Internal Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD 21205, USA. nlechtz@jhmi.edu
RATIONALE: Lung compliance has been found to be low in patients with chronic diaphragmatic weakness or paralysis but has not been well-studied in patients with amyotrophic lateral sclerosis (ALS). Noninvasive positive-pressure ventilation (NPPV) prolongs survival in ALS patients but may also have additional beneficial effects. OBJECTIVES: This study evaluated static expiratory lung compliance (CL) in subjects with ALS and determined the effect of lung inflation with supramaximal inflation on CL. DESIGN: This was a prospective trial comparing CL before and after supramaximal lung inflation via mouthpiece-delivered positive pressure. SETTING: A single university medical
center with an multidisciplinary ALS center. PARTICIPANTS: Fourteen subjects with ALS were compared to 4 healthy volunteers. INTERVENTIONS: Subjects underwent a battery of pulmonary function tests including for CL. Then they used positive pressure administered via a mouthpiece set to 10 cm H2O above their maximal static recoil pressure for 5 min. The CL measurement was then repeated. RESULTS: The mean (+/- SD) baseline CL was reduced (164.1 +/- 82.1 mL/cm H2O) in subjects with ALS and was significantly lower than that in healthy volunteers (237.5 mL/cm H2O; p = 0.04). CL increased significantly in subjects with evidence of diaphragm weakness (change in CL, 11.3 +/- 16.7 mL/cm H2O; p = 0.03). Healthy volunteers did not have an increase in CL. CONCLUSIONS: Patients with ALS and diaphragmatic weakness have reduced CL, and brief supramaximal inflation increases CL. These findings suggest that atelectasis or increased alveolar surface forces are present in ALS patients and that these patients will have increased work of breathing. Some of the beneficial effects demonstrated with NPPV therapy may be through its effects on CL and the work of breathing.
Publication Types:
Clinical Trial
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16685025 [PubMed - indexed for MEDLINE]
7: Trends Pharmacol Sci. 2006 May;27(5):267-73.
Targets in ALS: designing multidrug therapies.
Carri MT, Grignaschi G, Bendotti C.
Department of Biology, University of Rome Tor Vergata, Via della Ricerca
Scientifica, Rome 00133, Italy.
Amyotrophic lateral sclerosis (ALS) is an incurable disease that arises from the progressive loss of motoneurons. Even when caused by a single gene defect, as in
the case of mutations in the enzyme Cu-Zn superoxide dismutase (SOD1), ALS is
the result of a complex cascade that involves crosstalk among motoneurons, glia
and muscles, and evolves through the action of converging toxic mechanisms.
Transgenic rodents that express human mutant SOD1 and develop a progressive
paralytic disease are widely used to screen potential therapeutics. Treatments that interfere with a specific event in the neurotoxic cascade have been reported to produce a modest increase in rodent lifespan. Multi-intervention approaches, including novel methods to intercept the damage and to deliver molecules to vulnerable cells, have recently been shown to be more effective. Thus, new avenues for promising therapeutic approaches can be derived from multidrug treatments and/or the delivery of growth factors by viral vectors, in combination with exercise and/or diet regimens.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16690390 [PubMed - indexed for MEDLINE]
6: South Med J. 2006 May;99(5):551-2.
Normal chest radiograph in terminal respiratory failure due to amyotrophic lateral sclerosis.
Won C, Banerjee D, Stark P, Kuschner WG.
Publication Types:
Case Reports
Letter
PMID: 16711329 [PubMed - indexed for MEDLINE]
5: Neurology. 2006 May 23;66(10):1580-1.
Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel
mutations in SETX.
Asaka T, Yokoji H, Ito J, Yamaguchi K, Matsushima A.
Division of Molecular Genetics and Clinical Research, National Nanao Hospital,
Nanao 926-0841, Japan. asaka-t@nanao.hosp.go.jp
Mutations in the Senataxin gene (SETX) are associated with autosomal recessive
ataxia-ocular apraxia 2 (AOA2) and autosomal dominant juvenile ALS (ALS4). Here,
the authors describe novel homozygous missense mutations in SETX, M274I, and
R1294C, found in two siblings with ataxia, peripheral neuropathy, and increased
serum alpha-fetoprotein level and three other siblings with heterozygous
missense mutations who were neurologically asymptomatic. The results demonstrate
that the double missense mutations are responsible for AOA2 but not for ALS4.
Publication Types:
Case Reports
Comparative Study
PMID: 16717225 [PubMed - indexed for MEDLINE]
4: J Negat Results Biomed. 2006 May 29;5:7.
Sporadic ALS is not associated with VAPB gene mutations in Southern Italy.
Conforti FL, Sprovieri T, Mazzei R, Ungaro C, Tessitore A, Tedeschi G, Patitucci
A, Magariello A, Gabriele A, Labella V, Simone IL, Majorana G, Monsurro MR,
Valentino P, Muglia M, Quattrone A.
Institute of Neurological Sciences, National Research Council, Mangone, Cosenza,
Italy. fl.conforti@isn.cnr.it
Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DHPLC revealed 5 variant profiles in 83 out of 125 SALS patients. Direct sequencing of these PCR
products revealed 3 nucleotide substitutions. Two of these were found within intron 3 of the gene, harbouring 4 variant DHPLC profiles. The third nucleotide variation (Asp130Glu) was the only substitution present in the coding region of the VAPB gene, and it occurred within exon 4. It was found in three patients out of 125. The frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. In conclusion, our study suggests that VAPB mutations are not a common cause of adult-onset SALS.
PMID: 16729899 [PubMed - indexed for MEDLINE]
3: Rev Med Suisse. 2006 May 3;2(64):1152-4, 1156-7.
Kato AC, Vingerhoets FJ, Magistris MR, Kuntzer T, Burkhard PR.
Departement des neurosciences fondamentales, Faculte de medecine, CMU, Geneve.
Ann.Kato@unige.ch
Since its description by Charcot in 1869, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis (ALS) has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics have now identified two genes, SODI and ALS2 as primary causes of the disease and has implicated others as
potential contributors. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response that it provokes, these model systems underscore the involvement of
non-neuronal cells in disease progression and provide new therapeutic strategies.
Publication Types:
English Abstract
Review
PMID: 16734186 [PubMed - indexed for MEDLINE]
2: Caring. 2006 May;25(5):50.
ALS and MS patients: The role of long-term home care.
Trueman CA.
PMID: 16752542 [PubMed - indexed for MEDLINE]
1: An Med Interna. 2006 May;23(5):246-7.
Rubio Nazabal E, Alvarez Perez P, Fernandez Cuoto F, Lopez Facal M, Rey del Corral P.
Publication Types:
Case Reports
Letter
PMID: 16913072 [PubMed - indexed for MEDLINE]
