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27: Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8.
Altered axonal excitability properties in amyotrophic lateral sclerosis:
impaired potassium channel function related to disease stage.
Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori
T, Bostock H.
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba,
Japan. VZR03355@nifty.ne.jp
Fasciculations are a characteristic feature of amyotrophic lateral sclerosis
(ALS), and can arise proximally or distally in the motor neuron, indicating a
widespread disturbance in membrane excitability. Previous studies of axonal
excitability properties (i.e. threshold electrotonus, strength-duration time
constant) have suggested respectively that change in potassium or sodium
channels may be involved. To reinvestigate these changes and explore their
correlation with disease stage, multiple axonal excitability properties
(threshold electrotonus, strength-duration time constant, recovery cycle and
current-threshold relationship) were measured for the median nerve at the wrist
in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there
were greater changes in depolarizing threshold electrotonus (i.e. less
accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P
< 0.001). These abnormalities were more prominent in patients with moderately
reduced CMAP (1-5 mV). Modelling the excitability changes in this group
supported the hypothesis that axonal potassium conductances are reduced,
resulting in increased supernormality despite membrane depolarization. The
tendency for strength-duration time constant to be prolonged in ALS was only
significant for patients with normal CMAP amplitude (>5 mV). Patients with
severely reduced CMAP (<1 mV) alone showed reduced threshold changes to
hyperpolarizing current. These results suggest a changing pattern of abnormal
membrane properties with disease progression. First, persistent Na+ conductance
increases, possibly associated with collateral sprouting, and then K(+)
conductances decline. Both changes cause axonal hyperexcitability, and may
contribute to the generation of fasciculations. These serial changes in axonal
properties could provide insights into the pathophysiology of ALS, and
implications for future therapeutic options.
PMID: 16467388 [PubMed - indexed for MEDLINE]
26: Neurology. 2006 Apr 25;66(8):1218-22. Epub 2006 Feb 15.
Identification of potential CSF biomarkers in ALS.
Pasinetti GM, Ungar LH, Lange DJ, Yemul S, Deng H, Yuan X, Brown RH, Cudkowicz
ME, Newhall K, Peskind E, Marcus S, Ho L.
Geriatric Research, Education, and Clinical Center, Bronx Veterans Affairs
Medical Center, Bronx, NY, USA. giulio.pasinetti@mssm.edu
BACKGROUND: The clinical diagnosis of ALS is based entirely on clinical
features. Identification of biomarkers for ALS would be important for diagnosis
and might also provide clues to pathogenesis. OBJECTIVE: To determine if there
is a specific protein profile in the CSF that distinguishes patients with ALS
from those with purely motor peripheral neuropathy (PN) and healthy control
subjects. METHODS: CSF obtained from patients with ALS, disease controls
(patients with other neurologic disorders), and normal controls were analyzed
using the surface-enhanced laser desorption/ionization time-of-flight mass
spectrometry proteomics technique. Biomarker sensitivity and specificity was
calculated with receiver operating characteristic curve methodology. ALS
biomarkers were purified and sequence identified by mass spectrometry-directed
peptide sequencing. RESULTS: In initial proteomic discovery studies, three
protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in
concentration in the CSF from patients with ALS (n = 36) than in normal controls
(n = 21) were identified. A combination of three protein species (the
"three-protein" model) correctly identified patients with ALS with 95% accuracy,
91% sensitivity, and 97% specificity from the controls. Independent validation
studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN
(n = 7) subjects confirmed the ability of the three CSF protein species to
separate patients with ALS from other diseases. Protein sequence analysis
identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein
species as a peptic fragment of the neurosecretory protein VGF. CONCLUSION:
Additional application of a "three-protein" biomarker model to current
diagnostic criteria may provide an objective biomarker pattern to help identify
patients with ALS.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Validation Studies
PMID: 16481598 [PubMed - indexed for MEDLINE]
25: Brain. 2006 Apr;129(Pt 4):868-76. Epub 2006 Feb 22.
Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to
a locus on chromosome 9p13.2-21.3.
Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T,
Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE.
Department of Neurology, King's College London School of Medicine, London, UK.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in approximately 10% of cases and FTD in approximately 30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc
superoxide dismutase 1 (SOD1) are found in approximately 20% of familial and approximately 3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in approximately 30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report
the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02
(theta = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2-21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16495328 [PubMed - indexed for MEDLINE]
24: Nat Genet. 2006 Apr;38(4):411-3. Epub 2006 Feb 26.
ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.
Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V,
Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr,
Hardiman O.
Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland. mattgreenway@rcsi.ie
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16501576 [PubMed - indexed for MEDLINE]
23: Biochem Biophys Res Commun. 2006 Apr 21;342(4):1034-9. Epub 2006 Feb 20.
Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis
and Parkinson's disease.
Goldknopf IL, Sheta EA, Bryson J, Folsom B, Wilson C, Duty J, Yen AA, Appel SH.
Power3 Medical Products, Inc., The Woodlands, TX, USA.
igoldknopf@power3.medical.com
We have used quantitative 2D gel electrophoresis to analyze serum proteins from
422 patients with neurodegenerative diseases and normal individuals in an
unbiased approach to identify biomarkers. Differences in abnormal serum levels
were found between amyotrophic lateral sclerosis (ALS), Parkinson's disease
(PD), and related disorders for 34 protein biomarker spots, nine of which were
related to the complement system. Of these nine, four spots originated from the
Complement C3b-alpha-chain (C3c(1), C3c(2a), C3c(2b), and C3dg). The C3c spots
(C3c(1), C3c(2a), and C3c(2b)) had the same amino acid sequence and
glycosylation, though only C3c(1) was phosphorylated. In addition, Complement
Factors H, Bb, and Pre-Serum amyloid protein displayed different serum
concentrations in ALS, PD, and normal sera, whereas Complement C4b gamma-chain
and Complement Factor I did not. The differential expression of the complement
proteins provides potentially useful biomarkers as well as evidence for the
involvement of inflammatory processes in the pathogenesis of ALS and PD.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16516157 [PubMed - indexed for MEDLINE]
22: Lancet Neurol. 2006 Apr;5(4):291-2; author reply 292-3.
Comment on:
Lancet Neurol. 2006 Feb;5(2):140-7.
Non-invasive ventilation in amyotrophic lateral sclerosis.
Servera E, Sancho J.
Publication Types:
Comment
Letter
PMID: 16545744 [PubMed - indexed for MEDLINE]
21: Brain Res. 2006 Apr 14;1083(1):196-203. Epub 2006 Mar 20.
Parvalbumin and calbindin D-28k immunoreactivity in transgenic mice with a G93A
mutant SOD1 gene.
Sasaki S, Warita H, Komori T, Murakami T, Abe K, Iwata M.
Department of Neurology, Neurological Institute, Tokyo Women's Medical
University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
ssasaki@nij.twmu.ac.jp
Immunohistochemical study was performed to examine if calcium-binding proteins
are involved in the degeneration of motor neurons in the brain stems and the
spinal cords of transgenic mice carrying a G93A mutant human SOD1 gene.
Specimens from age-matched non-transgenic wild-type mice served as controls. In
the spinal cord of the controls, the density of parvalbumin-immunoreactive
neurons was highest in the large anterior horn neurons and lower in the
posterior horn neurons in the spinal cord. On the other hand, calbindin D-28k
immunoreactivity was much less apparent than that observed with parvalbumin
antisera. Rexed's lamina II was densely immunostained for calbindin D-28k,
whereas, in the anterior horn, calbindin-D-28k-positive small neurons were
barely dispersed in a scattered pattern. In transgenic mice,
parvalbumin-positive anterior horn neurons were severely reduced, even at the
presymptomatic stage, whereas calbindin-positive neurons were largely preserved.
At the symptomatic stage, both parvalbumin and calbindin D-28k immunoreactivity
markedly diminished or disappeared in the anterior horn. Immunoblotting analysis
revealed a significant reduction of immunoreactivity to parvalbumin antibody in
transgenic mice compared with the controls. In the brain stem,
parvalbumin-positive oculomotor and abducens neurons and the calbindin
D-28k-positive sixth nucleus were well-preserved in transgenic mice as well as
in the controls. Thus, the diffuse and severe loss of parvalbumin
immunoreactivity of large motor neurons even at early stages in SOD1-transgenic
mice and the absence of calbindin D-28k immunoreactivity of normal large motor
neurons suggest that these calcium-binding proteins may contribute to selective
vulnerability and an early loss of function of large motor neurons in this
SOD1-transgenic mouse model.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16546142 [PubMed - indexed for MEDLINE]
20: BMC Neurosci. 2006 Apr 3;7:29.
A ketogenic diet as a potential novel therapeutic intervention in amyotrophic
lateral sclerosis.
Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, Humala N,
Thiyagarajan M, Wang J, Pasinetti GM.
Neuroinflammation Research Laboratories, Department of Psychiatry, USA.
rudy.zhao@mssm.edu
BACKGROUND: The cause of neuronal death in amyotrophic lateral sclerosis (ALS)
is uncertain but mitochondrial dysfunction may play an important role. Ketones
promote mitochondrial energy production and membrane stabilization. RESULTS:
SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known
formulations for humans. Motor performance, longevity, and motor neuron counts
were measured in treated and disease controls. Because mitochondrial dysfunction
plays a central role in neuronal cell death in ALS, we also studied the effect
that the principal ketone body, D-beta-3 hydroxybutyrate (DBH), has on
mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times
higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline
motor performance 25 days later than disease controls. KD animals weighed 4.6 g
more than disease control animals at study endpoint; the interaction between
diet and change in weight was significant (p = 0.047). In spinal cord sections
obtained at the study endpoint, there were more motor neurons in KD fed animals
(p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex
I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32
immunopositive motor neurons was also inhibited by DBH. CONCLUSION: This is the
first study showing that diet, specifically a KD, alters the progression of the
clinical and biological manifestations of the G93A SOD1 transgenic mouse model
of ALS. These effects may be due to the ability of ketone bodies to promote ATP
synthesis and bypass inhibition of complex I in the mitochondrial respiratory
chain.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
PMID: 16584562 [PubMed - indexed for MEDLINE]
19: Rev Neurol (Paris). 2006 Apr;162(4):445-53.
Robert D, Bianco-Blache A, Spezza C, Verschueren A, Pouget J, Giovanni A.
Federation ORL, CHU La Timone, 264, rue Saint-Pierre, 13385 Marseille Cedex 5.
Swallowing and speech disorders are the dramatic consequences of bulbar and
pseudo-bulbar syndrome in ALS. Evaluation is necessary to guide speech therapy
and to measure the effects of treatment. This article revues the different
examinations used to assess bulbar and pseudobulbar involvement in an ALS
patient: oromotor assessment, evaluation of the functions with self assessment,
perceptive and objective evaluation of speech disorders, fiberoptic endoscopic
evaluation of dysphagia (FEES) and videofluoroscopy.
Publication Types:
English Abstract
Review
PMID: 16585905 [PubMed - indexed for MEDLINE]
18: Rev Neurol (Paris). 2006 Apr;162(4):502-7.
Couratier P, Torny F, Lacoste M.
Centre SLA, Service de Neurologie, CHU Dupuytren, Limoges. philippe.couratier@unilim.fr
Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of the peripheral and central motor neurons. The principal consequence is a loss of motor functions. Evaluation of motor deficit implies an assessment of the resulting deficiency or incapacity and final disability. Many evaluation are proposed for patient follow-up in order to analyze the state of motor function and their consequences on activities of everyday life. Few recommendations can be formulated. Scales must be validated and relatively simple to use and generate ordinate results allowing statistical analysis. The choice of which
scale to use depends on the clinical objective. Global scales (ALS Functional
rating Scale, ALS Severity Scale, Appel scale, Norris scale and Honda scale) can
be used to evaluate progression of the disability. Some of these scales are strongly correlated with patient survival. Other scales (ALS Health State Scale, global clinical impression) are used to classify patients by homogeneous stage of gravity. Still other scales, such as the Sadoul and Borg scales and the Epworth score are designed for more specific evaluation of a given function. The clinician should be aware of these different scales and their relative utility. Knowledge of these scales, their validity, their sensitivity to modification, and their specificity and interpretation pitfalls is a prerequisite to good evaluation in daily practice and clinical research.
Publication Types:
Comparative Study
English Abstract
Review
PMID: 16585911 [PubMed - indexed for MEDLINE]
17: Rev Neurol (Paris). 2006 Apr;162(4):544-8.
[Case management of amyotrophic lateral sclerosis patients. Consensus
development conference, Nice, France, 23-24 November 2005. French Neurology
Society. Association of Independent French-speaking Neurologists]
Societe Francaise de Neurologie; Association des Neurologues Liberaux de Langue
Francaise; Haute Autorite de Sante.
Publication Types:
Consensus Development Conference
Practice Guideline
Research Support, Non-U.S. Gov't
PMID: 16585919 [PubMed - indexed for MEDLINE]
16: Sci Am. 2006 Apr;294(4):35.
As luck would have it.
Shermer M.
PMID: 16596876 [PubMed - indexed for MEDLINE]
15: Neuropathol Appl Neurobiol. 2006 Apr;32(2):141-56.
Serine proteases purified from sera of patients with amyotrophic lateral
sclerosis (ALS) induce contrasting cytopathology in murine motoneurones to IgG.
Demestre M, Howard RS, Orrell RW, Pullen AH.
Sobell Department of Motor Neuroscience, Institute of Neurology, University College London, London, UK.
Affinity purified IgG from sera of patients with amyotrophic lateral sclerosis
(ALS) is claimed to enhance transmitter release, induce apoptotic death of
cultured motoneurones, and elicit a distinctive cytopathology with raised Ca(2+)
in mouse motoneurones. An alternative hypothesis attributes these events to
serine proteases in ALS sera. To test this, motoneurones in BALB/c mice injected
intraperitoneally with plasminogen affinity purified from sera of ALS patients and healthy controls were analysed using immunochemical and ultrastructural morphometric methods. The responses were validated in motoneurones of mice injected with commercially purified plasminogen, tissue plasminogen activator (tPA), or plasmin. Motoneurones in non-injected mice had normal morphology and ultrastructure without evidence of electron-dense degeneration. Purified plasminogen from both ALS patients and healthy controls, evoked electron-dense motoneurone degeneration, as did commercially purified plasminogen and tPA. The common cytopathology comprised disruption and distension of Nissl body rough endoplasmic reticulum, cytoplasmic polyribosomal proliferation, and significant Ca(2+) enhancement in mitochondria. By contrast, using affinity purified serum immunoglobulins, ALS-IgG but not IgG from healthy or disease controls, elicited necrosis, with 30% of ALS-IgGs tested evoking electron-dense degeneration in 40% of motoneurones. The primary cytopathology was extensive swelling of Golgi endoplasmic reticulum and mitochondria, with enhancement of Ca(2+) in Golgi endoplasmic reticulum and presynaptic boutons. We conclude that serine proteases purified from sera of ALS patients elicits a distinctive cytopathology and pattern of Ca(2+) enhancement in motoneurones different from that found on passive transfer of affinity purified ALS-IgG.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16599943 [PubMed - indexed for MEDLINE]
14: Mol Neurobiol. 2006 Apr;33(2):113-31.
Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target?
Bacman SR, Bradley WG, Moraes CT.
Department of Neurology, University of Miami, Miller School of Medicine, FL, USA.
Despite numerous reports demonstrating mitochondrial abnormalities associated
with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16603792 [PubMed - indexed for MEDLINE]
13: Arch Neurol. 2006 Apr;63(4):557-60.
Can selection of rapidly progressing patients shorten clinical trials in amyotrophic lateral sclerosis?
de Carvalho M, Swash M.
Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal.
BACKGROUND: The marked variability in progression of amyotrophic lateral sclerosis (ALS) requires large numbers of patients to detect a significant effect in current clinical trial designs. OBJECTIVE: To test the utility of a lead-in period to assess rate of progression so that patients with rapidly progressive ALS can be selected for subsequent clinical trials. DESIGN: Prospective study. SETTING: The ALS Center, University of Lisbon, Lisbon,
Portugal. PATIENTS: Fifty-seven consecutively recruited patients assessed at diagnosis and 3 months later (end of lead-in period). INTERVENTIONS: Change in ALS Functional Rating Scale (ALS-FRS) score was analyzed to establish a statistically significant cutoff point to define patients with rapid (group 1) or slow (group 2) progression. Patients from both groups were reexamined 1 and 3 months after the lead-in period. MAIN OUTCOME MEASURES: Changes in ALS-FRS score, motor unit number estimation, and neurophysiologic index, and resultant grouping of patients according to rate of progression at 1 and 3 months. RESULTS: Both the 80th percentile and 2 SDs above the mean of the change in ALS-FRS score identified the same patients. Twelve patients showed rapid progression (group 1) and 45 showed slow progression (group 2). One month after the lead-in period there was a significant reduction in ALS-FRS score, motor
unit number estimation, and neurophysiologic index in group 1, and after 3 months all these measurements changed significantly in both groups. CONCLUSIONS: This strategy of selecting patients with rapidly progressing ALS for inclusion in exploratory, short phase II clinical trials offers substantial savings in costs and time, and could accelerate the process of testing potentially useful drugs for the treatment of ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16606769 [PubMed - indexed for MEDLINE]
12: Brain Res Bull. 2006 Apr 28;69(4):465-74. Epub 2006 Mar 10.
Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis.
Rizzardini M, Lupi M, Mangolini A, Babetto E, Ubezio P, Cantoni L.
Laboratory of Molecular Pathology, Istituto di Ricerche Farmacologiche Mario
Negri, Via Eritrea 62, 20157 Milan, Italy.
G93A Cu/Zn superoxide dismutase (SOD1), a human mutant SOD1 associated with
familial amyotrophic lateral sclerosis, increased the toxicity of the mitochondrial toxin rotenone in the NSC-34 motoneuronal cell line. G93ASOD1 cells died more than untransfected and wild-type SOD1 cells after 6 and 24h exposure to 12.5 microM rotenone. Biparametric flow cytometry showed that rotenone induced rapid hyperpolarization of mitochondrial membrane potential (deltapsi(m)) in all the cell lines, followed by depolarization, and then by cell death. However, G93ASOD1 mitochondria were significantly more likely to shift from a hyperpolarized to a depolarized condition, and within the still viable cell population there was a higher proportion with depolarized
mitochondria, a condition that can be envisaged as a commitment to cell death.
ATP, which is needed to prevent loss of deltapsi(m), decreased more rapidly and to a greater extent in rotenone-treated G93ASOD1 cells than in the untransfected and wtSOD1cells. In all the cell lines, 1h after rotenone exposure, mitochondrial hyperpolarization was accompanied by the formation of a comparable amount of reactive oxygen species. However, G93ASOD1 cells reached the highest reactive oxygen species level since their basal level was higher than in untransfected and wild-type SOD1 cells. Our findings indicate that the mutant protein G93ASOD1 enhances the vulnerability of motor neurons to rotenone by mechanism(s) involving oxidative stress and perturbed mitochondrial homeostasis. This suggests that motor neurons from individuals carrying the mutant G93ASOD1 are at greater risk of death after inhibition of the electron transport chain.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16624679 [PubMed - indexed for MEDLINE]
11: J Neurosci. 2006 Apr 19;26(16):4147-54.
Overloading of stable and exclusion of unstable human superoxide dismutase-1
variants in mitochondria of murine amyotrophic lateral sclerosis models.
Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brannstrom T, Rehnmark A,
Marklund SL.
Department of Medical Biosciences, Umea University, SE-901 85 Umea, Sweden.
Mutants of human superoxide dismutase-1 (hSOD1) cause amyotrophic lateral sclerosis (ALS), and mitochondria are thought to be primary targets of the cytotoxic action. The high expression rates of hSOD1s in transgenic ALS models give high levels of the stable mutants G93A and D90A as well as the wild-type human enzyme, significant proportions of which lack Cu and the intrasubunit disulfide bond. The endogenous murine SOD1 (mSOD1) also lacks Cu and is disulfide reduced but is active and oxidized in mice expressing the low-level unstable mutants G85R and G127insTGGG. The possibility that the molecular alterations may cause artificial loading of the stable hSOD1s into mitochondria was explored. Approximately 10% of these hSOD1s were localized to mitochondria, reaching levels 100-fold higher than those of mSOD1 in control mice. There was no difference between brain and spinal cord and between stable mutants and the
wild-type hSOD1. mSOD1 was increased fourfold in mitochondria from high-level
hSOD1 mice but was normal in those with low levels, suggesting that the Cu deficiency and disulfide reduction cause mitochondrial overloading. The levels of G85R and G127insTGGG mutant hSOD1s in mitochondria were 100- and 1000-fold lower than those of stable mutants. Spinal cords from symptomatic mice contained hSOD1 aggregates covering the entire density gradient, which could contaminate isolated organelle fractions. Thus, high hSOD1 expression rates can cause artificial loading of mitochondria. Unstable low-level hSOD1s are excluded from mitochondria, indicating other primary locations of injury. Such models may be preferable for studies of ALS pathogenesis.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16624935 [PubMed - indexed for MEDLINE]
10: Aging Cell. 2006 Apr;5(2):153-65.
Overexpression of Abeta is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in an amyotrophic lateral sclerosis mouse model.
Li QX, Mok SS, Laughton KM, McLean CA, Volitakis I, Cherny RA, Cheung NS, White
AR, Masters CL.
Department of Pathology, The University of Melbourne, and The Mental Health
Research Institute of Victoria, Parkville, Vic. 3010, Australia.
q.li@unimelb.edu.au
Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate
the motor impairment of human amyotrophic lateral sclerosis (ALS). The
amyloid-beta (Abeta) peptide associated with Alzheimer's disease is neurotoxic.
To investigate the potential role of Abeta in ALS development, we generated a
double transgenic mouse line that overexpresses SOD1(G93A) and amyloid precursor
protein (APP)-C100. The transgenic mouse C100.SOD1(G93A) overexpresses Abeta and
shows earlier onset of motor impairment but has the same lifespan as the single
transgenic SOD1(G93A) mouse. To determine the mechanism associated with this
early-onset phenotype, we measured copper and zinc levels in brain and spinal
cord and found both significantly elevated in the single and double transgenic
mice compared with their littermate control mice. Increased glial fibrillary
acidic protein and decreased APP levels in the spinal cord of C100.SOD1(G93A)
mice compared with the SOD1(G93A) mice agree with the neuronal damage observed
by immunohistochemical analysis. In the spinal cords of C100.SOD1(G93A) double
transgenic mice, soluble Abeta was elevated in mice at end-stage disease
compared with the pre-symptomatic stage. Buffer-insoluble SOD1 aggregates were
significantly elevated in the pre-symptomatic mice of C100.SOD1(G93A) compared
with the age-matched SOD1(G93A) mice, correlating with the earlier onset of
motor impairment in the C100.SOD1(G93A) mice. This study supports abnormal SOD1
protein aggregation as the pathogenic mechanism in ALS, and implicates a
potential role for Abeta in the development of ALS by exacerbating SOD1(G93A)
aggregation.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16626394 [PubMed - indexed for MEDLINE]
9: J Palliat Med. 2006 Apr;9(2):304-8.
Self-reported quality of life in amyotrophic lateral sclerosis.
Nygren I, Askmark H.
Department of Neuroscience, Neurology, Uppsala University Hospital, Sweden.
ingela.nygren@neurologi.uu.se
OBJECTIVES: To continuously assess overall quality of life (QOL) and disease
progression in patients with amyotrophic lateral sclerosis (ALS) at different
stages of the disease and compare the results between these two variables.
DESIGN/SUBJECTS: Twenty-six patients with ALS were interviewed with a
questionnaire to assess their QOL from 0 to 10, where 10 is the highest QOL and
questions concerning physical function, psychological status, and civil status.
Their disease progression was estimated by ALS Functioning Rating Scale (ALS
FRS). Nine patients were interviewed only once and 17 patients were interviewed
2-7 times. The interviews were repeated every second visit (range, 4-7 months).
All values were ranked and linear regression was used to calculate the slope of
QOL and ALS FRS. RESULTS: The mean QOL value for all 26 patients was 5.8
(0-10-point scale). For the 17 patients interviewed 2-7 times, which correspond
to a follow-up period of 5-28 months, there was no significant change in
QOL-value (p = 0.247) among the interviews despite a significant disease
progression (p = 0.0001). CONCLUSION: It can be concluded that ALS does not
necessarily result in a low overall QOL and that despite disease progression
overall QOL changes only slightly over time.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16629560 [PubMed - indexed for MEDLINE]
8: Clin Genet. 2006 Apr;69(4):358-9.
Paraoxonase-1 Q192R polymorphism and risk of sporadic amyotrophic lateral sclerosis.
Slowik A, Tomik B, Partyka D, Turaj W, Pera J, Dziedzic T, Szermer P, Figlewicz
DA, Szczudlik A.
Publication Types:
Comparative Study
Letter
Research Support, Non-U.S. Gov't
PMID: 16630171 [PubMed - indexed for MEDLINE]
7: Neurology. 2006 Apr 25;66(8):1211-7.
The effect of noninvasive ventilation on ALS patients and their caregivers.
Mustfa N, Walsh E, Bryant V, Lyall RA, Addington-Hall J, Goldstein LH, Donaldson
N, Polkey MI, Moxham J, Leigh PN.
Respiratory Muscle Laboratory, Guy's, King's, and St Thomas' School of Medicine,
King's College Hospital, UK. Naveed.Mustfa@uhns.nhs.uk
BACKGROUND: Noninvasive ventilation (NIV) reduces mortality and improves some
aspects of quality of life (QoL) in ALS. However, concerns remain that progressive disability may negate these benefits and unnecessarily burden caregivers. METHODS: Thirty-nine patients requiring NIV were offered treatment. Twenty-six were established on NIV, but 13 declined or could not tolerate NIV. Fifteen patients without respiratory muscle weakness (RMW) but with similar ALS severity and age were studied in parallel. Caregivers of 21 NIV, 7 untreated, and 10 patients without RMW participated. Patients and caregivers had detailed QoL measurements for 12 months. NIV patients underwent cognitive testing before and after treatment. RESULTS: RMW correlated with lower QoL. The median survival of untreated patients (18 days; 95% CI 11 to 25 days) was shorter than for NIV patients (298 days; 95% CI 192 to 404 days) and non-RMW patients (370 days; 95% CI 278 to 462 days; log rank test [2 df] = 81, p = 0.00001). A wide range of QoL
measures improved within 1 month of starting NIV, and improvements were maintained for 12 months. QoL of non-RMW patients declined as RMW progressed. Caregivers of NIV and non-RMW patients showed similar increases in burden, but NIV patient caregivers developed a deterioration in the Short Form-36 Vitality score. No improvements were found on measures of learning and recall in the NIV patients. CONCLUSIONS: Respiratory muscle weakness has a greater impact on quality of life (QoL) than overall ALS severity. Noninvasive ventilation (NIV) improves QoL despite ALS progression. NIV has no impact on most aspects of caregiver QoL and does not significantly increase caregiver burden or stress.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16636239 [PubMed - indexed for MEDLINE]
6: BMC Neurol. 2006 Apr 25;6:17.
Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral
Sclerosis.
Grosskreutz J, Kaufmann J, Fradrich J, Dengler R, Heinze HJ, Peschel T.
Dept. of Neurology, Medical School Hannover, Hannover, Germany.
grosskreutz.julian@mh-hannover.de
BACKGROUND: Widespread cortical atrophy in Amyotrophic Lateral Sclerosis (ALS)
has been described in neuropathological studies. The presence of cortical
atrophy in conventional and scientific neuroimaging has been a matter of debate.
In studies using computertomography, positron emission tomography, proton
magnetic resonance spectroscopy and conventional T2-weighted and proton-weighted
images, results have been variable. Recent morphometric studies by magnetic
resonance imaging have produced conflicting results regarding the extent of grey
and white matter involvement in ALS patients. METHODS: The authors used
optimized voxel-based morphometry as an unbiased whole brain approach to detect
differences between regional grey and white matter volumes. Seventeen patients
with a diagnosis of ALS according to El-Escorial criteria and seventeen
age-matched controls received a high resolution anatomical T1 scan. RESULTS: In
ALS patients regional grey matter volume (GMV) reductions were found in the pre-
and postcentral gyrus bilaterally which extended to premotor, parietal and
frontal regions bilaterally compared with controls (p < 0.05, corrected for the
entire volume). The revised ALS functional rating scale showed a positive
correlation with GMV reduction of the right medial frontal gyrus corresponding
to the dorsolateral prefrontal cortex. No significant differences were found for
white matter volumes or when grey and white matter density images were
investigated. There were no further correlations with clinical variables found.
CONCLUSION: In ALS patients, primary sensorimotor cortex atrophy can be regarded
as a prominent feature of the disease. Supporting the concept of ALS being a
multisystem disorder, our study provides further evidence for extramotor
involvement which is widespread. The lack of correlation with common clinical
variables probably reflects the fact that heterogeneous disease processes
underlie ALS. The discrepancy within all published morphometric studies in ALS
so far may be related to differences in patient cohorts and several
methodological factors of the data analysis process. Longitudinal studies are
required to further clarify the time course and distribution of grey and white
matter pathology during the course of ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16638121 [PubMed - indexed for MEDLINE]
5: Eur J Neurol. 2006 Apr;13(4):416-8.
Dopamine transporter immunoreactivity in peripheral blood mononuclear cells in
amyotrophic lateral sclerosis.
Buttarelli FR, Circella A, Pellicano C, Pontieri FE.
Dipartimento di Scienze Neurologiche, II Facolta di Medicina e Chirurgia,
Universita degli Studi di Roma La Sapienza, Italy.
Amyotrophic lateral sclerosis (ALS) is a chronic progressive neuromuscular
disorder of unknown etiology, characterized by weakness, muscle wasting,
fasciculations, and increased reflexes, with conserved intellect and higher
functions. The neuropathology of ALS is mostly confined to damage of the motor
neurons in the cerebral cortex, some motor nuclei of the brainstem, and anterior
horns of the spinal cord. However, there is evidence for the involvement of
other neuronal systems in the disease. In particular, damage of the dopamine
neurons has been shown by neurochemical and imaging studies in the brain and
spinal cord of ALS patients. Recent reports suggest that peripheral blood
mononuclear cells (PBMC) may represent a useful in vivo model to study
neurochemical alterations that occur in neurodegenerative disorders. Here we
demonstrate the significant reduction of dopamine transporter immunoreactivity
in PBMC of patients affected by ALS with respect to healthy subjects. These
results extend our knowledge of damage of the dopamine system in ALS to
peripheral cells. Thus, the original concept of ALS as an isolated degeneration
of motor neurons seems to extend to a more widespread understanding of the
disease with involvement of other neuronal systems in the central as well as
peripheral nervous system.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16643322 [PubMed - indexed for MEDLINE]
4: Neuro Endocrinol Lett. 2006 Feb-Apr;27(1-2):133-6.
Age related profiles of free amino acids in human skeletal muscle.
Stuerenburg HJ, Stangneth B, Schoser BG.
Neurological Department, Median-Klinik Bad Suelze, Bad Suelze, Germany.
stuerenburg@uke.uni-hamburg.de
Sarcopenia describes the involuntary decline in muscle mass with aging, coupled
with fatigue, and loss of force and function. We investigated 113 human muscle
biopsy specimens obtained from patients with neuromuscular diseases and
controls. We measured 21 amino acids in these muscle biopsies. Age emerged as a
significant negative predictor of cytosolic concentration ratio of glutamine to
total branched chain amino acids and of glutamine to total aromatic amino acids
using stepwise multiple linear regression analysis. This pattern of alteration
corresponds well to documented alterations in skeletal muscle of critically ill
patients and after immobilization. Additionally, in myositis, citrulline was
significantly elevated, while glutamate, lysine and taurine were significantly
reduced. Furthermore, in sporadic amyotrophic lateral sclerosis (sALS) the total
aromatic amino acids, arginine, glutamate, threonine, and tyrosine were
significantly elevated. This study provides evidence, that alteration of
glutamine is correlated to aging and might reflect increased proteolysis in aged
and diseased human skeletal muscle.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16648814 [PubMed - indexed for MEDLINE]
3: Neuropathology. 2006 Apr;26(2):115-28.
Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam.
Oyanagi K, Kawakami E, Kikuchi-Horie K, Ohara K, Ogata K, Takahama S, Wada M, Kihira T, Yasui M.
Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience,
Japan. k123ysm@tmin.ac.jp
Parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) are fatal neurological diseases. The incidence on Guam was very high between 1950 and 1965 but decreased dramatically after 1965. It is thought that drinking water containing low levels of calcium (Ca) and magnesium (Mg), and high levels of aluminum and of a plant excitatory neurotoxin are involved in the pathogenesis of these diseases. The present experiment was performed in rats that were exposed to low Ca and/or Mg intake over two generations, thus simulating the conditions of human life on Guam, where several generations live continuously in the same environment. Significant loss of dopaminergic neurons was identified exclusively in the substantia nigra in 1-year-old rats that had
been exposed continuously to low Mg intake (one-fifth of the normal level) over
generations. The present study suggests that low Mg intake over generations may
be involved in the pathogenesis of substantia nigra degeneration in humans.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16708544 [PubMed - indexed for MEDLINE]
2: Rinsho Shinkeigaku. 2006 Apr;46(4):297-300.
[Usefulness of polysomnography at an early stage of amyotrophic lateral
sclerosis]
Sugie M, Ando N, Ueno S.
Department of Neurology, National Hospital Organization Nara Medical Center.
A 47-year-old man who presented moderate muscle weakness in the neck and all the
extremities was diagnosed as having early stage of amyotrophic lateral sclerosis
(ALS). He did not have bulbar dysfunction and respiratory distress. His pulmonary function tests and arterial blood gas analysis showed no abnormalities, but polysomnography (PSG) revealed sleep-disordered breathing requiring mechanical support ventilation. Bi-level positive airway pressure treatment was started only at night, which improved both sleep-disordered breathing and daytime activity. PSG should be considered in ALS patients at an early clinical stage in order to predict mild respiratory dysfunction.
Publication Types:
Case Reports
English Abstract
PMID: 16768102 [PubMed - indexed for MEDLINE]
1: Brain Pathol. 2006 Apr;16(2):143-54.
Neural stem cell systems: diversities and properties after transplantation in animal models of diseases.
Conti L, Reitano E, Cattaneo E.
Department of Pharmacological Sciences and Center of Excellence on
Neurodegenerative Diseases, University of Milano, Milano, Italy.
Currently available effective treatments of the diseased or damaged central nervous system (CNS) are restricted to a limited pharmacological relief of symptoms or those given to avoid further damage. Therefore the search is on for treatments that can restore function in the CNS. During recent years replacement of damaged neurons by cell transplantation is being enthusiastically explored as a potential treatment for many neurodegenerative diseases, stroke and traumatic brain injury. Several references in both scientific journals and popular newspapers concerning different types of cultured stem cells, potentially exploitable to treat pathological conditions of the brain, raise important questions pertinent to the fundamental and realistic differences between grafts of primary neural cells and the transplantation of in vitro expanded neural stem cells (NSCs). Our aim is to review the available information on the grafting of different NSC types into the adult rodent brain, focusing on critical aspects for the development of clinical therapies to replace damaged neurons.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16768755 [PubMed - indexed for MEDLINE]
