7: Curr Opin Investig Drugs. 2006 Jan;7(1):54-9.
Does VEGF represent a potential treatment for amyotrophic lateral sclerosis?
Ilzecka J.
Department of Neurology, Medical University, Jaczewskiego 8, 20-954 Lublin,
Poland. ilzecka@onet.pl
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
The pathogenesis of ALS is unclear and there is no effective treatment. Vascular
endothelial growth factor (VEGF) is a cytokine that has a protective function
via angiogenic, neurotrophic, gliotrophic and anti-apoptotic activity. Data
indicate that VEGF can inhibit neurodegeneration in ALS and may have therapeutic
potential in this disease. The use of gene therapy to deliver VEGF into the
central nervous system is being evaluated.
Publication Types:
Review
PMID: 16425672 [PubMed - indexed for MEDLINE]
6: Neurology. 2006 Jan 24;66(2 Suppl 1):S118-22.
Developing therapeutics for the diseases of protein misfolding.
May BC, Govaerts C, Cohen FE.
Institute for Neurodegenerative Diseases, University of California, San
Francisco, CA 94143-2240, USA. alchemi@itsa.ucsf.edu
Our current structural and biologic understanding of the misfolding diseases has
restricted the development of therapies that target these diseases at a
molecular level. The prion diseases are illustrative of this group of misfolding
disorders and provide a model system for therapeutic intervention. Strategies to
inhibit the replication and accumulation of the prion protein are being
developed and have entered animal and clinical studies. Due to the underlying
molecular basis of this disease class, many of the therapeutic approaches used
to target prion misfolding have parallels in other misfolding diseases.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432139 [PubMed - indexed for MEDLINE]
5: Neurology. 2006 Jan 24;66(2):265-7.
Comment in:
Neurology. 2006 Oct 10;67(7):1314-5; author reply 1314-5.
Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.
Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K,
Sugino M, Hanafusa T.
Division of Neurology, First Department of Internal Medicine, Osaka Medical
College, Osaka, Japan. in1110@poh.osaka-med.ac.jp
The authors calculated the progression rate (DeltaFS) using the total revised
ALS Functional Rating Scale (ALSFRS-R) and symptom duration at diagnosis in 82
Japanese patients with ALS. Survival (death or tracheostomy) differed
significantly with the DeltaFS and postdiagnostic period according to log-rank
testing, but Cox proportional hazards modeling revealed no strong association
between total ALSFRS-R and mortality, suggesting that the DeltaFS provides an
additional predictive index beyond ALSFRS-R alone.
Publication Types:
Evaluation Studies
Research Support, Non-U.S. Gov't
PMID: 16434671 [PubMed - indexed for MEDLINE]
4: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004156.
Update of:
Cochrane Database Syst Rev. 2004;(1):CD004156.
Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.
Ashworth NL, Satkunam LE, Deforge D.
University of Alberta, Division of Physical Medicine and Rehabilitation,
Glenrose Rehabilitation Hospital, 1226 GW, 10230 - 111 Avenue, Edmonton,
Alberta, Canada, T5G 0B7. ashworth@cha.ab.ca
BACKGROUND: Spasticity commonly affects patients with motor neuron disease. It
is likely to contribute to worsening muscle dysfunction, increased difficulty
with activities of daily living and deteriorating quality of life. OBJECTIVES:
The objective of this review is to systematically review treatments for
spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials
register (January 2003 and January 2005), MEDLINE (January 1966 to February
2005), EMBASE (January 1980 to February 2005), CINAHL (January 1982 to February
2005), AMED (January 1985 to February 2005) and LILACS (January 1982 to January
2003). We reviewed the bibliographies of the randomized controlled trials
identified, and contacted authors and experts in the field. SELECTION CRITERIA:
We included quasi-randomized or randomized controlled trials of participants
with probable or definite amyotrophic lateral sclerosis according to the El
Escorial diagnostic criteria (or a revised version) or the Airlie House
revision. We would have included trials of physical therapy, modalities,
prescription medications, non-prescription medications, chemical neurolysis,
surgical interventions, and alternative therapies. Our primary outcome measure
was reduction in spasticity at three months or greater as measured by the
Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures
were: validated measures based on history, physical examination, physiological
measures, measures of function, measures of quality of life, serious adverse
events, and measures of cost. DATA COLLECTION AND ANALYSIS: We identified only
one randomized controlled trial that met our inclusion criteria. Two authors
extracted the data. We also contacted the author of the paper and obtained
information not available in the published article. MAIN RESULTS: The included
study was a trial of moderate intensity, endurance type exercise versus 'usual
activities' in 25 patients with amyotrophic lateral sclerosis. At three months
patients performing the 15 minute twice daily exercises had significantly less
spasticity overall (mean reduction of -0.43, 95% CI -1.03 to +0.17 in the
treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control)
but the mean change between groups was not significant (-0.68, 95% CI -1.62 to
+0.26), as measured by the Ashworth scale. AUTHORS' CONCLUSIONS: The single
trial performed was too small to determine whether individualised moderate
intensity endurance type exercises for the trunk and limbs are beneficial or
harmful. No other medical, surgical or alternative treatment and therapy has
been evaluated in a randomized fashion in this patient population. More research
is needed.
Publication Types:
Review
PMID: 16437474 [PubMed - indexed for MEDLINE]
3: Neuroscience. 2006;138(4):1179-94. Epub 2006 Jan 25.
Early signs of motoneuron vulnerability in a disease model system:
Characterization of transverse slice cultures of spinal cord isolated from
embryonic ALS mice.
Avossa D, Grandolfo M, Mazzarol F, Zatta M, Ballerini L.
Neurobiology Sector and Istituto Nazionale di Fisica della Materia Unit,
International School for Advanced Studies, via Beirut 2-4, 34014 Trieste, Italy.
Mutations in the SOD1 gene are associated with familial amyotrophic lateral
sclerosis. The mechanisms by which these mutations lead to cell loss within the
spinal cord ventral horns are unknown. In the present report we used the G93A
transgenic mouse model of amyotrophic lateral sclerosis to develop and
characterize an in vitro tool for the investigation of subtle alterations of
spinal tissue prior to frank neuronal degeneration. To this aim, we developed
organotypic slice cultures from wild type and G93A embryonic spinal cords. We
combined immunocytochemistry and electron microscopy techniques to compare wild
type and G93A spinal cord tissues after 14 days of growth under standard in
vitro conditions. By SMI32 and choline acetyl transferase immunostaining, the
distribution and morphology of motoneurons were compared in the two culture
groups. Wild type and mutant cultures displayed no differences in the analyzed
parameters as well as in the number of motoneurons. Similar results were
observed when glial fibrillary acidic protein and myelin basic protein-positive
cells were examined. Cell types within the G93A slice underwent maturation and
slices could be maintained in culture for at least 3 weeks when prepared from
embryos. Electron microscopy investigation confirmed the absence of early signs
of mitochondria vacuolization or protein aggregate formation in G93A ventral
horns. However, a significantly different ratio between inhibitory and
excitatory synapses was present in G93A cultures, when compared with wild type
ones, suggesting the expression of subtle synaptic dysfunction in G93A cultured
tissue. When compared with controls, G93A motoneurons exhibited increased
vulnerability to AMPA glutamate receptor-mediated excitotoxic stress prior to
clear disease appearance. This in vitro disease model may thus represent a
valuable tool to test early mechanisms contributing to motoneuron degeneration
and potential therapeutic molecular interventions.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16442737 [PubMed - indexed for MEDLINE]
2: Neurol Neurochir Pol. 2006 Jan-Feb;40(1):28-33.
Kawulak M, Lipniacki A.
Samodzielna Pracownia Wirusologii, Narodowy Instytut Zdrowia Publicznego, ul.
Chelmska 30/34, 00-725 Warszawa.
BACKGROUND AND PURPOSE: The role of viral infection in the pathogenesis of ALS
has been raised many times in the previous papers. The presence of an
enterovirus genome has previously been confirmed using PCR RT and PCR in situ in
spinal cord tissue samples taken from patients who died of ALS. Viral genome
sequencing has also been used to show 91% and 88% homogeneity with ECHO 6 and 7
viruses, respectively. A year later the same method did not confirm the presence
of the virus in spinal cord fragments taken from 30 patients who died of ALS nor
in an 18 person control group. The present study was aimed to find persistent
ECHO 6 and 7 viral infections in tissue samples taken from patients who died of
ALS. MATERIAL AND METHODS: RNA was isolated from frozen medulla oblongata
samples taken from six patients who died of ALS (hospitalized in the
Neurological Clinic CSK AM in the years 2000-2002). The presence of RNA was
confirmed using RNA beta-actine. Oligo 2 and 3 as well as pEforward and pErevers
primers were used for amplification. RESULTS: All samples returned negative
results. CONCLUSIONS: In the samples studied no correlation was found between
ECHO 6 and 7 viral infections and ALS.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
PMID: 16463219 [PubMed - indexed for MEDLINE]
1: Curr Neurol Neurosci Rep. 2006 Jan;6(1):37-46.
Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.
Andersen PM.
Department of Neurology, Umea University Hospital, SE-901 85, Umea, Sweden.
Peter.Andersen@neuro.umu.se
This review highlights recent epidemiologic, clinical-genetic, and neurochemical
advances in our understanding of sporadic amyotrophic lateral sclerosis (ALS)
and their relationships to familial ALS caused by superoxide dismutase (SOD1)
gene mutations. It is of fundamental importance to recognize that ALS is a
biologically heterogeneous syndrome in which genetics, environment, and aging
are inter-related. The discovery of mutations in the SOD1 gene is the greatest
breakthrough in ALS research since Charcot's description of the disorder, but
the putative toxic gain of function of mutant SOD1 remains elusive despite
intense research. Currently, two dominant theories for the pathogenesis of SOD1
mutations exist: specific protein cytotoxicity and protein aggregation. Mutant
SOD1 interacts specifically with neurofilament-light chain mRNA and the
dynein/dynactin complex, suggesting that cytoskeletal defects and axonal
transport are key players. In addition, mutant SOD1 protein has increased
propensity to form aggregate-prone monomers, and the degree of instability
correlates inversely with length of survival; therefore, increased propensity to
aggregate may be the unifying common denominator for the 119 diverse SOD1
mutations.
Publication Types:
Review
PMID: 16469270 [PubMed - indexed for MEDLINE]
