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33: Muscle Nerve. 2006 Aug;34(2):235-7.
Botulinum toxin improves sialorrhea and quality of living in bulbar amyotrophic lateral sclerosis.
Verma A, Steele J.
Department of Neurology, Kessenich Family MDA-ALS Center, 1150 NW 14th Street,
Suite 701, University of Miami Miller School of Medicine, Miami, Florida 33136,
USA. averma@med.miami.edu
Sialorrhea is frequently a socially disabling symptom in patients with bulbar amyotrophic lateral sclerosis (ALS). In this open-label prospective study, we report the effect of botulinum toxin A (Botox) injection into the parotid glands in 10 patients with bulbar ALS and socially disabling sialorrhea. We applied three different outcome measures to determine the effect of Botox therapy on sialorrhea. Botox significantly improved the degree of sialorrhea and a drooling impact score and, by inference, the quality of living, in over half of the patients with bulbar ALS and severe sialorrhea. The beneficial effect of Botox lasted for at least 2 months in those who responded. No major adverse effects
were noted. Local injection of a small dose of Botox into the parotid glands can
control sialorrhea and potentially improve living quality in some patients with
bulbar ALS.
Publication Types:
Clinical Trial
PMID: 16583370 [PubMed - indexed for MEDLINE]
32: J Neurol. 2006 Aug;253(8):1060-3. Epub 2006 Apr 11.
Rapid improvement in cortical neuronal integrity in amyotrophic lateral
sclerosis detected by proton magnetic resonance spectroscopic imaging.
Kalra S, Tai P, Genge A, Arnold DL.
Division of Neurology, Department of Medicine, University of Alberta, 2E3.18 WMC
8440-112 Street, Edmonton, T6G 2B7, Alberta, Canada. sanjay.kalra@ualberta.ca
Riluzole prolongs survival in amyotrophic lateral sclerosis. The temporal and
spatial profile of its effect on the brain is unknown. We used proton magnetic
resonance spectroscopic imaging to evaluate the neuronal response to 1 day of
riluzole treatment in motor and non-motor regions of the brain. In 10 patients
the N-acetylaspartate/total creatine (NAA/Cr) ratio increased in the precentral
gyrus and supplementary motor area, but not in the post-central gyrus or
parietal lobe. Improvement in cortical neuronal metabolic function in the motor
cortex occurs early with riluzole treatment.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16609809 [PubMed - indexed for MEDLINE]
31: J Neurol Neurosurg Psychiatry. 2006 Aug;77(8):948-50. Epub 2006 Apr 13.
Positive effects of tertiary centres for amyotrophic lateral sclerosis on
outcome and use of hospital facilities.
Chio A, Bottacchi E, Buffa C, Mutani R, Mora G; PARALS.
Divisione di Neurologia 1, Dipartimento di Neuroscienze, Universita di Torino,
Torino, Italy. achio@usa.net
OBJECTIVE: To evaluate the effects of tertiary centres for amyotrophic lateral sclerosis (ALS) on ALS outcome and the use of hospital facilities. METHODS: The study was based on the data of an epidemiological, prospective, population-based register on ALS (Piemonte and Valle d'Aosta Register for amyotrophic lateral sclerosis, PARALS). The 221 patients recruited between 1995 and 1996 were prospectively followed up for outcome and use of hospital-based services. RESULTS: In all, 97 patients were followed up by tertiary ALS centres and 124 by general neurological clinics. Patients followed up by tertiary ALS centres were found to be 4 years younger and underwent percutaneous endoscopic gastronomy and non-invasive positive-pressure ventilation more often. Patients followed up by tertiary ALS centres were found to have a considerably longer median survival time (1080 v 775 days), even when stratifying by age, site of onset and
respiratory function at diagnosis. In Cox multivariate analysis, attending a tertiary ALS centre was observed to be an independent positive prognostic factor. Moreover, patients attending a tertiary ALS centre were admitted to hospital less often (1.2 v 3.3) and were more frequently admitted for planned interventions. Conversely, patients followed up by general neurological clinics were more frequently admitted for acute events. Also, the hospital stay was considerably shorter for patients attending tertiary ALS centres (5.8 v 12.4 days). CONCLUSIONS: Improved survival was seen in patients with ALS attending
tertiary ALS centres, independently from all other known prognostic factors, possibly through a better implementation of supportive treatments. Moreover, because of these centres, the hospitalisation rate was markedly reduced, thus offering a cost-effective service to patients with ALS and to the community as a whole.
Publication Types:
Multicenter Study
Research Support, Non-U.S. Gov't
PMID: 16614011 [PubMed - indexed for MEDLINE]
30: J Neurol Sci. 2006 Aug 15;247(1):59-63. Epub 2006 Apr 24.
Longitudinal assessment of noninvasive positive pressure ventilation adjustments in ALS patients.
Gruis KL, Brown DL, Lisabeth LD, Zebarah VA, Chervin RD, Feldman EL.
TC 1920/0316, Department of Neurology, University of Michigan, Ann Arbor,
Michigan, USA. kgruis@umich.edu
The absence of data guiding optimal titration of noninvasive positive pressure
ventilation (NIPPV) over time in ALS patients may contribute to the under-prescribing of NIPPV. We conducted a retrospective, single-center, chart review assessment of NIPPV pressure settings used for symptomatic treatment of ALS patients to determine NIPPV adjustments, and to compare survival between those who were tolerant and intolerant to NIPPV. All subjects were started on nocturnal NIPPV at 8 and 3 cm H2O inspiratory and expiratory pressure, respectively. Of the 18 tolerant subjects identified, 4 (22%) had no NIPPV pressure changes before death; 8 (44%), 1 change; 4 (22%), 2 changes; 1 (6%), 3
changes; and 1 (6%), 5 changes. Most pressure changes occurred during the first
year of NIPPV initiation. The maximum pressure needed for comfort by any patient
in this study was 19/5 cm H2O, while 4 (22%) found the original 8/3 cm H2O settings to be sufficient until death. Subjects in the tolerant group had better survival, when adjusting for age and site of symptom onset (bulbar versus limb), with a hazard ratio of 0.23 [95% confidence interval: 0.10, 0.54]. The current data suggest that ALS patients who are tolerant to NIPPV typically need at least one upward change in pressure settings. Tolerance to relatively low NIPPV inspiratory pressures is associated with improved survival.
PMID: 16631799 [PubMed - indexed for MEDLINE]
29: Muscle Nerve. 2006 Aug;34(2):253-4.
Comment on:
Muscle Nerve. 2006 May;33(5):598-608.
Mitochondrial dysfunction in amyotrophic lateral sclerosis also affects skeletal
muscle.
Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, Loeffler JP.
Publication Types:
Comment
Letter
PMID: 16642501 [PubMed - indexed for MEDLINE]
28: J Neurol Sci. 2006 Aug 15;247(1):21-8. Epub 2006 May 3.
Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS
population: should all sporadic ALS cases also be screened for SOD1?
Gamez J, Corbera-Bellalta M, Nogales G, Raguer N, Garcia-Arumi E, Badia-Canto M,
Llado-Carbo E, Alvarez-Sabin J.
Department of Neurology, Hospital Universitari Vall d'Hebron, UAB, Passeig Vall
d'Hebron, 119-135, 08035 Barcelona, Spain. 12784jgc@comb.es
BACKGROUND: SOD1 gene mutations are the most common identified cause of ALS,
accounting for approximately 20% of familial ALS cases and around 4% of sporadic
ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No
previous epidemiological studies have been carried out in Catalonia. OBJECTIVE:
To determine the prevalence of SOD1 gene mutations in a Catalan ALS population,
and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS: 30
different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1
mutations using direct sequence analysis. RESULTS: Five of the 30 FALS pedigrees
(16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R,
D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the
sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1
mutations in our series was 6.45%. In the SALS group, D90A was identified in a
patient presenting the typical Scandinavian phenotype. A 53-year-old woman with
no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS
cases carried the A140A SOD1 mutant. CONCLUSIONS: The prevalence of the SOD1
mutation in FALS in Catalonia is similar to levels in other Mediterranean
countries, but lower than those in reports studying the Belgian, Japanese, and
Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients
with no family history of ALS. These results may have significant repercussions
on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases
must therefore be considered.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16674979 [PubMed - indexed for MEDLINE]
27: Clin Nutr. 2006 Aug;25(4):705.
Comment on:
Clin Nutr. 2005 Oct;24(5):848-61.
What can we do for ALS patients with low vital capacity needing a digestive access for enteral nutrition?
Desport JC, Couratier P, Preux PM.
Publication Types:
Comment
Letter
PMID: 16769158 [PubMed - indexed for MEDLINE]
26: Eur J Pharmacol. 2006 Aug 7;542(1-3):100-5. Epub 2006 May 20.
AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.
Kim K, Moore DH, Makriyannis A, Abood ME.
Forbes Norris MDA/ALS Research Center, California Pacific Medical Center Research Institute, 475 Brannan St Suite 220, San Francisco, CA 94107, USA.
Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive.
Motor neuron degeneration is the primary pathology in ALS; however non-neuronal
cells contribute to the disease process. In particular, inflammatory processes
have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor
selective agonist that has been shown to be effective in models of inflammation
and hyperalgesia. Here we report that treatment with AM1241 was effective at
slowing signs of disease progression when administered after onset of signs in
an ALS mouse model (hSOD1(G93A) transgenic mice). Administration at the onset of
tremors delayed motor impairment in treated mice when compared to vehicle
controls. Three conditions of ALS, the loss of motor function, paralysis scoring
and weight loss, were analyzed using a mathematical model. Loss of motor
function (as assessed by performance on a rotarod) was delayed by 12.5 days in
male mice by AM1241. In female mice, AM1241 extended rotarod performance by 3
days, although this was not statistically significant. In male mice, AM1241 also
extended by 5 days the time to reach the 50% point on a visually-assessed
performance scale. AM1241 did not affect weight loss or survival (129.8+/-1.7
days, vehicle; 129.1+/-7.0 days, AM1241, n=16). As AM1241 was well tolerated by
the animals, cannabinoid CB2 receptor-selective compounds may be the basis for
developing new drugs for the treatment of ALS and other chronic
neurodegenerative diseases.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16781706 [PubMed - indexed for MEDLINE]
25: Cell Mol Life Sci. 2006 Aug;63(15):1725-35.
Rubinstein-Taybi syndrome: molecular findings and therapeutic approaches to improve cognitive dysfunction.
Hallam TM, Bourtchouladze R.
Helicon Therapeutics, Inc., One Bioscience Park Drive, Farmingdale, New York 11735, USA.
Rubinstein-Taybi syndrome (RTS) is a rare human genetic disorder characterized by mental retardation and physical abnormalities. Many RTS patients have a genetic mutation which has been mapped to chromosome 16p13.3, a genomic region encoding cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). CBP is a transcriptional co-activator that binds to CREB when the latter is phosphorylated and promotes gene transcription. CREB-dependent gene transcription has been shown to underlie long-term memory formation. In this review we will focus on recent findings regarding the biology of CBP and its role in memory formation and cognitive dysfunction in RTS. We will also review the role of CBP in other neurological disorders, including Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Finally, we will discuss novel therapeutic approaches targeted to CBP/CREB function for treating the
cognitive dysfunction of RTS and other neurological disorders.
Publication Types:
Review
PMID: 16786226 [PubMed - indexed for MEDLINE]
24: J Neurochem. 2006 Aug;98(3):926-38. Epub 2006 Jun 19.
Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin.
Millecamps S, Robertson J, Lariviere R, Mallet J, Julien JP.
Research Centre of Centre Hospitalier Universitaire de Quebec, Department of Anatomy and Physiology of Laval University, Quebec, Canada.
Peripherin is a type III neuronal intermediate filament detected in motor neuron inclusions of amyotrophic lateral sclerosis (ALS) patients. We previously reported that overexpression of peripherin provokes late-onset motor neuron dysfunction in transgenic mice. Here, we show that peripherin overexpression slows down axonal transport of neurofilament (NF) proteins, and that the transport defect precedes by several months the appearance of axonal spheroids in adult mice. Defective NF transport by peripherin up-regulation was further confirmed with dorsal root ganglia (DRG) neurons cultured from peripherin transgenic embryos. Immunofluorescence microscopy and western blotting revealed that excess peripherin provokes reduction in levels of hyperphosphorylated NF-H
species in DRG neurites. Similarly the transport of a green fluorescent protein (GFP)-tagged NF-M, delivered by means of a lentiviral construct, was impaired in DRG neurites overexpressing peripherin. These results demonstrate that peripherin overexpression can cause defective transport of type IV NF proteins, a phenomenon that may account for the progressive formation of ALS-like spheroids in axons.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16787413 [PubMed - indexed for MEDLINE]
23: Clin Neurophysiol. 2006 Aug;117(8):1850-61. Epub 2006 Jun 21.
Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.
Stewart HG, Andersen PM, Eisen A, Weber M.
Institute of Clinical Neurosciences, Umea University Hospital, Umea, Sweden.
OBJECTIVE: To examine corticomotoneuronal function in amyotrophic lateral
sclerosis (ALS) patients carrying superoxide dismutase 1 (SOD1) mutations using
peristimulus time histograms (PSTH). METHODS: Six I113T, 3 A4V, one G41D and one
G114A patient were studied along with 21 healthy control subjects. Analyses included comparison with previously reported data from 8 D90A homozygous and 12 sporadic ALS (SALS) patients examined by the authors using identical methodology. RESULTS: Cortical threshold was significantly reduced in A4V patients (41.3%) compared to I113T (58%), SALS (57%) and D90A (71%) patients, as well as healthy controls (49.7%). Estimated excitatory postsynaptic potentials (EPSPs) were significantly larger in A4V patients (4.39 mV) compared to healthy controls (2.95 mV), I113T (2.71 mV) and SALS (2.39 mV) patients. Clinical features and PSTH parameters in I113T were similar to SALS, however, PSTH primary peaks (PP) were significantly more dispersed, 9.5 ms compared to 4ms in SALS. PSTHs from single G41D and G114A patients were unremarkable, apart from large EPSP amplitudes in the G114A patient. CONCLUSIONS: ALS patients with A4V and I113T SOD1 mutations have distinctive corticomotoneuronal changes that are different from those in D90A homozygous and SALS patients. SIGNIFICANCE: PSTH studies should be considered for future in vivo studies of SOD1 pathophysiology in ALS.
Publication Types:
Comparative Study
Historical Article
Research Support, Non-U.S. Gov't
PMID: 16793335 [PubMed - indexed for MEDLINE]
33: Muscle Nerve. 2006 Aug;34(2):235-7.
Botulinum toxin improves sialorrhea and quality of living in bulbar amyotrophic lateral sclerosis.
Verma A, Steele J.
Department of Neurology, Kessenich Family MDA-ALS Center, 1150 NW 14th Street,
Suite 701, University of Miami Miller School of Medicine, Miami, Florida 33136,
USA. averma@med.miami.edu
Sialorrhea is frequently a socially disabling symptom in patients with bulbar amyotrophic lateral sclerosis (ALS). In this open-label prospective study, we report the effect of botulinum toxin A (Botox) injection into the parotid glands in 10 patients with bulbar ALS and socially disabling sialorrhea. We applied three different outcome measures to determine the effect of Botox therapy on sialorrhea. Botox significantly improved the degree of sialorrhea and a drooling impact score and, by inference, the quality of living, in over half of the patients with bulbar ALS and severe sialorrhea. The beneficial effect of Botox lasted for at least 2 months in those who responded. No major adverse effects
were noted. Local injection of a small dose of Botox into the parotid glands can
control sialorrhea and potentially improve living quality in some patients with
bulbar ALS.
Publication Types:
Clinical Trial
PMID: 16583370 [PubMed - indexed for MEDLINE]
32: J Neurol. 2006 Aug;253(8):1060-3. Epub 2006 Apr 11.
Rapid improvement in cortical neuronal integrity in amyotrophic lateral
sclerosis detected by proton magnetic resonance spectroscopic imaging.
Kalra S, Tai P, Genge A, Arnold DL.
Division of Neurology, Department of Medicine, University of Alberta, 2E3.18 WMC
8440-112 Street, Edmonton, T6G 2B7, Alberta, Canada. sanjay.kalra@ualberta.ca
Riluzole prolongs survival in amyotrophic lateral sclerosis. The temporal and
spatial profile of its effect on the brain is unknown. We used proton magnetic
resonance spectroscopic imaging to evaluate the neuronal response to 1 day of
riluzole treatment in motor and non-motor regions of the brain. In 10 patients
the N-acetylaspartate/total creatine (NAA/Cr) ratio increased in the precentral
gyrus and supplementary motor area, but not in the post-central gyrus or
parietal lobe. Improvement in cortical neuronal metabolic function in the motor
cortex occurs early with riluzole treatment.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16609809 [PubMed - indexed for MEDLINE]
31: J Neurol Neurosurg Psychiatry. 2006 Aug;77(8):948-50. Epub 2006 Apr 13.
Positive effects of tertiary centres for amyotrophic lateral sclerosis on
outcome and use of hospital facilities.
Chio A, Bottacchi E, Buffa C, Mutani R, Mora G; PARALS.
Divisione di Neurologia 1, Dipartimento di Neuroscienze, Universita di Torino,
Torino, Italy. achio@usa.net
OBJECTIVE: To evaluate the effects of tertiary centres for amyotrophic lateral sclerosis (ALS) on ALS outcome and the use of hospital facilities. METHODS: The study was based on the data of an epidemiological, prospective, population-based register on ALS (Piemonte and Valle d'Aosta Register for amyotrophic lateral sclerosis, PARALS). The 221 patients recruited between 1995 and 1996 were prospectively followed up for outcome and use of hospital-based services. RESULTS: In all, 97 patients were followed up by tertiary ALS centres and 124 by general neurological clinics. Patients followed up by tertiary ALS centres were found to be 4 years younger and underwent percutaneous endoscopic gastronomy and non-invasive positive-pressure ventilation more often. Patients followed up by tertiary ALS centres were found to have a considerably longer median survival time (1080 v 775 days), even when stratifying by age, site of onset and
respiratory function at diagnosis. In Cox multivariate analysis, attending a tertiary ALS centre was observed to be an independent positive prognostic factor. Moreover, patients attending a tertiary ALS centre were admitted to hospital less often (1.2 v 3.3) and were more frequently admitted for planned interventions. Conversely, patients followed up by general neurological clinics were more frequently admitted for acute events. Also, the hospital stay was considerably shorter for patients attending tertiary ALS centres (5.8 v 12.4 days). CONCLUSIONS: Improved survival was seen in patients with ALS attending
tertiary ALS centres, independently from all other known prognostic factors, possibly through a better implementation of supportive treatments. Moreover, because of these centres, the hospitalisation rate was markedly reduced, thus offering a cost-effective service to patients with ALS and to the community as a whole.
Publication Types:
Multicenter Study
Research Support, Non-U.S. Gov't
PMID: 16614011 [PubMed - indexed for MEDLINE]
30: J Neurol Sci. 2006 Aug 15;247(1):59-63. Epub 2006 Apr 24.
Longitudinal assessment of noninvasive positive pressure ventilation adjustments in ALS patients.
Gruis KL, Brown DL, Lisabeth LD, Zebarah VA, Chervin RD, Feldman EL.
TC 1920/0316, Department of Neurology, University of Michigan, Ann Arbor,
Michigan, USA. kgruis@umich.edu
The absence of data guiding optimal titration of noninvasive positive pressure
ventilation (NIPPV) over time in ALS patients may contribute to the under-prescribing of NIPPV. We conducted a retrospective, single-center, chart review assessment of NIPPV pressure settings used for symptomatic treatment of ALS patients to determine NIPPV adjustments, and to compare survival between those who were tolerant and intolerant to NIPPV. All subjects were started on nocturnal NIPPV at 8 and 3 cm H2O inspiratory and expiratory pressure, respectively. Of the 18 tolerant subjects identified, 4 (22%) had no NIPPV pressure changes before death; 8 (44%), 1 change; 4 (22%), 2 changes; 1 (6%), 3
changes; and 1 (6%), 5 changes. Most pressure changes occurred during the first
year of NIPPV initiation. The maximum pressure needed for comfort by any patient
in this study was 19/5 cm H2O, while 4 (22%) found the original 8/3 cm H2O settings to be sufficient until death. Subjects in the tolerant group had better survival, when adjusting for age and site of symptom onset (bulbar versus limb), with a hazard ratio of 0.23 [95% confidence interval: 0.10, 0.54]. The current data suggest that ALS patients who are tolerant to NIPPV typically need at least one upward change in pressure settings. Tolerance to relatively low NIPPV inspiratory pressures is associated with improved survival.
PMID: 16631799 [PubMed - indexed for MEDLINE]
29: Muscle Nerve. 2006 Aug;34(2):253-4.
Comment on:
Muscle Nerve. 2006 May;33(5):598-608.
Mitochondrial dysfunction in amyotrophic lateral sclerosis also affects skeletal
muscle.
Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, Loeffler JP.
Publication Types:
Comment
Letter
PMID: 16642501 [PubMed - indexed for MEDLINE]
28: J Neurol Sci. 2006 Aug 15;247(1):21-8. Epub 2006 May 3.
Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS
population: should all sporadic ALS cases also be screened for SOD1?
Gamez J, Corbera-Bellalta M, Nogales G, Raguer N, Garcia-Arumi E, Badia-Canto M,
Llado-Carbo E, Alvarez-Sabin J.
Department of Neurology, Hospital Universitari Vall d'Hebron, UAB, Passeig Vall
d'Hebron, 119-135, 08035 Barcelona, Spain. 12784jgc@comb.es
BACKGROUND: SOD1 gene mutations are the most common identified cause of ALS,
accounting for approximately 20% of familial ALS cases and around 4% of sporadic
ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No
previous epidemiological studies have been carried out in Catalonia. OBJECTIVE:
To determine the prevalence of SOD1 gene mutations in a Catalan ALS population,
and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS: 30
different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1
mutations using direct sequence analysis. RESULTS: Five of the 30 FALS pedigrees
(16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R,
D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the
sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1
mutations in our series was 6.45%. In the SALS group, D90A was identified in a
patient presenting the typical Scandinavian phenotype. A 53-year-old woman with
no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS
cases carried the A140A SOD1 mutant. CONCLUSIONS: The prevalence of the SOD1
mutation in FALS in Catalonia is similar to levels in other Mediterranean
countries, but lower than those in reports studying the Belgian, Japanese, and
Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients
with no family history of ALS. These results may have significant repercussions
on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases
must therefore be considered.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16674979 [PubMed - indexed for MEDLINE]
27: Clin Nutr. 2006 Aug;25(4):705.
Comment on:
Clin Nutr. 2005 Oct;24(5):848-61.
What can we do for ALS patients with low vital capacity needing a digestive access for enteral nutrition?
Desport JC, Couratier P, Preux PM.
Publication Types:
Comment
Letter
PMID: 16769158 [PubMed - indexed for MEDLINE]
26: Eur J Pharmacol. 2006 Aug 7;542(1-3):100-5. Epub 2006 May 20.
AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.
Kim K, Moore DH, Makriyannis A, Abood ME.
Forbes Norris MDA/ALS Research Center, California Pacific Medical Center Research Institute, 475 Brannan St Suite 220, San Francisco, CA 94107, USA.
Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive.
Motor neuron degeneration is the primary pathology in ALS; however non-neuronal
cells contribute to the disease process. In particular, inflammatory processes
have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor
selective agonist that has been shown to be effective in models of inflammation
and hyperalgesia. Here we report that treatment with AM1241 was effective at
slowing signs of disease progression when administered after onset of signs in
an ALS mouse model (hSOD1(G93A) transgenic mice). Administration at the onset of
tremors delayed motor impairment in treated mice when compared to vehicle
controls. Three conditions of ALS, the loss of motor function, paralysis scoring
and weight loss, were analyzed using a mathematical model. Loss of motor
function (as assessed by performance on a rotarod) was delayed by 12.5 days in
male mice by AM1241. In female mice, AM1241 extended rotarod performance by 3
days, although this was not statistically significant. In male mice, AM1241 also
extended by 5 days the time to reach the 50% point on a visually-assessed
performance scale. AM1241 did not affect weight loss or survival (129.8+/-1.7
days, vehicle; 129.1+/-7.0 days, AM1241, n=16). As AM1241 was well tolerated by
the animals, cannabinoid CB2 receptor-selective compounds may be the basis for
developing new drugs for the treatment of ALS and other chronic
neurodegenerative diseases.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16781706 [PubMed - indexed for MEDLINE]
25: Cell Mol Life Sci. 2006 Aug;63(15):1725-35.
Rubinstein-Taybi syndrome: molecular findings and therapeutic approaches to improve cognitive dysfunction.
Hallam TM, Bourtchouladze R.
Helicon Therapeutics, Inc., One Bioscience Park Drive, Farmingdale, New York 11735, USA.
Rubinstein-Taybi syndrome (RTS) is a rare human genetic disorder characterized by mental retardation and physical abnormalities. Many RTS patients have a genetic mutation which has been mapped to chromosome 16p13.3, a genomic region encoding cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). CBP is a transcriptional co-activator that binds to CREB when the latter is phosphorylated and promotes gene transcription. CREB-dependent gene transcription has been shown to underlie long-term memory formation. In this review we will focus on recent findings regarding the biology of CBP and its role in memory formation and cognitive dysfunction in RTS. We will also review the role of CBP in other neurological disorders, including Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Finally, we will discuss novel therapeutic approaches targeted to CBP/CREB function for treating the
cognitive dysfunction of RTS and other neurological disorders.
Publication Types:
Review
PMID: 16786226 [PubMed - indexed for MEDLINE]
24: J Neurochem. 2006 Aug;98(3):926-38. Epub 2006 Jun 19.
Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin.
Millecamps S, Robertson J, Lariviere R, Mallet J, Julien JP.
Research Centre of Centre Hospitalier Universitaire de Quebec, Department of Anatomy and Physiology of Laval University, Quebec, Canada.
Peripherin is a type III neuronal intermediate filament detected in motor neuron inclusions of amyotrophic lateral sclerosis (ALS) patients. We previously reported that overexpression of peripherin provokes late-onset motor neuron dysfunction in transgenic mice. Here, we show that peripherin overexpression slows down axonal transport of neurofilament (NF) proteins, and that the transport defect precedes by several months the appearance of axonal spheroids in adult mice. Defective NF transport by peripherin up-regulation was further confirmed with dorsal root ganglia (DRG) neurons cultured from peripherin transgenic embryos. Immunofluorescence microscopy and western blotting revealed that excess peripherin provokes reduction in levels of hyperphosphorylated NF-H
species in DRG neurites. Similarly the transport of a green fluorescent protein (GFP)-tagged NF-M, delivered by means of a lentiviral construct, was impaired in DRG neurites overexpressing peripherin. These results demonstrate that peripherin overexpression can cause defective transport of type IV NF proteins, a phenomenon that may account for the progressive formation of ALS-like spheroids in axons.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16787413 [PubMed - indexed for MEDLINE]
23: Clin Neurophysiol. 2006 Aug;117(8):1850-61. Epub 2006 Jun 21.
Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.
Stewart HG, Andersen PM, Eisen A, Weber M.
Institute of Clinical Neurosciences, Umea University Hospital, Umea, Sweden.
OBJECTIVE: To examine corticomotoneuronal function in amyotrophic lateral
sclerosis (ALS) patients carrying superoxide dismutase 1 (SOD1) mutations using
peristimulus time histograms (PSTH). METHODS: Six I113T, 3 A4V, one G41D and one
G114A patient were studied along with 21 healthy control subjects. Analyses included comparison with previously reported data from 8 D90A homozygous and 12 sporadic ALS (SALS) patients examined by the authors using identical methodology. RESULTS: Cortical threshold was significantly reduced in A4V patients (41.3%) compared to I113T (58%), SALS (57%) and D90A (71%) patients, as well as healthy controls (49.7%). Estimated excitatory postsynaptic potentials (EPSPs) were significantly larger in A4V patients (4.39 mV) compared to healthy controls (2.95 mV), I113T (2.71 mV) and SALS (2.39 mV) patients. Clinical features and PSTH parameters in I113T were similar to SALS, however, PSTH primary peaks (PP) were significantly more dispersed, 9.5 ms compared to 4ms in SALS. PSTHs from single G41D and G114A patients were unremarkable, apart from large EPSP amplitudes in the G114A patient. CONCLUSIONS: ALS patients with A4V and I113T SOD1 mutations have distinctive corticomotoneuronal changes that are different from those in D90A homozygous and SALS patients. SIGNIFICANCE: PSTH studies should be considered for future in vivo studies of SOD1 pathophysiology in ALS.
Publication Types:
Comparative Study
Historical Article
Research Support, Non-U.S. Gov't
PMID: 16793335 [PubMed - indexed for MEDLINE]
22: Trends Mol Med. 2006 Aug;12(8):345-7. Epub 2006 Jul 14.
Another angiogenic gene linked to amyotrophic lateral sclerosis.
Lambrechts D, Lafuste P, Carmeliet P, Conway EM.
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KU Leuven, B-3000 Leuven, Belgium.
A new study by Greenway and colleagues links mutations in the angiogenin gene to
patients with amyotrophic lateral sclerosis (ALS)--a progressive and fatal motoneuron disease. This is an unexpected finding because angiogenin was originally identified as a molecule involved in the formation of blood vessels (angiogenesis). Angiogenin bears striking similarity to vascular endothelial growth factor (VEGF), which is the prototypic angiogenic factor that has recently emerged as a molecule with important neuroprotective activities. Besides VEGF, angiogenin is the second so-called angiogenic factor implicated in ALS, raising the question of whether additional angiogenic factors might have a role in ALS. Overall, these findings identify angiogenin as a novel candidate gene in the pathogenesis of ALS--a discovery that ultimately might lead to the development of new therapeutic strategies.
PMID: 16843725 [PubMed - indexed for MEDLINE]
21: Int J Neurosci. 2006 Aug;116(8):907-14.
Consequences of misdiagnosing mitochondrial disorder.
Finsterer J.
Krankenanstalt Rudolfstiftung, Vienna, Austria. duarte@aonmail.at
Diagnosing mitochondrial disorder remains a challenge. In a 75-year-old women,
with short stature, muscle cramps, ptosis, fasciculations and progressive, proximal limb weakness and wasting, hyponatriemia, abnormal lactate-stress-test, and slightly abnormal electromyography, muscle biopsy suggested granulomatous myositis. Corticosteroids and azathioprin were ineffective. After a second work-up amyotrophic-lateral-sclerosis was diagnosed. Riluzole was started, without effect. She developed respiratory insufficiency, requiring mechanical ventilation. Apical ballooning was found. After switching to non-invasive positive pressure ventilation and physiotherapy, she markedly improved. After a third diagnostic work-up, mitochondrial disorder was suspected. Unfortunately, she died suddenly from a cardiac arrhythmia at home. Mitochondrial disorder may mimic motor neuron disease, muscle biopsy may mimic myositis, and may show only little evidence for respiratory chain disorder.
Publication Types:
Case Reports
PMID: 16861155 [PubMed - indexed for MEDLINE]
20: Respir Care. 2006 Aug;51(8):871-81; discussion 881-4.
Respiratory effects of amyotrophic lateral sclerosis: problems and solutions.
Lechtzin N.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns
Hopkins University, Baltimore MD 21205, USA. nlechtz1@jhmi.edu
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
Most patients die from respiratory complications. Fortunately, there are a growing number of treatment options that can improve both survival and quality of life for patients with ALS. This review discusses the respiratory evaluation and treatment of patients with ALS, about which a great deal is known. It also includes material on related problems, such as speech and swallowing difficulties and end-of-life care.
PMID: 16867198 [PubMed - indexed for MEDLINE]
19: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12132-7. Epub 2006 Jul 28.
The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice.
Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S.
Department of Neurology, Columbia University, New York, NY 10032, USA.
ALS is a fatal paralytic disorder characterized by a progressive loss of spinal cord motor neurons. Herein, we show that NADPH oxidase, the main reactive oxygen species-producing enzyme during inflammation, is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model of this disease. We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival. We also show that NADPH oxidase-derived oxidant products damage proteins such as insulin-like growth factor 1 (IGF1) receptors, which are located on motor neurons. Our in vivo and in vitro data
indicate that such an oxidative modification hinders the IGF1/Akt survival pathway in motor neurons. These findings suggest a non-cell-autonomous mechanism through which inflammation could hasten motor neuron death and contribute to the selective motor neuronal degeneration in 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.
PMID: 16877542 [PubMed - indexed for MEDLINE]
18: Nat Med. 2006 Aug;12(8):885-7
ALS: life and death in a bad neighborhood.
Monk PN, Shaw PJ.
Publication Types:
News
PMID: 16892030 [PubMed - indexed for MEDLINE]
17: No To Shinkei. 2006 Aug;58(8):661-9.
Nakajima T.
Niigata National Hospital, National Hospital Organization, Japan.
Publication Types:
Evaluation Studies
PMID: 16986672 [PubMed - indexed for MEDLINE]
16: No To Shinkei. 2006 Aug;58(8):653-9.
Kondo K.
Department of Neurology, Yoka Hospital, Yabu-city, Hyogo, Japan.
PMID: 16986671 [PubMed - indexed for MEDLINE]
15: No To Shinkei. 2006 Aug;58(8):645-51.
Reiko N.
Neurology Clinic Namba, Okayama, Japan.
Taking into account how to care patients at home with intractable neurological
disease and their family, I have introduced the achievement of the medical
caring technique by an aged family member, the risks of the PEG and acute
respiratory failures under BiPAP, the problems in home rehabilitation, and the
experiences of home terminal care, from the view point of a practicing
physician. Home caring pursues to support patients and their family to live
peacefully with disease with highest quality of life. Hospice caring is also an
important issue. From now on, I would like to try to give even better home care
by early recognition of problems and by cooperating with hospitals, clinics and
other field workers.
Publication Types:
English Abstract
PMID: 16986670 [PubMed - indexed for MEDLINE]
14: No To Shinkei. 2006 Aug;58(8):639-43.
Igata A.
Nagoya University of Arts and Sciences, Nissin-city, Aichi, Japan.
PMID: 16986669 [PubMed - indexed for MEDLINE]
13: Neuroepidemiology. 2006;27(3):130-5. Epub 2006 Aug 1.
Amyotrophic lateral sclerosis and exposure to environmental toxins: an
Australian case-control study.
Morahan JM, Pamphlett R.
Department of Pathology, University of Sydney, Sydney, Australia.
It has been suggested that environmental toxins could be risk factors for sporadic amyotrophic lateral sclerosis (SALS). We therefore analysed epidemiological data on 179 SALS cases and 179 age-, ethnicity- and sex-matched controls in Australia using self-reporting questionnaires. SALS was associated with solvent/chemical exposure (OR = 1.92, 95% CI: 1.26-2.93), overall herbicide/pesticide exposure (OR = 1.57, 95% CI: 1.03-2.41) and industrial herbicide/pesticide exposure (OR = 5.58, 95% CI: 2.07-15.06). Exposure to herbicides/pesticides showed a dose-response effect. All positive findings were more statistically significant in males. These findings support those from northern hemisphere studies, indicating that environmental toxins can be risk factors for SALS. Copyright (c) 2006 S. Karger AG, Basel.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16946624 [PubMed - indexed for MEDLINE]
12: Neuroepidemiology. 2006;27(3):117-21. Epub 2006 Aug 1.
Effect of reproductive factors and postmenopausal hormone use on the risk of
amyotrophic lateral sclerosis.
Popat RA, Van Den Eeden SK, Tanner CM, Bernstein AL, Bloch DA, Leimpeter A,
McGuire V, Nelson LM.
Department of Health Research and Policy, Division of Epidemiology, Stanford
University School of Medicine, Stanford, Calif, USA. rpopat@stanford.edu
OBJECTIVE: To examine the associations of reproductive factors and
postmenopausal hormone use with the risk of amyotrophic lateral sclerosis (ALS)
among women. METHODS: This case-control study was conducted within the Kaiser
Permanente Medical Care Program (KPMCP) of Northern California during the years
1996-2000. Among the 193 postmenopausal women, 62 were incident ALS cases and
131 were controls randomly selected from KPMCP members and frequency matched by
age and respondent type (self versus proxy) to the cases. Statistical analyses
were carried out using logistic regression. RESULTS: Reproductive factors such
as age at menarche, age at final menstrual period, parity, oral contraceptive
use, and type of menopause (natural vs. hysterectomy with or without
oophorectomy) were not associated with risk of ALS. Postmenopausal hormone use
was positively, but not significantly, associated with the risk of ALS (adjusted
OR 1.9, 95% CI 0.9-3.8). CONCLUSIONS: Reproductive factors were not associated
with ALS risk. There is no evidence that suggests a protective effect of
postmenopausal hormone use against the development of ALS. However, due to
insufficient power, we cannot rule out a possible increase in ALS risk
associated with postmenopausal hormone use. Copyright (c) 2006 S. Karger AG,
Basel
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16946622 [PubMed - indexed for MEDLINE]
11: J Neurosci. 2006 Aug 23;26(34):8774-86.
Comment in:
J Neurosci. 2006 Dec 13;26(50):12849-51.
Complete dissociation of motor neuron death from motor dysfunction by Bax
deletion in a mouse model of ALS.
Gould TW, Buss RR, Vinsant S, Prevette D, Sun W, Knudson CM, Milligan CE,
Oppenheim RW.
Department of Neurobiology and Anatomy and Program in Neuroscience, Wake Forest
University, Winston-Salem, North Carolina 27157-1010, USA.
The death of cranial and spinal motoneurons (MNs) is believed to be an essential
component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested
this hypothesis by crossing Bax-deficient mice with mice expressing mutant
superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax
deletion failed to prevent neuromuscular denervation and mitochondrial
vacuolization, MNs were completely rescued from mutant SOD1-mediated death.
However, Bax deficiency extended lifespan and delayed the onset of motor
dysfunction of SOD1 mutants, suggesting that Bax acts via a mechanism distinct
from cell death activation. Consistent with this idea, Bax elimination delayed
the onset of neuromuscular denervation, which began long before the activation
of cell death proteins in SOD1 mutants. Additionally, we show that denervation
preceded accumulation of mutant SOD1 within MNs and astrogliosis in the spinal
cord, which are also both delayed in Bax-deficient SOD1 mutants. Interestingly,
MNs exhibited mitochondrial abnormalities at the innervated neuromuscular junction at the onset of neuromuscular denervation. Additionally, both MN presynaptic terminals and terminal Schwann cells expressed high levels of mutant SOD1 before MNs withdrew their axons. Together, these data support the idea that clinical symptoms in the SOD1 G93A model of ALS result specifically from damage to the distal motor axon and not from activation of the death pathway, and cast doubt on the utility of anti-apoptotic therapies to combat ALS. Furthermore, they suggest a novel, cell death-independent role for Bax in facilitating mutant SOD1-mediated motor denervation.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16928866 [PubMed - indexed for MEDLINE]
10: Tanpakushitsu Kakusan Koso. 2006 Aug;51(10 Suppl):1423-7.
Niwa J, Sobue G.
Publication Types:
Review
PMID: 16922412 [PubMed - indexed for MEDLINE]
9: J Biol Chem. 2006 Oct 13;281(41):30524-33. Epub 2006 Aug 18.
Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide
dismutase proteins by macroautophagy and the proteasome.
Kabuta T, Suzuki Y, Wada K.
Department of Degenerative Neurological Diseases, National Institute of
Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo
187-8502, Japan.
Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause approximately 20%
of familial cases of amyotrophic lateral sclerosis (fALS). Accumulating evidence
indicates that a gain of toxic function of mutant SOD1 proteins is the cause of
the disease. It has also been shown that the ubiquitin-proteasome pathway plays
a role in the clearance and toxicity of mutant SOD1. In this study, we investigated the degradation pathways of wild-type and mutant SOD1 in neuronal and nonneuronal cells. We provide here the first evidence that wild-type and mutant SOD1 are degraded by macroautophagy as well as by the proteasome. Based on experiments with inhibitors of these degradation pathways, the contribution of macroautophagy to mutant SOD1 clearance is comparable with that of the proteasome pathway. Using assays that measure cell viability and cell death, we observed that under conditions where expression of mutant SOD1 alone does not induce toxicity, macroautophagy inhibition induced mutant SOD1-mediated cell death, indicating that macroautophagy reduces the toxicity of mutant SOD1 proteins. We therefore propose that both macroautophagy and the proteasome are
important for the reduction of mutant SOD1-mediated neurotoxicity in fALS. Inhibition of macroautophagy also increased SOD1 levels in detergent-soluble and -insoluble fractions, suggesting that both detergent-soluble and -insoluble SOD1 are degraded by macroautophagy. These findings may provide further insights into the mechanisms of pathogenesis of fALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16920710 [PubMed - indexed for MEDLINE]
8: Neuromuscul Disord. 2006 Aug;16(8):510-3. Epub 2006 Aug 21.
A case of neuromuscular mimicry.
Bos MM, Overeem S, van Engelen BG, Scheffer H, van den Elzen C, Ter Laak H,
Lammens M, Schelhaas HJ, Zwarts MJ.
Department of Neurology, Radboud University, Nijmegen Medical Center, Nijmegen,
Netherlands. m.m.bos@neuro.umcn.nl
Recognizing an ALS-mimic can be challenging. Here, we describe a patient with a
slowly progressive dysarthria and dysphagia, with fasciculations of the tongue
and general hyperreflexia, fulfilling the diagnostic criteria of 'clinical probable ALS'. Because of a non-conclusive EMG, a muscle biopsy was performed that surprisingly showed widespread nemaline rods. The clinical features and the histological findings were compatible with a sporadic late onset nemaline myopathy. Three years after initial presentation the patient died and post-mortem examination not only showed nemaline bodies in every muscle examined, but also revealed an unsuspected final diagnosis: sarcoid brainstem encephalitis. Nemaline rods can be found in various disorders, and
neurosarcoidosis should be added to this list.
Publication Types:
Case Reports
PMID: 16919950 [PubMed - indexed for MEDLINE]
7: Recenti Prog Med. 2006 Jul-Aug;97(7-8):408-10.
Cristani A, Romagnoli E.
Unita operativa di Medicina II, Dipartimento di Medicina Interna e Specialita Mediche, Ospedale Policlinico, Universita di Modena e Reggio Emilia. cristani.alessandro@policlinico.mo.it
From "Lou" Gehirg to Gianluca Signorini: the history of almost 70 years of link between amyotrophic lateral sclerosis and sport. From first intuitions and assumptions to late epidemiological evidences supporting the possible relation between Italian soccer and amyotrophic lateral sclerosis; comparison among old and new aetiopathogenetic hypothesis.
Publication Types:
Biography
English Abstract
Historical Article
Personal Name as Subject:
Gehrig HL
Signorini G
PMID: 16913179 [PubMed - indexed for MEDLINE]
6: Arch Neurol. 2006 Aug;63(8):1144-8.
Detection of cerebral degeneration in amyotrophic lateral sclerosis using
high-field magnetic resonance spectroscopy.
Kalra S, Hanstock CC, Martin WR, Allen PS, Johnston WS.
Division of Neurology, Department of Medicine, University of Alberta, Walter C.
Mackenzie Health Sciences Centre, 8440 112th Street, Edmonton, Alberta, Canada.
sanjay.kalra@ualberta.ca
BACKGROUND: Clinical assessment is insensitive to the degree of cerebral
involvement in amyotrophic lateral sclerosis (ALS). Regional brain
concentrations N-acetylaspartylglutamate (NAA) plus myo-inositol (Ins), as
measured by magnetic resonance spectroscopy, are respectively decreased and
increased, suggesting that these compounds may provide a biomarker of the degree
of cerebral involvement in ALS. OBJECTIVE: To test the hypothesis that the
NAA/Ins ratio may provide an index of cerebral involvement in patients with ALS.
DESIGN: High-field (3.0-T) magnetic resonance spectroscopy was performed to
determine the NAA/creatine plus phosphocreatine (NAA/Cr), NAA/choline (NAA/Cho),
Ins/Cr, and NAA/Ins ratios in the motor cortex. PARTICIPANTS: Seventeen patients
with ALS and 15 healthy control subjects were studied. RESULTS: In patients with
ALS, the greatest abnormality was a 22% decrease in NAA/Ins (71% sensitivity and
93% specificity, P = .001); Ins/Cr was increased 18% (88% sensitivity and 53%
specificity, P = .04), NAA/Cr was decreased 10% (88% sensitivity and 47%
specificity, P = .04), and NAA/Cho was decreased 14% (53% sensitivity and 87%
specificity, P = .047). Correlation of the ALS Functional Rating Scale with
NAA/Ins approached statistical significance (R = 0.43, P = .07). CONCLUSION: The
NAA/Ins ratio may provide a meaningful biomarker in ALS given its optimal
sensitivity and specificity profile.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16908742 [PubMed - indexed for MEDLINE]
5: Arch Neurol. 2006 Aug;63(8):1139-43.
Slower disease progression and prolonged survival in contemporary patients with
amyotrophic lateral sclerosis: is the natural history of amyotrophic lateral
sclerosis changing?
Czaplinski A, Yen AA, Simpson EP, Appel SH.
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
BACKGROUND: In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival. OBJECTIVE: To analyze whether survival and disease progression in patients with ALS have changed during the past 20 yars. DESIGN: By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2,
1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy). CONCLUSIONS: Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are
needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16908741 [PubMed - indexed for MEDLINE]
4: J Neuropathol Exp Neurol. 2006 Aug;65(8):816-25.
Intrathecal upregulation of granulocyte colony stimulating factor and its
neuroprotective actions on motor neurons in amyotrophic lateral sclerosis.
Tanaka M, Kikuchi H, Ishizu T, Minohara M, Osoegawa M, Motomura K, Tateishi T,
Ohyagi Y, Kira J.
Department of Neurology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan.
To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed
fluorescent bead-based immunoassay. We also conducted immunohistochemical
analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well
as cell culture analyses of relevant cytokines and their receptors. We found
that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. In spinal cords, G-CSF was expressed in reactive
astrocytes in ALS cases but not controls, whereas G-CSF receptor expression was
significantly decreased in motor neurons of spinal cords from ALS cases.
Biologically, G-CSF had a protective effect on the NSC34 cell line under
conditions of both oxidative and nutritional stress. We suggested that G-CSF has
potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motorneuron damage.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16896315 [PubMed - indexed for MEDLINE]
3: J Neurochem. 2006 Aug;98(4):1141-8.
Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse
model of amyotrophic lateral sclerosis.
Petri S, Kiaei M, Damiano M, Hiller A, Wille E, Manfredi G, Calingasan NY, Szeto
HH, Beal MF.
Department of Neurology and Neuroscience, Weill Medical College of Cornell
University, New York, NY, USA. Petri.susanne@mh-hannover.de
Reactive oxygen species (ROS) play a major role in the pathogenesis of neurodegenerative diseases. They are important contributors to necrotic and apoptotic cell death. A major proportion of cellular ROS is generated at the inner mitochondrial membrane by the respiratory chain. In the present study, we investigated a novel peptide antioxidant (SS-31) targeted to the inner mitochondrial membrane for its therapeutic effects both in vitro and in vivo in the G93A mouse model of amyotrophic lateral sclerosis (ALS). SS-31 protected against cell death induced by hydrogen peroxide in vitro in neuronal cells stably transfected with either wild-type or mutant Cu/Zn superoxide dismutase (SOD1). Daily intraperitoneal injections of SS-31 (5 mg/kg), starting at 30 days
of age, led to a significant improvement in survival and motor performance. In comparison with vehicle-treated G93A mice, SS-31-treated mice showed a decreased cell loss and a decrease in immunostaining for markers of oxidative stress in the lumbar spinal cord. This further enhances the concept that pharmacological modification of oxidative stress is a therapeutic option for the treatment of ALS.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16895581 [PubMed - indexed for MEDLINE]
2: Neurology. 2006 Aug 8;67(3):508-10.
Lack of association of VEGF promoter polymorphisms with sporadic ALS.
Chen W, Saeed M, Mao H, Siddique N, Dellefave L, Hung WY, Deng HX, Sufit RL, Heller SL, Haines JL, Pericak-Vance M, Siddique T.
Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
The authors tested the association of three vascular endothelial growth factor (VEGF) promoter polymorphisms with sporadic ALS (SALS) to verify the results of a previous study and to investigate their modifier effects on the subphenotypes of SALS in a large family-based and case-control cohort of North American white subjects (N = 1,603). They did not find any association of the VEGF promoter polymorphisms with SALS or its subphenotypes, suggesting that they do not have a direct causal role in ALS.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16894118 [PubMed - indexed for MEDLINE]
1: J Neurochem. 2006 Aug;98(3):782-91.
Slow and selective death of spinal motor neurons in vivo by intrathecal infusion
of kainic acid: implications for AMPA receptor-mediated excitotoxicity in ALS.
Sun H, Kawahara Y, Ito K, Kanazawa I, Kwak S.
Department of Neurology, Graduate School of Medicine, The University of Tokyo,
Tokyo, Japan.
Excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been proposed to play a major role in the selective death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), and motor neurons are more vulnerable to AMPA receptor-mediated excitotoxicity than are other neuronal subclasses. On the basis of the above evidence, we aimed to develop a rat model of ALS by the long-term activation of AMPA receptors through continuous infusion of kainic acid (KA), an AMPA receptor agonist, into the spinal subarachnoid space. These rats displayed a progressive motor-selective behavioral deficit with delayed loss of spinal motor neurons, mimicking the clinicopathological characteristics of ALS. These changes were significantly
ameliorated by co-infusion with 6-nitro-7-sulfamobenso(f)quinoxaline-2,3-dione
(NBQX), but not with d(-)-2-amino-5-phosphonovaleric acid (APV), and were exacerbated by co-infusion with cyclothiazide, indicative of an AMPA receptor-mediated mechanism. Among the four AMPA receptor subunits, expression of GluR3 mRNA was selectively up-regulated in motor neurons but not in dorsal horn neurons of the KA-infused rats. The up-regulation of GluR3 mRNA in this model may cause a molecular change that induces the selective vulnerability of motor neurons to KA by increasing the proportion of GluR2-lacking (i.e. calcium-permeable) AMPA receptors. This rat model may be useful in investigating
ALS etiology.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16893420 [PubMed - indexed for MEDLINE]
