9: BMC Med Genet. 2007 Apr 24;8:23.
Academic Neurology Unit, University of Sheffield, E Floor, Medical School, Beech Hill Road, Sheffield S10 2RX, UK. alicebrockington@yahoo.co.uk
BACKGROUND: Vascular endothelial growth factor (VEGF) has neurotrophic activity which is mediated by its main agonist receptor, VEGFR2\. Dysregulation of VEGF causes motor neurone degeneration in a mouse model of amyotrophic lateral sclerosis (ALS), and expression of VEGFR2 is reduced in motor neurones and spinal cord of patients with ALS\. METHODS: We have screened the promoter region and 4 exonic regions of functional significance of the VEGFR2 gene in a UK population of patients with ALS, for mutations and polymorphisms that may affect expression or function of this VEGF receptor\. RESULTS: No mutations were identified in the VEGFR2 gene\. We found no association between polymorphisms in the regulatory regions of the VEGFR2 gene and ALS\. CONCLUSION: Mechanisms other than genetic variation may downregulate expression or function of the VEGFR2 receptor in patients with ALS.
PMID: 17456229 [PubMed - indexed for MEDLINE]
8: Neurology. 2007 Apr 24;68(17):1402-10.
Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University, New York, NY 10032, USA. hm246@columbia.edu
OBJECTIVE: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS\. METHODS: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging ((1)H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects\. RESULTS: (1)H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values\. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001)\. MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls\. All objective markers correlated well with the ALS Functional Rating Scale-Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity\. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline\. CONCLUSIONS: (1)H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.
PMID: 17452585 [PubMed - indexed for MEDLINE]
7: Science. 2007 Apr 20;316(5823):353.
PMID: 17446359 [PubMed - indexed for MEDLINE]
6: Neurology. 2007 Apr 10;68(15):1233-5.
Department of Neurology, John Radcliffe Hospital, Headley Way, Oxford, UK. turnermr@doctors.org.uk
PMID: 17420412 [PubMed - indexed for MEDLINE]
5: Curr Drug Deliv. 2007 Apr;4(2):161-7.
.Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. mfarah2@jhem.jhmi.edu
RNA interference (RNAi) has emerged as a potential therapeutic approach for neurodegenerative diseases, particularly those associated with autosomal dominant patterns of inheritance\. In proof of concept experiments, several groups have demonstrated efficacy of using viral vectors expressing short hairpin RNA (shRNA) directed against therapeutically relevant genes in mouse models of neurodegenerative diseases, including spinocerebellar ataxia, Amyotrophic Lateral Sclerosis, Huntington's Disease and amyloidosis (a pathological aspect of Alzheimer's Disease)\. Although viral-based RNAi has limitations that most likely will preclude its usage in humans, a few recent developments underscore the potential of non-viral-based delivery of relevant RNAi as therapeutics for neurodegenerative diseases\. Here, I will review the recent literature on effectiveness of RNAi as a therapeutic strategy in mouse models of neurodegenerative diseases.
PMID: 17456035 [PubMed - indexed for MEDLINE]
4: Neurology. 2007 Apr 3;68(14):1161-2; author reply 1162. Substance via MeSH, LinkOutComment on:Neurology. 2006 Aug 22;67(4):592-6.
PMID: 17404204 [PubMed - indexed for MEDLINE]
3: Neurology. 2007 Apr 3;68(14):1156-7.
Center for the Study of Brain Diseases, Universite de Montreal CHUM Research Center, Notre Dame Hospital, Montreal, QC, Canada. nicolas.dupre@cha.quebec.qc.ca
PMID: 17404201 [PubMed - indexed for MEDLINE]
2: Brain Nerve. 2007 Apr;59(4):383-91. [Article in Japanese]
Eleanor and Lou Gehrig MDA/ALS Research Center, Neurological Institute, Columbia University, 710 West 168th Street, New York, NY 10032, USA.
In the early 1990s, a number of major events took place in the history of the treatment and science of ALS\. A cause of familial ALS, the mutation of superoxide dismutase 1, was discovered and very shortly after, an animal model expressing the human SOD1 mutation for familial ALS was generated\. Around the same time, the first medication for the treatment of ALS, riluzole, was approved\. Clinical neurologists started to focus more attention on quality of life and standardizing care for patients with ALS, including devising approaches for presenting and discussing the diagnosis, using aggressive symptomatic treatments, and developing a multidisciplinary care system\. Since then, nutritional and respiratory care has markedly improved\. Respiratory care for those with terminal ALS in Japan has been distinct and perhaps more effective compared to the rest of the world, and this unique experience must be broadly published and shared with others\. In 1999, the ALS Treatment Guidelines were published by the American Academy of Neurology and are now under revision\. A monitoring system to determine the impact the Guidelines had on actual patient care has taught us that caregivers have only slowly accepted the recommendation to improve quality of care\. The team approach, using a multidisciplinary care system from diagnosis to the end of life, is essential to improve care for both the patient and family\. Coinciding with the progress in ALS treatment, basic science and translational research also produced dramatic progress in ALS drug discovery\. Over the past 15 years, more than 25 potential drugs have been tested in randomized controlled trials\. Despite this progress, we have no medications other than riluzole\. Although it may be true that ALS research is in its early stages compared to research in other diseases with no cure--it is probably behind cancer research by at least 20 or 30 years--we need to drastically change our approach to drug development\. At a national level, we need to create a strong, cohesive team with support from a number of funding agencies, oversight from a regulatory agency, and investigators who all think "outside the box." In addition, we should obtain ideas and suggestions from accomplished experts outside of the field of ALS and put competition aside as we work together to develop strategic plans for the ALS drug development that is essential to beat this devastating disease.
PMID: 17447525 [PubMed - indexed for MEDLINE]
1: Arch Neurol. 2007 Apr;64(4):530-4.
Department of Neurology, ALS Center, University of California, San Francisco, CA 94117, USA. jennifer.murphy@ucsf.edu
OBJECTIVE: To identify the nature and prevalence of cognitive and behavioral abnormalities in patients with amyotrophic lateral sclerosis (ALS)\. DESIGN: Survey of clinical characteristics\. SETTING: Multidisciplinary clinic within a university medical center\. Patients A volunteer sample of 30 new patients with ALS were recruited consecutively\. Of those invited, 23 participants (20 with sporadic ALS and 3 with familial ALS) enrolled\. Participants ranged in age from 27 to 80 years (mean age, 56.5 years); the education level ranged from 12 to 21 years (mean education level, 3.5 years of college); and 17 participants (74%) were male\. MAIN OUTCOME MEASURES: Neuropsychological tests, neurobehavioral interviews, and structured magnetic resonance imaging\. RESULTS: Patients were classified into subtypes of frontotemporal lobar degeneration (n = 5), suspected Alzheimer disease (n = 1), and subthreshold variants of cognitive impairment (n = 2), behavioral impairment (n = 4), and cognitively and behaviorally normal (n = 11)\. Five neuropsychological tests, 2 behavioral abnormalities, and right hemisphere gray matter reductions differentiated patients into normal and abnormal groups\. CONCLUSIONS: In this sample, a sizable proportion of patients with ALS possess a range of behavioral and cognitive changes that lie on a spectrum of frontotemporal impairment\. Right hemisphere atrophy may be a biomarker for cognitive impairment in patients with ALS.
PMID: 17420314 [PubMed - indexed for MEDLINE]
