36: Exp Brain Res. 2006 Jul;172(3):361-9. Epub 2006 Mar 25.
Subcortical reorganization in amyotrophic lateral sclerosis.
Konrad C, Jansen A, Henningsen H, Sommer J, Turski PA, Brooks BR, Knecht S.
Department of Psychiatry and Psychotherapy, IZKF, University of Muenster,
Albert-Schweitzer-Str. 11, 48149 Muenster, Germany. konradc@uni-muenster.de
The cerebral cortex reorganizes in response to central or peripheral lesions.
Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance
imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS
leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a - albeit finally ineffective - mechanism to compensate for the ongoing loss of motor neurons in ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16463149 [PubMed - indexed for MEDLINE]
35: Exp Neurol. 2006 Jul;200(1):166-71. Epub 2006 Mar 3.
The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.
Lorenzl S, Narr S, Angele B, Krell HW, Gregorio J, Kiaei M, Pfister HW, Beal MF.
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05)
prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days,
mean +/- SD), however, administration at disease onset did not significantly
improve survival time. Our experiments show that MMPs are expressed in an animal
model of ALS and may play a role in the complex pathophysiologic changes. Early
pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the
animals which suggest a role of MMPs in the early phase of the disease.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16516196 [PubMed - indexed for MEDLINE]
34: Mol Cell Proteomics. 2006 Jul;5(7):1233-44. Epub 2006 Mar 29.
Informatics-assisted protein profiling in a transgenic mouse model of amyotrophic lateral sclerosis.
Lukas TJ, Luo WW, Mao H, Cole N, Siddique T.
Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
t-lukas@northwestern.edu
One of the causes of amyotrophic lateral sclerosis (ALS) is due to mutations in Cu,Zn-superoxide dismutase (SOD1). The mutant protein exhibits a toxic gain of function that adversely affects the function of neurons in the spinal cord, brain stem, and motor cortex. A proteomic analysis of protein expression in a widely used mouse model of ALS was undertaken to identify differences in protein expression in the spinal cords of mice expressing a mutant protein with the G93A mutation found in human ALS. Protein profiling was done on soluble and particulate fractions of spinal cord extracts using high throughput two-dimensional liquid chromatography coupled to tandem mass spectrometry. An integrated proteomics-informatics platform was used to identify relevant
differences in protein expression based upon the abundance of peptides identified by database searching of mass spectrometry data. Changes in the expression of proteins associated with mitochondria were particularly prevalent in spinal cord proteins from both mutant G93A-SOD1 and wild-type SOD1 transgenic mice. G93A-SOD1 mouse spinal cord also exhibited differences in proteins associated with metabolism, protein kinase regulation, antioxidant activity, and lysosomes. Using gene ontology analysis, we found an overlap of changes in mRNA expression in presymptomatic mice (from microarray analysis) in three different gene categories. These included selected protein kinase signaling systems, ATP-driven ion transport, and neurotransmission. Therefore, alterations in selected cellular processes are detectable before symptomatic onset in ALS mouse models. However, in late stage disease, mRNA expression analysis did not reveal
significant changes in mitochondrial gene expression but did reveal concordant
changes in lipid metabolism, lysosomes, and the regulation of neurotransmission.
Thus, concordance of proteomic and mRNA expression data within multiple
categories validates the use of gene ontology analysis to compare different
types of "omic" data.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16571896 [PubMed - indexed for MEDLINE]
33: Mol Cell Biochem. 2006 Jul;287(1-2):201-11. Epub 2006 Apr 1.
Novel mutations that enhance or repress the aggregation potential of SOD1.
Krishnan U, Son M, Rajendran B, Elliott JL.
Department of Neurology, University of Texas, Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, Texas, 75390, USA.
Mutations in SOD1 cause FALS by a gain of function likely related to protein misfolding and aggregation. SOD1 mutations encompass virtually every domain of the molecule, making it difficult to identify motifs important in SOD1 aggregation. Zinc binding to SOD1 is important for structural integrity, and is hypothesized to play a role in mutant SOD1 aggregation. To address this question, we mutated the unique zinc binding sites of SOD1 and examined whether these changes would influence SOD1 aggregation. We generated single and multiple mutations in SOD1 zinc binding residues (H71, H80 and D83) either alone or in combination with an aggregate forming mutation (A4V) known to cause disease. These SOD1 mutants were assayed for their ability to form aggregates.Using an in vitro cellular SOD1 aggregation assay, we show that combining A4V with mutations
in non-zinc binding domains (G37R or G85R) increases SOD1 aggregation potential.
Mutations at two zinc binding residues (H71G and D83G) also increase SOD1 aggregation potential. However, an H80G mutation at the third zinc binding residue decreases SOD1 aggregation potential even in the context of other aggregate forming SOD1 mutations. These results demonstrate that various mutations have different effects on SOD1 aggregation potential and that the H80G mutation appears to uniquely act as a dominant inhibitor of SOD1 aggregation.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16583143 [PubMed - indexed for MEDLINE]
32: Histol Histopathol. 2006 Jul;21(7):729-42.
Histological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis.
Kato M, Kato S, Abe Y, Nishino T, Ohama E, Aoki M, Itoyama Y.
Division of Pathology, Tottori University Hospital, Nishi-cho 36-1, Yonago 683-8504, Japan. makato@grape.med.tottori-u.ac.jp
Histological rescue of superoxide dismutase1 (SOD1)-mutated hepatocytes from mutant SOD1 stress is investigated from the viewpoint of upregulation of the redox system [peroxiredoxin (Prx) and glutathione peroxidase (GPx)]. Histopathological and immunohistochemical studies using antibodies against PrxI/PrxII/GPxI were carried out on specimens from four different strains of animal models of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). In the livers of the ALS animal models in the presymptomatic stage without motor neuron loss, both swollen and eosinophilic hepatocytes with vacuolation pathology were observed. After developing motor deficits, this swelling and vacuolation ceased to be apparent. In the terminal stage when
severe motor neuron loss was observed, these hepatocytes recovered and appeared
normal. In redox system-related immunohistochemical preparations, almost all of
the normal hepatocytes expressed the redox system-related enzymes PrxI/PrxII/GPxI. In the presymptomatic stage, some hepatocytes did not express redox system-related enzymes. After clinical onset, over 75% of hepatocytes showed overexpression of PrxI/PrxII/GPxI, i. e., upregulation of the redox system. At the end stage, near normal PrxI/PrxII/GPxI expression was observed again in the hepatocytes. Redox system upregulation in SOD1-mutated hepatocytes rescues hepatocytes from the mutant SOD1 stress that leads to motor neuron death.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16598672 [PubMed - indexed for MEDLINE]
31: J Neurol Sci. 2006 Jul 15;246(1-2):131-7. Epub 2006 Apr 17.
Nestin immunoreactivity of Purkinje cells in Creutzfeldt-Jakob disease.
Mizuno Y, Ohama E, Hirato J, Nakazato Y, Takahashi H, Takatama M, Takeuchi T,
Okamoto K.
Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22
Showa-machi, Maebashi, Gunma 371-8511, Japan. mizunoy@med.gunma-u.ac.jp
Nestin, an intermediate filament protein, is mainly expressed in neural progenitor/stem cells in the central nervous system. Recently, we reported that nestin is expressed in Purkinje cells in patients with Creutzfeldt-Jakob disease (CJD). In this study, we examined a total of 19 CJD cerebella to analyze the intensity and pattern of nestin immunoreactivity of Purkinje cells in different pathological stages of degeneration in the cerebellar cortex. The results showed that the Purkinje cells were immunoreactive with nestin regardless of the severity of degenerative cerebellar cortex. Furthermore, we noted several different types of nestin immunoreactivity, indicated by diffuse and fine, coarse, and inclusion-like immunostainings within Purkinje cell bodies as well as dot-like staining outside of the cell bodies. In contrast, on examination of cerebella from non-CJD patients, 6 of 30 cases showed nestin immunoreactivity to a lesser extent. Thus, nestin-positive Purkinje cells are more common in CJD cerebella than in non-CJD cerebella. Although the mechanism of nestin expression in Purkinje cells is not yet understood, we suggest that such nestin-positive Purkinje cells are being reactivated to survive the cell death.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16616189 [PubMed - indexed for MEDLINE]
30: DNA Repair (Amst). 2006 Jul 13;5(7):761-72. Epub 2006 Apr 18.
MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides.
Nakabeppu Y, Kajitani K, Sakamoto K, Yamaguchi H, Tsuchimoto D.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan. yusaku@bioreg.kyuhsu-u.ac.jp
In human and rodent cells, MTH1, an oxidized purine nucleoside triphosphatase, efficiently hydrolyzes oxidized dGTP, GTP, dATP and ATP such as 2'-deoxy-8 oxoguanosine triphosphate (8-oxo-dGTP) and 2'-deoxy-2-hydroxyadenosine triphosphate (2-OH-dATP) in nucleotide pools, thus avoiding their incorporation into DNA or RNA. MTH1 is expressed in postmitotic neurons as well as in proliferative tissues, and it is localized both in the mitochondria and nucleus, thus suggesting that MTH1 plays an important role in the prevention of the mutagenicity and cytotoxicity of such oxidized purines as 8-oxoG which are known to accumulate in the cellular genome. Our recent studies with MTH1-deficient mice or cells revealed that MTH1 efficiently minimizes accumulation of 8-oxoG in both nuclear and mitochondrial DNA in the mouse brain as well as in cultured cells, thus contributing to the protection of the brain from oxidative stress.
Publication Types:
Review
PMID: 16621731 [PubMed - indexed for MEDLINE]
29: Neuroimage. 2006 Jul 15;31(4):1487-505. Epub 2006 Apr 19.
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data.
Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE,
Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE.
Oxford University Centre for Functional MRI of the Brain (FMRIB), Dept. Clinical Neurology, University of Oxford, UK. steve@fmrib.ox.ac.uk
There has been much recent interest in using magnetic resonance diffusion imaging to provide information about anatomical connectivity in the brain, by measuring the anisotropic diffusion of water in white matter tracts. One of the measures most commonly derived from diffusion data is fractional anisotropy (FA), which quantifies how strongly directional the local tract structure is. Many imaging studies are starting to use FA images in voxelwise statistical analyses, in order to localise brain changes related to development, degeneration and disease. However, optimal analysis is compromised by the use of standard registration algorithms; there has not to date been a satisfactory
solution to the question of how to align FA images from multiple subjects in a way that allows for valid conclusions to be drawn from the subsequent voxelwise analysis. Furthermore, the arbitrariness of the choice of spatial smoothing extent has not yet been resolved. In this paper, we present a new method that aims to solve these issues via (a) carefully tuned non-linear registration, followed by (b) projection onto an alignment-invariant tract representation (the "mean FA skeleton"). We refer to this new approach as Tract-Based Spatial Statistics (TBSS). TBSS aims to improve the sensitivity, objectivity and
interpretability of analysis of multi-subject diffusion imaging studies. We describe TBSS in detail and present example TBSS results from several diffusion imaging studies.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16624579 [PubMed - indexed for MEDLINE]
28: Brain. 2006 Jul;129(Pt 7):1859-71. Epub 2006 May 3.
Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis.
Ciccarelli O, Behrens TE, Altmann DR, Orrell RW, Howard RS, Johansen-Berg H, Miller DH, Matthews PM, Thompson AJ.
Department of Headache, Brain Injury and Neurorehabilitation, Institute of Neurology, University College London UK. o.ciccarelli@ion.ucl.ac.uk
The goal of probabilistic tractography is to obtain a connectivity index along a white matter pathway that reflects fibre organization and is sensitive to pathological abnormalities contributing to disability. Here, we present the development of voxel-based connectivity measures along the tractography-derived corticospinal tract (CST). We investigated whether these connectivity measures are different in patients with amyotrophic lateral sclerosis (ALS) and correlate with the rate of disease progression. We also investigated whether fractional anisotropy (FA), which reflects directional coherence of fibre tracts, is
reduced in the CST of ALS patients and relates to disease progression rate.
Thirteen patients with probable or definite ALS and 19 healthy subjects were studied. The probabilistic tractography algorithm segmented the bilateral CST, along which FA and connectivity values were obtained. To take into account the asymmetric distribution of connectivity values, two summary statistic measures that focused on voxels with higher connectivity values were selected and then used in the analysis, together with the mean connectivity and the mean FA. To complete the analysis, the same summary measures for FA were included. Differences in all these indices between patients with moderate or rapid disease progression rate and controls were investigated using linear regression,
adjusted for age and white matter fraction. The association between FA or connectivity in the CST and the disease progression rate was assessed using linear regression. Patients with a rapid disease progression rate had significantly lower summary connectivity measures than controls in the left CST, but there was only a borderline statistical difference in mean connectivity. Patients with rapid progression had a significantly lower mean FA, and any other FA measure, in both CSTs than controls. When only patients were considered, strong associations between the rate of disease progression and all the connectivity measures in the left CST were found (P-values between P < 0.001 and P = 0.002, partial correlation coefficients between -0.90 and -0.82). However, there was no evidence of an association between disease progression rate and any of the FA measures in the bilateral CST. Our findings suggest that FA and connectivity provide complementary information, since FA is sensitive to the detection of all the group differences, whereas the summary connectivity measures correlate with disease progression rate. The development of such connectivity measures raises their potential as markers of disease progression in ALS, and provides guidance for their use in other neurological diseases.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16672290 [PubMed - indexed for MEDLINE]
27: J Neurobiol. 2006 Jul;66(8):882-95.
Dynamic expression of neurotrophic factor receptors in postnatal spinal motoneurons and in mouse model of ALS.
Zhang J, Huang EJ.
Department of Pathology, University of California San Francisco and Pathology,
Service 113B, VA Medical Center, 94121, USA.
Neurotrophic factors support the survival of spinal motoneurons (MNs) and have been considered as strong candidates for treating motoneuron diseases. However, it is unclear if the right combination of neurotrophic factor receptors is present in postnatal spinal MNs. In this study, we show that the level of c-ret expression remains relatively stable in embryonic and postnatal spinal MNs. In contrast, the mRNA and protein of GFRalpha1 and -2 are progressively down-regulated in postnatal life. By 3 and 6 months of age, both receptors are barely detectable in spinal MNs. The down-regulation of GFRalpha1 appears accelerated in transgenic mice expressing mutant SOD1(G93A). Despite the
progressive loss of GFRalpha1 and -2, phosphorylation of c-ret shows no detectable reduction on tyrosine residues or on serine 696. In addition to the GFR alpha subunits, expression of TrkB also shows a dynamic change. During embryogenesis, there is twice as much full-length TrkB as the truncated TrkB isoform. However, this ratio is reversed in postnatal spinal cord. Expression of the mutant SOD1(G93A) appears to have no effect on the TrkB receptor ratio. Taken together, our data indicate that the expression of neurotrophic factor receptors, GFRalpha1, -2, and TrkB, is not static, but undergoes dynamic changes in postnatal spinal MNs. These results provide insights into the use of
neurotrophic factors as therapeutic agents for ALS. Copyright 2006 Wiley Periodicals, Inc.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16680759 [PubMed - indexed for MEDLINE]
26: Clin Neurophysiol. 2006 Jul;117(7):1458-66. Epub 2006 Jun 8.
Axonal excitability properties in amyotrophic lateral sclerosis.
Vucic S, Kiernan MC.
Prince of Wales Medical Research Institute, Prince of Wales Clinical School, University of New South Wales, and Prince of Wales Hospital, Randwick, Sydney, NSW 2031, Australia.
OBJECTIVE: To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). METHODS: A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. RESULTS: Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). CONCLUSIONS: Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including
increased persistent Na+ channel conduction, and abnormalities of fast paranodal
K+ and internodal slow K+ channel function, in ALS patients. SIGNIFICANCE: An
increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.
Publication Types:
Historical Article
Research Support, Non-U.S. Gov't
PMID: 16759905 [PubMed - indexed for MEDLINE]
25: AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1234-8.
Diffusion tensor imaging in amyotrophic lateral sclerosis: volumetric analysis of the corticospinal tract.
Wang S, Poptani H, Bilello M, Wu X, Woo JH, Elman LB, McCluskey LF, Krejza J, Melhem ER.
Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) allows direct visualization and volumetric analysis of the corticospinal tract (CST). The purpose of this study was to determine whether color maps and fiber tracking derived from DTI data are valuable in detecting and quantifying CST degeneration in patients with amyotrophic lateral sclerosis (ALS). METHODS: Sixteen patients with ALS with clinical signs of upper motor neuron (UMN) involvement and 17 healthy subjects were studied with the use of DTI. Disease severity was determined by means of the ALS Functional Rating Scale-Revised (ALSFRS-R) and an UMN involvement score. DTI was acquired with a 12-direction, single-shot,
spin-echo echo-planar sequence. The CST from the lower pons to the corona radiata at the level of the corpus callosum on 4 contiguous coronal sections was manually segmented by using color maps generated from the DTI data. The left and right CST volumes were measured separately and normalized to the total intracranial volume. Normalized CST volumes were compared between patients with ALS and healthy subjects. RESULTS: The CST volumes of patients with ALS were significantly reduced (P < .01, unpaired t test) compared with healthy subjects, in both affected and nonaffected hemispheres. No significant correlation was found between CST volumes and any of the clinical parameters, including disease duration, ALSFRS-R, or UMN involvement score. CONCLUSION: This study shows that volumetric analysis by using DTI-based color maps is valuable in detecting and monitoring structural degeneration of the CST. This will lead to objective and quantitative assessment of axonal degeneration in ALS.
PMID: 16775271 [PubMed - indexed for MEDLINE]
24: Cytotherapy. 2006;8(3):196-201.
Comment in:
Cytotherapy. 2006;8(3):194-5.
Autoreactive T cells induce in vitro BM mesenchymal stem cell transdifferentiation to neural stem cells.
Moviglia GA, Varela G, Gaeta CA, Brizuela JA, Bastos F, Saslavsky J.
Instituto Regina Mater, Paraguay 2452, Buenos Aires, 1121 ABL, Argentina.
gmoviglia@reginamater.com
BACKGROUND: The degree of post-injury inflammation of the damaged area of a spinal cord is the main difference between the natural successful repair in inferior vertebrates and failure in superior vertebrates. The treatment of rats with anti-myelin lymphocytes after experimental spinal cord injury induces their functional recovery. On the other hand, mesenchymal stem cells (MSC) from adult BM implanted in injured areas recover the morphology and function of spinal cord in mammals. The purpose of this study was to determine whether there is a direct relationship between anti-nervous tissue T cells and MSC reparatory properties. METHODS: Circulating autoreactive lymphocytes of patients with spinal cord injuries and amyotrophic lateral sclerosis were isolated and activated in vitro. These cells were cocultured with autologous MSC for 2-15 days. Cocultures of non-selected lymphocytes were used as controls. RESULTS: After 48 h of coculture, MSC adopted a spindle shape with polarization of the cytoplasm that resembled bipolar neurons. Their nuclei diminished the nucleolus number and the chromatin lost its granular appearance. After 15 days of culture the cells developed the typical structure of a neural network. No morphologic changes were observed in control cultures. The differentiated cells reacted positively to tubuline III, GFAP and nestin. No differences were observed between the different patient cell sources. DISCUSSION: We observed that autoreactive cells may induce the transdifferentiation of MSC to neural stem cells. This T-cell-MSC interaction may be a common phenomenon during physiologic nerve tissue repair.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16793728 [PubMed - indexed for MEDLINE]
23: Cytotherapy. 2006;8(3):202-9.
Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients.
Moviglia GA, Fernandez Vina R, Brizuela JA, Saslavsky J, Vrsalovic F, Varela G, Bastos F, Farina P, Etchegaray G, Barbieri M, Martinez G, Picasso F, Schmidt Y, Brizuela P, Gaeta CA, Costanzo H, Moviglia Brandolino MT, Merino S, Pes ME, Veloso MJ, Rugilo C, Tamer I, Shuster GS.
Instituto Regina Mater, Paraguay 2452, Buenos Aires, 1121 ABL, Argentina. gmoviglia@reginamater.com
BACKGROUND: This is a preliminary report on successful results obtained during treatment of two patients with chronic spinal cord injury. The therapeutic approach was based on the generation of controlled inflammatory activity at the injury site that induced a microenvironment for the subsequent administration of autologous, BM-driven transdifferentiated neural stem cells (NSC). METHODS: BM
mesenchymal stem cells (MSC) were cocultured with the patient's autoimmune T (AT) cells to be transdifferentiated into NSC. Forty-eight hours prior to NSC implant, patients received an i.v. infusion of 5 x 10(8) to 1 x 10(9) AT cells. NSC were infused via a feeding artery of the lesion site. Safety evaluations
were performed everyday, from the day of the first infusion until 96 h after the second infusion. After treatment, patients started a Vojta and Bobath neurorehabilitation program. RESULTS: At present two patients have been treated. Patient 1 was a 19-year-old man who presented paraplegia at the eight thoracic vertebra (T8) with his sensitive level corresponding to his sixth thoracic metamere (T6). He received two AT-NSC treatments and neurorehabilitation for 6 months. At present his motor level corresponds to his first sacral metamere (S1) and his sensitive level to the fourth sacral metamere (S4). Patient 2 was a 21-year-old woman who had a lesion that extended from her third to her fifth cervical vertebrae (C3-C5). Prior to her first therapeutic cycle she had severe quadriplegia and her sensitive level corresponded to her second cervical metamere (C2). After 3 months of treatment her motor and sensitive levels reached her first and second thoracic metameres (T1-T2). No adverse events were detected in either patient. DISCUSSION: The preliminary results lead us to think that this minimally invasive approach, which has minor adverse events, is effective for the repair of chronic spinal cord lesions.
Publication Types:
Case Reports
Clinical Trial
Research Support, Non-U.S. Gov't
PMID: 16793729 [PubMed - indexed for MEDLINE]
22: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10218-23. Epub 2006 Jun 23.
Folding of Cu/Zn superoxide dismutase suggests structural hotspots for gain of neurotoxic function in ALS: parallels to precursors in amyloid disease.
Nordlund A, Oliveberg M.
Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 10691 Stockholm, Sweden.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to misfolding of the ubiquitous enzyme Cu/Zn superoxide dismutase (SOD). In contrast to other protein-misfolding disorders with similar neuropathogenesis, ALS is not always associated with the in vivo deposition of protein aggregates. Thus, under the assumption that all protein-misfolding disorders share at primary level a similar disease mechanism, ALS constitutes an interesting disease model for identifying the yet-mysterious precursor states from which the cytotoxic pathway emerges. In this study, we have mapped out the conformational repertoire of the apoSOD monomer through analysis of its folding behavior. The results allow us to target the regions of the SOD structure that are most
susceptible to unfolding locally under physiological conditions, leading to the exposure of structurally promiscuous interfaces that are normally hidden in the protein's interior. The structure of this putative ALS precursor is strikingly similar to those implicated in amyloid disease.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16798882 [PubMed - indexed for MEDLINE]
21: J Rehabil Med. 2006 Jul;38(4):250-4.
Symptoms, clinical and physiological findings motivating home mechanical ventilation in patients with neuromuscular diseases.
Laub M, Berg S, Midgren B.
Department of Respiratory Medicine, University Hospital, Lund, Sweden. ml@laub.dk
OBJECTIVE: To clarify the relationship between symptoms, clinical signs and physiological abnormalities that were motivating the initiation of home mechanical ventilation in patients suffering from neuromuscular diseases. METHODS: From The Swedish Home Mechanical Ventilation Register we identified 352 patients with neuromuscular diseases and we looked at circumstances (acute vs elective) and clinical motives for starting ventilatory support. RESULTS: Home mechanical ventilation was commenced electively in 268 patients (76%) and among these daytime sleepiness was the most common motive, being reported in 56% of the patients. In the 24 children with spinal muscular atrophy, however, 96% started ventilation electively and cough insufficiency was the most common motive. The patients were moderately hypercapnic (PaCO(2): 7.0 kPa, SD 1.3). None of the clinical motives were related to the PaCO(2) level. Average PaO(2) was above 8 kPa in all groups, but lowest in the patients with post-polio and dystrophia myotonica. Mean vital capacity was close to 40% of predicted, but significantly lower in the Duchenne patients (26% of predicted). CONCLUSION: Daytime sleepiness was the most common clinical symptom motivating home mechanical ventilation in this group of patients with chronic hypercapnic respiratory insufficiency secondary to neuro/myopathies. Respiratory function testing is therefore suggested to be included in the diagnostic work up of daytime sleepiness in these patients.
PMID: 16801208 [PubMed - indexed for MEDLINE]
20: Ann Neurol. 2006 Jul;60(1):95-104.
Progressive spinal axonal degeneration and slowness in ALS2-deficient mice.
Yamanaka K, Miller TM, McAlonis-Downes M, Chun SJ, Cleveland DW.
Ludwig Institute for Cancer Research and Department of Medicine and Neurosciences, University of California, San Diego, La Jolla, 92093-0670, USA. kyamanaka@ucsd.edu
OBJECTIVE: Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal
recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons. The goal of this study was to elucidate how the motor system is affected by the deletion of ALS2. METHODS: ALS2-deficient mice were generated by gene targeting. Motor function and upper and lower motor neuron pathology were examined in ALS2-deficient mice and in mutant superoxide dismutase 1 (SOD1) mice that develop ALS-like disease from expression of an ALS-linked mutation in SOD1. RESULTS: ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice. Despite the vulnerability of these spinal axons, lower motor neurons in ALS2-deficient mice were preserved. Behavioral studies demonstrated slowed movement without muscle weakness in ALS2(-/-) mice, consistent with upper motor neuron defects that lead to spasticity in humans. INTERPRETATION: The combined evidence from mice and humans shows that deficiency in ALS2 causes an upper motor neuron disease that in humans closely resembles a severe form of hereditary spastic paralysis, and that is quite distinct from amyotrophic lateral sclerosis.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16802286 [PubMed - indexed for MEDLINE]
19: Ann Neurol. 2006 Jul;60(1):22-31.
Comment in:
Ann Neurol. 2006 Jul;60(1):9A-11A.
Trial of celecoxib in amyotrophic lateral sclerosis.
Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB.
Neurology Clinical Trials Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02172, USA. mcudkowicz@partners.org
OBJECTIVE: To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS). METHODS: A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate
of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates. RESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment. INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.
Publication Types:
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16802291 [PubMed - indexed for MEDLINE]
18: Neurol Res. 2006 Jul;28(5):523-6.
Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis.
Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, Testa L, Livigni S, Fagioli F.
Department of Neurology, Eastern Piedmont University of Novara, Novara, Italy.
mazzini.l@libero.it
OBJECTIVES: Our study was aimed to evaluate the feasibility and safety of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored amyotrophic lateral sclerosis (ALS) patients. METHODS: Seven patients affected by definite ALS were enrolled in the study and two patients were treated for compassionate use and monitored for at least 3 years. Bone marrow was collected from the posterior iliac crest according to the standard procedure and MSCs were expanded ex vivo according to Pittenger's protocol. The cells were suspended in 2 ml autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector. RESULTS: The in vitro expanded MSCs did not show any bacterial o fungal contamination, hemopoietic cell contamination, chromosomic alterations and early cellular senescence. No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation and leg sensory dysesthesia, both reversible after a mean period of 6 weeks. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. A significant slowing down of the linear decline of the forced vital capacity was evident in four patients 36 months after MSCs transplantation. CONCLUSIONS: Our results demonstrate that direct injection of autologous expanded MSCs into the spinal cord of ALS patients is safe, with no significant
acute or late toxicity, and well tolerated. The clinical results seem to be encouraging.
Publication Types:
Clinical Trial
Research Support, Non-U.S. Gov't
PMID: 16808883 [PubMed - indexed for MEDLINE]
17: Neurosurgery. 2006 Jul;59(1):172-82; discussion 172-82.
X-Linked inhibitor of apoptosis protein gene-based neuroprotection for the peripheral nervous system.
Garrity-Moses ME, Teng Q, Krudy C, Yang J, Federici T, Boulis NM.
Cleveland Clinic Foundation, Lerner Research Institute, Department of Neuroscience and Center for Neurological Restoration, Cleveland, Ohio 44195, USA.
OBJECTIVE: The recently discovered X-linked inhibitor of apoptosis protein (XIAP) is among the most potent inhibitors of programmed cell death. In the current experiment, we examine the potential of adenoviral XIAP gene delivery to protect neurons of the peripheral nervous system using in vitro models of amyotrophic lateral sclerosis (ALS) and diabetic neuropathy. METHODS: XIAP complementary deoxyribonucleic acid was fused in frame with the green fluorescent protein sequence and cloned into a first generation adenoviral vector. The impact of XIAP gene expression on glutamate-induced apoptosis was measured in the neuronal SH-SY5Y cell line with immunohistochemistry for active caspase-3 and with cell density assays. Next, the effect of XIAP expressing neurons on the survival of uninfected neighboring neurons was measured. Finally, the impact of XIAP gene expression on glutamate-induced apoptosis was assessed in embryonic motor neuron and dorsal root ganglion cultures. RESULTS: XIAP gene expression reduced the percentage of active caspase-3 positive SH-SY5Y neurons and preserved cell density after glutamate exposure. In heterogeneously infected cultures, cells infected with XIAP were protected, but uninfected neighboring cells were not. In primary E15 models, inhibition of proapoptotic effects was demonstrated after glutamate insult in motor neurons and glucose insult indorsal root ganglion cells. CONCLUSION: XIAP gene delivery through the neurosurgical delivery of viral vectors may provide a means for neuroprotection in ALS and diabetic neuropathy.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16823314 [PubMed - indexed for MEDLINE]
16: Neurology. 2006 Jul 11;67(1):20-7.
Neuroprotective agents for clinical trials in ALS: a systematic assessment.
Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME.
Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General
Hospital, Boston, USA. traynorb@mail.nih.gov
BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and
efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.
Publication Types:
Review
PMID: 16832072 [PubMed - indexed for MEDLINE]
15: Eur J Neurol. 2006 Jul;13(7):789-92.
Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy.
Zoccolella S, Beghi E, Palagano G, Fraddosio A, Samarelli V, Lamberti P, Lepore V, Serlenga L, Logroscino G; SLAP registry.
Department of Neurological Sciences, University of Bari, Bari.
Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population-based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population-based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998-1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar-ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4-118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1-7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population-based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex.
UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials.
Publication Types:
Comparative Study
Multicenter Study
PMID: 16834713 [PubMed - indexed for MEDLINE]
14: Chest. 2006 Jul;130(1):287-90.
Comment in:
Chest. 2006 Dec;130(6):1949; author reply 1949-50.
A 52-year-old man with daytime sleepiness, sialorrhea, and facial fasciculations.
Ahuja A, Gothi D, Joshi JM.
Department of Respiratory Medicine, T.N. Medical College, BYL Nair Hospital, Mumbai 400 008, India.
Publication Types:
Case Reports
PMID: 16840414 [PubMed - indexed for MEDLINE]
13: N Engl J Med. 2006 Jul 20;355(3):296-304.
Comment in:
N Engl J Med. 2006 Oct 19;355(16):1740; author reply 1740.
Case records of the Massachusetts General Hospital. Case 22-2006--a 77-year-old man with a rapidly progressive gait disorder.
O'Neill GN, Gonzalez RG, Cros DP, Ackerman RH, Brown RH Jr, Stemmer-Rachamimov A.
Departments of Neurology, Massachusetts General Hospital, USA.
Publication Types:
Case Reports
Clinical Conference
PMID: 16855271 [PubMed - indexed for MEDLINE]
12: Int J Neurosci. 2006 Jul;116(7):775-826.
Serotonergic mechanisms in amyotrophic lateral sclerosis.
Sandyk R.
The Carrick Institute for Clinical Ergonomics Rehabilitation, and Applied Neurosciences, School of Engineering Technologies State University of New York at Farmingdale, Farmingdale, New York 11735, USA. rsandyk@optonline.net
Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most
severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons.
Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through
transcranial administration of AC pulsed picotesla electromagnetic fields) to
prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2
receptor agonists have been shown to prevent glutamate-induced neurotoxicity in
primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.
Publication Types:
Review
PMID: 16861147 [PubMed - indexed for MEDLINE]
11: Neurol Med Chir (Tokyo). 2006 Jul;46(7):366-70.
Cervical spondylotic amyotrophy treated by anterior decompression. Three case reports.
Mori K, Yamamoto T, Nakao Y, Maeda M.
Department of Neurosurgery, Juntendo University, Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295, Japan. kmori@med-juntendo.jp
Cervical spondylotic amyotrophy (CSA) is a rare type of cervical spondylotic disorder. The surgical treatment of CSA is controversial. We treated three patients with the proximal type of CSA by anterior decompression. Three men (65, 61, and 58 years old) presented with CSA manifesting as unilateral muscle weakness and atrophy in the deltoid and biceps muscles without significant sensory deficit. Preoperative neuroradiological examinations revealed anterolateral spinal cord compression in one patient and ventral root compression in two patients at the C4-5 and C5-6 spaces. Magnetic resonance (MR)
imaging showed no abnormal intramedullary signal intensity in any patient. Vertebrotomy deviated to the lesion side was performed to provide a better view of the laterally situated osteophytes. Anterior decompression was focused on the paramedial to lateral area, and further foraminotomy was performed according to the radiological findings. After decompression, intervertebral instrumentation was performed using titanium cervical cages. Two of the patients had good recovery of motor strength and one had moderate recovery despite persistent motor atrophy. Surgical intervention is effective in patients with CSA despite severe muscle atrophy unless MR imaging shows the presence of severe degenerative intramedullary lesion.
Publication Types:
Case Reports
PMID: 16861833 [PubMed - indexed for MEDLINE]
10: JAAPA. 2006 Jul;19(7):29-35.
Misdiagnosis and missed diagnoses in patients with ALS.
Cristini J.
Department of Neurology, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Publication Types:
Review
PMID: 16869150 [PubMed - indexed for MEDLINE]
9: Science. 2006 Jul 28;313(5786):428-31.
Comment in:
Science. 2006 Sep 22;313(5794):1737.
Neurodegenerative disease. Guam's deadly stalker: on the loose worldwide?
Miller G.
Publication Types:
News
PMID: 16873621 [PubMed - indexed for MEDLINE]
8: Science. 2006 Jul 28;313(5786):431.
Neurodegenerative disease. From cycad flour, a new suspect emerges.
Miller G.
Publication Types:
News
PMID: 16873622 [PubMed - indexed for MEDLINE]
7: J Neuroimmunol. 2006 Jul;176(1-2):198-215.
Neurodegeneration and neuroprotection in multiple sclerosis and other
neurodegenerative diseases.
Dhib-Jalbut S, Arnold DL, Cleveland DW, Fisher M, Friedlander RM, Mouradian MM,
Przedborski S, Trapp BD, Wyss-Coray T, Yong VW.
UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, and The
Cleveland Clinic, OH, USA. jalbutsu@umdnj.edu
Multiple sclerosis is considered a disease of myelin destruction; Parkinson's
disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor
neuron death; and Alzheimer's, a disease of plaques and tangles. Although these
disorders differ in important ways, they also have common pathogenic features,
including inflammation, genetic mutations, inappropriate protein aggregates
(e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to
apoptosis, such as oxidative stress and mitochondrial dysfunction. In most
disorders, it remains uncertain whether inflammation and protein aggregation are
neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate
neuronal diseases should facilitate development of neuroprotective and
neurorestorative strategies.
Publication Types:
Clinical Conference
Research Support, Non-U.S. Gov't
PMID: 16983747 [PubMed - indexed for MEDLINE]
6: CNS Drug Rev. 2006 Summer;12(2):113-22.
Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's
disease and amyotrophic lateral sclerosis.
Matsuoka M, Hashimoto Y, Aiso S, Nishimoto I.
Department of Pharmacology, KEIO University School of Medicine, Shnanomachi,
Tokyo, Japan. sakimatu@sc.itc.keio.ac.jp
Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 10(5) times more potent as a neuroprotective than HN; at 10-picomolar and higher
concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-amino-acid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16958985 [PubMed - indexed for MEDLINE]
5: Nat Clin Pract Neurol. 2006 Jul;2(7):364-5.
Is pentoxifylline safe and effective in patients with amyotrophic lateral sclerosis?
Lindhorst S, Cudkowicz M.
Neurology Clinical Trials Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
PMID: 16932586 [PubMed - indexed for MEDLINE]
4: Nat Clin Pract Neurol. 2006 Jul;2(7):356-7.
How beneficial is noninvasive ventilation in patients with amyotrophic lateral
sclerosis?
Lechtzin N.
Johns Hopkins University, and Johns Hopkins ALS Clinic, Baltimore, MD 21205,
USA. nlechtz@jhmi.edu
PMID: 16932582 [PubMed - indexed for MEDLINE]
3: Brain Pathol. 2006 Jul;16(3):228-34.
Neurodegeneration with features of NIFID and ALS--extended clinical and
neuropathological spectrum.
Roeber S, Bazner H, Hennerici M, Porstmann R, Kretzschmar HA.
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universitat
Muenchen, Germany.
Heterogeneous clinical and neuropathological features have been observed in the recently described neuronal intermediate filament inclusion disease (NIFID). The
immunohistological findings common to all cases are alpha-internexin and neurofilament-positive neuronal cytoplasmic inclusions, which have not been found in comparable density in other neurodegenerative disorders. Notwithstanding these common features, the cases reported so far have shown differences concerning age at onset, constellation and dominance of symptoms as well as type and distribution of additional neuropathological findings. Here we present the first NIFID case that exhibits severe involvement of lower motor neurons. Also, this patient may have had a clinical onset of disease in early childhood, as she was diagnosed as having dysarthria, which could not be attributed to any other cause at the age of 3 years. This case is a further
contribution to the spectrum of this novel neurodegenerative disease.
Publication Types:
Case Reports
PMID: 16911480 [PubMed - indexed for MEDLINE]
2: Ann Otol Rhinol Laryngol. 2006 Jul;115(7):528-34.
Sensory testing in the assessment of laryngeal sensation in patients with
amyotrophic lateral sclerosis.
Amin MR, Harris D, Cassel SG, Grimes E, Heiman-Patterson T.
Voice Center, Department of Otolaryngology, Drexel University College of
Medicine, Philadelphia, Pennsylvania, USA.
OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron
disease of unknown cause. Mortality in the population is frequently due to
aspiration pneumonia. Although typically considered to be a disorder limited to
motor neuron involvement, some investigators have indicated that decreased
sensory function in ALS patients additionally contributes to the disease
process. The objective of this study was to evaluate laryngopharyngeal sensation
in the ALS population in order to quantify the range of sensory deficits and
correlate any abnormalities with demographic data to determine which patients
are at risk of having sensory deficits. METHODS: We examined the sensation of
the larynx in 22 patients with ALS to determine whether a sensory deficit was
present. After completion of a dysphagia questionnaire and medical history,
patients underwent flexible endoscopic evaluation of swallowing with sensory
testing (FEESST) to evaluate sensory function. Threshold values were determined
and recorded for initiation of the adductor reflex. RESULTS: The results of the
sensory and swallowing function assessments performed on 22 patients demonstrate
abnormal sensation in 54.5% of the tested population. Asymmetric findings were
noted in 75% of these patients. There was no correlation noted between the
presence of sensory deficits and the severity or duration of the disease.
CONCLUSIONS: Progressive dysphagia in the ALS population has typically been
attributed to muscle weakness. This study points to the presence of sensory
deficits in the larynx, which can further affect proper swallowing function.
Publication Types:
Comparative Study
PMID: 16900807 [PubMed - indexed for MEDLINE]
1: Neurol Sci. 2006 Jul;27(3):190-3.
Vitamin E intake and quality of life in amyotrophic lateral sclerosis patients:
a follow-up case series study.
Galbussera A, Tremolizzo L, Brighina L, Testa D, Lovati R, Ferrarese C,
Cavaletti G, Filippini G.
Department of Neurology, S. Gerardo Hospital and University of Milano-Bicocca,
Via Donizetti 106, I-20052, Monza (MI), Italy. galbuz@libero.it
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving
both upper and lower motor neurons, leading inexorably to death within a few
years. Although our understanding of the pathogenesis of this disease has grown
at a very fast rate in recent years, we do not yet have effective treatment options that can positively impact the quality of life (QoL) of these patients.
Interestingly, increasing experimental evidence suggests that oxidative stress
is involved in the pathogenesis of ALS and that vitamin E could reduce neuronal
damage. Hence, in this observational study we determined the QoL in 33 ALS
patients taking or not taking vitamin E supplementation (600 mg/day), using the
Italian version of the Short-Form 36-Item Health Survey (SF-36). No differences
were seen between the two groups of patients, therefore we do not recommend
routine use of vitamin E in ALS patients, at least in the absence of randomised
clinical trials specifically designed for addressing this issue.
PMID: 16897634 [PubMed - indexed for MEDLINE]
