October 2006

34: Rev Bras Otorrinolaringol (Engl Ed). 2005 Sep-Oct;71(5):566-9. Epub 2006 Mar 31.

Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis.

Manrique D.

Department of Otorhinolaryngology, UNIFESP.

AIM: To demonstrate the effect of local application of Botox(R) in patients with amyotrophic lateral sclerosis (ALS), following our 2002 institutional protocol of sialorrhea treatment. STUDY DESIGN: Clinical prospective. MATERIAL AND METHOD: Five patients with ALS assisted at Clinic of Otolaryngology of AACD (Associacao de Assistencia a Crianca Deficiente). They were all submitted to local application of Botox in salivary glands and followed up for a year. The protocol consisted of clinical questionnaire about the inability of swallowing saliva and its repercussions in quality of life. Patients were submitted to
previous odontological treatment, had intolerance to the adverse effects of anti-cholinergic agents and had not used Botox for at least six months. The application was guided by ultrasound and the doses were 30U in one point for submandibular gland, and 20U in two points for each parotid gland, after topic anesthetic with prilocaine. RESULTS: Five patients with ALS with sialorrhea, aged 45 to 59 years, were submitted to Botox salivary glands application. We observed that the symptoms of sialorrhea changed dramatically in four patients. Three patients stayed almost four months without complaints with repercussion in quality of life. No patient presented local or systemic effects with local
injection of Botox.

PMID: 16612515 [PubMed - indexed for MEDLINE]

33: Exp Neurol. 2006 Oct;201(2):293-300. Epub 2006 Jun 5.

In vivo quantification of spinal and bulbar motor neuron degeneration in the
G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent
diffusion coefficient.

Niessen HG, Angenstein F, Sander K, Kunz WS, Teuchert M, Ludolph AC, Heinze HJ,
Scheich H, Vielhaber S.

Department of Neurology II, Otto-Von-Guericke University Magdeburg, Leipziger
Str 44, Magdeburg, Germany. heiko.niessen@medizin.uni-magdeburg.de

Magnetic resonance imaging (MRI) has provided important information in
characterizing amyotrophic lateral sclerosis (ALS) in humans and in animal
models. A frequently used animal model to study mechanisms of pathogenesis and
the efficacy of drugs in ALS is a transgenic mouse over-expressing the human
mutated G93A-superoxide dismutase 1 (G93A-SOD1). In our study, we applied MRI to
find suitable progression markers, which can be used to monitor the development
of ALS and to evaluate therapeutic approaches at early stages of the disease.
Therefore, we generated parameter maps of the spin-spin relaxation time (T2) and
the apparent diffusion coefficient (ADC) starting at day 70 after birth, i.e.,
before motor scores decline around day 90. Depending on the progression of the
disease, G93A-SOD1 mice showed significantly increased values of T2 in the brain
stem motor nuclei Nc. V (trigeminal nucleus), VII (facial nucleus), and XII
(hypoglossal nucleus), and spinal cord compared to non-transgenic wild-type mice
and transgenic mice over-expressing the non-mutated wild-type human SOD1
(tg-SOD1). Similar effects in these motor nuclei were revealed by ADC mapping.
Furthermore, in the upper spinal cord, a dorsal-ventral difference with
significantly higher T2 values in the ventral part was demonstrated by T2
mapping. While both T2 and ADC might prove useful as progression markers and
enable the longitudinal non-invasive evaluation of ALS in G93A-SOD1 mice, the
potential is limited by age-dependent effects in case of ADC mapping.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 16740261 [PubMed - indexed for MEDLINE]

32: Exp Neurol. 2006 Sep;201(1):244-52. Epub 2006 Jun 9.

BMAA selectively injures motor neurons via AMPA/kainate receptor activation.

Rao SD, Banack SA, Cox PA, Weiss JH.

Department of Anatomy and Neurobiology, 2101 Gillespie Building, University of
California, Irvine, Irvine, CA 92697-4292, USA.

The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to
amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC)
based on its ability to induce a similar disease phenotype in primates and its
presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations ( approximately 30 muM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor
antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation
of AMPA/kainate receptors. Using microfluorimetric techniques, we further found
that BMAA induced preferential [Ca(2+)](i) rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons.
Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent
MN injury, consistent with the idea that BMAA is a crucial toxic component in
this plant. Present findings support the hypothesis that BMAA may contribute to
the selective MN loss in ALS/PDC.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16764863 [PubMed - indexed for MEDLINE]

31: Exp Neurol. 2006 Oct;201(2):277-80. Epub 2006 Jun 30.

Matrix metalloproteinases--a conceptional alternative for disease-modifying strategies in ALS/MND?

Ludolph AC.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, Ulm, Germany.
albert.ludolph@rku.de

PMID: 16808915 [PubMed - indexed for MEDLINE]

30: J Biol Chem. 2006 Oct 6;281(40):30152-65. Epub 2006 Jul 17.

Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1.

Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK.

Brain Injury and Repair Group, Howard Florey Institute, University of Melbourne,
Parkville, Victoria 3010, USA. j.atkin@hfi.unimelb.edu.au

Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 16847061 [PubMed - indexed for MEDLINE]

29: Muscle Nerve. 2006 Oct;34(4):391-405.

Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases.

Bogaert E, Van Damme P, Van Den Bosch L, Robberecht W.

Laboratory of Neurobiology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.

The angiogenic activity of vascular endothelial growth factor (VEGF) is well known. Recently, it has become evident that VEGF is involved in central nervous system physiology and may play a role in the pathogenesis of neurological diseases. In particular, it may be involved in the mechanism of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), and has been hypothesized to be implicated in the pathogenesis of peripheral neuropathies such as occur in the so-called POEMS syndrome and diabetes. VEGF is also being studied as a possible treatment option in some of these disorders. In this review we critically analyze the data supporting the notion that VEGF is a factor involved in motor neuron degeneration and review the studies linking VEGF to other diseases of the peripheral and central nervous systems.

Publication Types:
Review

PMID: 16856151 [PubMed - indexed for MEDLINE]

28: Muscle Nerve. 2006 Oct;34(4):444-50.

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease.

Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP, Dingwall C.

Neurodegeneration Research Department, GlaxoSmithKline Research & Development Ltd., New Frontiers Science Park, Third Avenue, Harlow, Essex, UK.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Transgenic mouse models show features that closely mimic those seen in the clinical situation, reflected in the molecular changes observed in mouse models and in tissues from patients. We report a dramatic increase in the expression of amyloid precursor protein (APP) in the hindlimb
muscles, but not the spinal cord of the G93A transgenic mouse model, significantly before the appearance of clinical abnormalities. APP levels were unchanged in nontransgenic mice and in mice overexpressing human wild-type Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate a similar change in APP expression in human deltoid muscle samples from ALS patients compared with age-matched controls. The inhibitory role of APP in innervation at the neuromuscular junction and increased expression in inclusion-body myositis suggest that presymptomatic upregulation of APP may be consistent with a potential role for APP in ALS pathology.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 16856153 [PubMed - indexed for MEDLINE]

27: J Neuroimmunol. 2006 Oct;179(1-2):87-93. Epub 2006 Jul 20.

MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS).

Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Lancero M, Narvaez A, McGrath MS.

University of California, San Francisco, San Francisco General Hospital, San Francisco, CA 94110, USA.

Recent studies suggest that monocyte activation may play a role in ALS pathogenesis. Therefore, monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), and plasma levels of MCP-1 were measured in 42 sALS patients, 38 healthy and 34 age-related macular degeneration (ARMD) controls. MCP-1 was elevated in both sALS and ARMD patients, but CCR2 levels were significantly decreased on sALS but not on ARMD monocytes. Loss of monocyte CCR2 expression was inversely correlated with degree of monocyte/macrophage activation in sALS and this decrease was unlikely due to receptor
down-regulation given the ARMD results. Defective monocyte/macrophages may play an active role in sALS.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16857270 [PubMed - indexed for MEDLINE]

26: J Telemed Telecare. 2006;12 Suppl 1:31-4.

Tele-treatment of patients with amyotrophic lateral sclerosis (ALS).

Nijeweme-d'Hollosy WO, Janssen EP, Huis in 't Veld RM, Spoelstra J, Vollenbroek-Hutten MM, Hermens HJ.

Roessingh Research and Development, Enschede, The Netherlands. wendy@ilca.nl

Management of patients with amyotrophic lateral sclerosis (ALS) mainly consists of (psycho) social support and advice on activities of daily living. We evaluated the effects of tele-treatment in addition to the conventional method of care in four patients with ALS. A Web application was built with information about ALS and a link to the tele-treatment environment. The latter contained a chat room and a link to start personal computer (PC)-based videoconferencing with a rehabilitation physician. The effect on quality of care was evaluated by questionnaires and interviews. The interviews showed that patients were
satisfied with tele-treatment and experienced a pleasant contact during teleconsultations. The rehabilitation physician experienced acceptance of tele-treatment by the patients and a decrease in the time needed for travelling. Tele-treatment was especially suitable for discussing the practical issues about ALS. On the other hand, psychosocial and emotional issues still needed to be discussed during traditional face-to-face contact. Therefore tele-treatment should only be given in addition to face-to-face contact, rather than as a replacement for it.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 16884573 [PubMed - indexed for MEDLINE]

25: Med Hypotheses. 2006;67(6):1363-71. Epub 2006 Aug 4.

Sporadic amyotrophic lateral sclerosis as an infectious disease: a possible role of cyanobacteria?

Stipa G, Taiuti R, de Scisciolo G, Arnetoli G, Tredici MR, Biondi N, Barsanti L, Lolli F.

Dipartimento di Scienze Neurologiche e Psichiatriche, Universita degli Studi di Firenze, and Neurofisiopatologia-Unita Spinale, Azienda Ospedaliero Universitaria Careggi, Italy.

The available epidemiological data for amyotrophic lateral sclerosis (ALS) support an infectious etiology and lead us to propose a new hypothesis. We examined older epidemiological data concerning categories of the population with increased incidence (aged people, people living in rural areas, farmers,
breeders), more recent epidemiological reports regarding Italian soccer players, AIDS patients, people living in highly polluted areas, and reports of cases of conjugal and pregnancy-associated ALS. The toxic and infectious hypotheses lead us to suggest a role for cyanobacteria in the production of endogenous
beta-N-methylamino-L-alanine. Infection from a cyanobacterium, or another ubiquitous bacterium having similar characteristics, may be the missing clue to the etiology of ALS. We speculate that ubiquitous bacteria secreting toxic amino acids and "colonizing" tissues and organs in the human body might be the common element linking motor neuron diseases in Guam to sporadic ALS in the rest of the world.

PMID: 16890380 [PubMed - indexed for MEDLINE]

24: J Biol Chem. 2006 Oct 6;281(40):30223-33. Epub 2006 Aug 4.

Characterization of amyotrophic lateral sclerosis-linked P56S mutation of
vesicle-associated membrane protein-associated protein B (VAPB/ALS8).

Kanekura K, Nishimoto I, Aiso S, Matsuoka M.

Departments of Pharmacology and Anatomy, Keio University School of Medicine, 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

The P56S mutation in VAPB (vesicle-associated membrane protein-associated protein B) causes autosomal dominant motoneuronal diseases. Although it was reported that the P56S mutation induces localization shift of VAPB from endoplasmic reticulum (ER) to non-ER compartments, it remains unclear what the physiological function of VAPB is and how the P56S mutation in VAPB causes motoneuronal diseases. Here we demonstrate that overexpression of wild type VAPB (wt-VAPB) promotes unfolded protein response (UPR), which is an ER reaction to suppress accumulation of misfolded proteins, and that small interfering RNA for VAPB attenuates UPR to chemically induced ER stresses, indicating that VAPB is physiologically involved in UPR. The P56S mutation nullifies the function of
VAPB to mediate UPR by inhibiting folding of VAPB that results in insolubility and aggregate formation of VAPB in non-ER fractions. Furthermore, we have found that expression of P56S-VAPB inhibits UPR, mediated by endogenous wt-VAPB, by inducing aggregate formation and mislocalization into non-ER fractions of wt-VAPB. Consequently, the P56S mutation in a single allele of the VAPB gene may diminish the activity of VAPB to mediate UPR to less than half the normal level. We thus speculate that the malfunction of VAPB to mediate UPR, caused by the P56S mutation, may contribute to the development of motoneuronal degeneration linked to VAPB/ALS8.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 16891305 [PubMed - indexed for MEDLINE]

23: Biol Trace Elem Res. 2006 Oct;113(1):93-104.

Upregulation of metallothionein-I mRNA expression in a rodent model for
amyotrophic lateral sclerosis.

Ono S, Endo Y, Tokuda E, Ishige K, Tabata K, Asami S, Ito Y, Suzuki T.

Laboratory of Clinical Pharmacy, College of Pharmacy, Nihon University,
Funabashi, Chiba, 274-8555, Japan.

Metallothionein (MT) mRNA expression was investigated in a rodent model (G93A SOD1 transgenic mouse) for a lethal motor neuron disease, amyotrophic lateral sclerosis (ALS). In 8-wk-old mice that did not yet exhibit motor paralysis, MT-I mRNA expression was already significantly upregulated in the region of the spinal cord responsible for motor paralysis. The expression of another isoform, MT-III, was not changed. In the cerebellum, which is not responsible for motor paralysis in ALS, neither the expression profiles of MT-I nor MT-III were altered. In 16-wk-old mice exhibiting motor paralysis, the expression of MT-I mRNA remained upregulated and the MT-III level tended to be elevated. Although no significant differences were found in the levels of both isoforms in the liver or kidney of 8-wk-old mice, the MT-I mRNA expression level was significantly upregulated in the kidney and liver of 16-wk-old mice. These results indicated that the MT-I isoform, but not the MT-III isoform, is associated with motor neuron death in ALS and suggested that the disease might be a systemic disorder to which the spinal cord is particularly susceptible.

PMID: 17114818 [PubMed - indexed for MEDLINE]

22: Curr Pharm Biotechnol. 2006 Oct;7(5):315-21.

DNA hypermethylation of myeloid cells, a novel therapeutic target in MDS and AML.

Muller CI, Ruter B, Koeffler HP, Lubbert M.

University of Freiburg Medical Center, Department Internal Medicine I, Div. Hematology/Oncology, Albert-Ludwigs-University, Hugstetter Str., D-79106 Freiburg, Germany.

Differential methylation of CpG islands is a regulatory mechanism for promoter activity of different classes of genes, including tissue-specific genes. These CpG islands are targets for transformation-associated, aberrant hypermethylation activity during leukemogenesis. Therefore the pharmacological reversion of this methylator phenotype (e.g. by reactivation of tumor suppressor gene expression) is an important rationale for development of inhibitors of DNA methyltransferase activity. In vitro, inhibition of methylation using azanucleosides results in modest differentiation of transformed myeloid cell lines. In vivo, low doses of these agents induce DNA demethylation of malignant myeloid cells. Indeed, the first drug specifically approved for the treatment of myelodysplastic syndrome (MDS) was the azanucleoside 5-azacytidine (Vidaza). The most potent DNA demethylating agent available, 5-aza-2' deoxycytidine (Decitabine, Dacogen) also has recently been approved by the U.S.A. FDA for treatment of MDS of all subtypes. About 30 % of MDS patients with an abnormal karyotype have normalization of their karyotype after receiving the drug. This activity is especially relevant in patients with high-risk karyotypic abnormalities (complex karyotype and/or abnormalities of chromosome 7) compared to patients with intermediate-risk karyotype. Both drugs offer a novel, non-intensive therapeutic approach, particularly in the older patient population who due to comorbidities and/or reduced performance status are ineligible for aggressive chemotherapies. Target genes being particularly prone to demethylation by these drugs in the aberrant cells (e.g. p15/INK4b) are under active investigation. Future translational and clinical studies will be aimed at improving the response rate and duration of response to non-intensive treatment with demethylating agents, by studying rational drug combinations e.g. with inhibitors of histone deacetylase activity.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

PMID: 17076647 [PubMed - indexed for MEDLINE]

21: Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004030.

Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.

Langmore SE, Kasarskis EJ, Manca ML, Olney RK.

University of California San Francisco, Department of Otolaryngology--Head and
Neck Surgery, 2380 Sutter Street, 2nd Floor, San Francisco, CA 94115, USA.
slangmore@ohns.ucsf.edu

BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. OBJECTIVES: The aim of this review is to examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival; (2) nutritional status; (3) quality of life. Another aim is to examine the minor and major complications of percutaneous endoscopic gastrostomy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (June 2005), MEDLINE (from January 1966 to June 2005), and EMBASE (from January 1980 to June 2005) for randomized controlled trials. In addition we searched MEDLINE (January 1966 to June 2005) and EMBASE (January 1980 to June 2005) to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles, proceedins
of scientific meetings, and enlisted personal communications to identify any additional references. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials were to have been selected. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. DATA COLLECTION AND ANALYSIS: We independently assessed study methodological design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, and (3) self-perceived quality of life We were also interested in reports of safety of the procedure as indicated by (4) minor and major complications of percutaneous endoscopic gastrostomy or other feeding tube placement. MAIN RESULTS: We found
no randomized controlled trials comparing the efficacy of enteral tube feeding
with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective case controlled studies in the 'Discussion' section of this review. AUTHORS' CONCLUSIONS: There are no randomized controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for survival. The 'best' evidence to date, based on controlled prospective cohort studies, suggests an advantage for survival in all people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has only
been addressed by a few researchers and needs more serious attention.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17054194 [PubMed - indexed for MEDLINE]

20: N Engl J Med. 2006 Oct 19;355(16):1740; author reply 1740.

Comment on:
N Engl J Med. 2006 Jul 20;355(3):296-304.

A man with a gait disorder.

Mast H, Kejda J, Mohr JP.

Publication Types:
Comment
Letter

PMID: 17050903 [PubMed - indexed for MEDLINE]

19: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16021-6. Epub 2006 Oct 16.

Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis.

Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH.

Department of Neurology, Methodist Neurological Institute, Houston, TX 77030, USA.

The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu(2+)/Zn(2+) superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1(G93A)) in CNS microglia contributes to motoneuron injury, PU.1(-/-) mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1(G93A), an animal model of familial ALS, transplanted into PU.1(-/-) mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1(G93A) in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1(-/-) mice were bred with mSOD1(G93A) mice. In mSOD1(G93A)/PU.1(-/-) mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1(G93A) expressing cells or mSOD1(G93A) mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1(G93A) microglia. Compared with wild-type microglia, mSOD1(G93A) microglia produced and released more superoxide and nitrite+nitrate, and induced more neuronal death. These data
demonstrate that the expression of mSOD1(G93A) results in activated and neurotoxic microglia, and suggests that the lack of mSOD1(G93A) expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 17043238 [PubMed - indexed for MEDLINE]

18: N Engl J Med. 2006 Oct 12;355(15):1611-3.

Amyotrophic lateral sclerosis--are microglia killing motor neurons?

Borchelt DR.

Department of Neuroscience, McKnight Brain Institute, SantaFe Health Alzheimer's
Disease Research Center, University of Florida, Gainesville, USA.

PMID: 17035656 [PubMed - indexed for MEDLINE]

52: Neurology. 2006 Oct 10;67(7):1314-5; author reply 1314-5.

Comment on:
Neurology. 2006 Jan 24;66(2):265-7.

Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.

Gordon PH, Cheung YK.

Publication Types:
Comment
Letter
Research Support, Non-U.S. Gov't

PMID: 17030785 [PubMed - indexed for MEDLINE]

17: Neurology. 2006 Oct 10;67(7):1294-6.

Development and evaluation of a self-administered version of the ALSFRS-R.

Montes J, Levy G, Albert S, Kaufmann P, Buchsbaum R, Gordon PH, Mitsumoto H.

Eleanor and Lou Gehrig MDA/ALS Research Center, Department of Neurology, College
of Physicians and Surgeons, Columbia University, New York, NY 10032.
jm598@columbia.edu

We evaluated the reliability and sensitivity to change over time of a newly
developed self-administered version of the ALS functional rating scale-revised
(ALSFRS-R) in 60 consecutive patients from an ALS clinic. The self-administered
ALSFRS-R showed excellent reliability (intraclass correlation = 0.93, 95% CI:
088 to 0.96) and similar sensitivity to change over time vs the standard
evaluator-administered ALSFRS-R.

Publication Types:
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

PMID: 17030772 [PubMed - indexed for MEDLINE]

16: Tidsskr Nor Laegeforen. 2006 Oct 5;126(19):2523-5.

Holmoy T, Worren T.

Nevrologisk avdeling, Ulleval universitetssykehus, 0407 Oslo, Norway.
trygve.holmoy@medisin.uio.no

BACKGROUND: Many patients with amyotrophic lateral sclerosis lose the ability to
speak, and in late-stage disease also the ability to communicate through
gestures. Social isolation is one of the greatest burdens of this disease.
Implementation of alternative and augmentative communication can increase the
quality of life even in advanced disease. MATERIALS AND METHODS: We have
systematically recorded alternative and augmentative communication aids given to
patients treated by the amyotrophic lateral sclerosis team at Ulleval University
Hospital from 1998 to 2005, and evaluated the results in the light of current
literature. RESULTS: 62 out of 92 patients received alternative and augmentative
communication aids. Alternative and augmentative communication was more often
used by female than male patients (p = 0.01). Except for two who developed
dementia, all patients were able to express basic needs until the terminal stage
of the disease. INTERPRETATION: Most patients retain enough mobility of head and
eyes to use communication aids until the terminal stage. Physicians must know
the possibilities and limitations of assisted and augmentative communication in
order to give appropriate treatment and information, also concerning
life-sustaining treatment.

Publication Types:
Case Reports
English Abstract

PMID: 17028633 [PubMed - indexed for MEDLINE]

15: Tidsskr Nor Laegeforen. 2006 Oct 5;126(19):2520-2.

Leirvik A, Liverod M, Holmoy T.

Det medisinske fakultet, Universitetet i Oslo, Oslo, Norway.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to loss of important body
functions, a huge need for assistance and is associated with a low quality of
life (QoL). We have investigated QoL in ALS patients treated by a multidisciplinary ALS team, and to which degree this team met the patients' needs. MATERIAL AND METHODS: The patients' health-related QoL was measured by use of SF-36, and content with the treatment offered by the team was evaluated through a structured interview of 14 ALS patients at the Neurological Department at Ulleval University Hospital, Oslo, Norway. RESULTS: The patients reported low scores for physical QoL, but mental QoL was close to that of the general population. The patients were generally content with the treatment given by the ALS team. They were most content with the practical help given to organize their homes and the accessibility of different members of the team. They were least
content with the psychological help and the information given to their relatives. Content with treatment was not correlated with self-perceived QoL or with physical disability. INTERPRETATION: Our findings suggest that the patients are content with the ALS team, but that their psychological reactions and information to relatives are not handled well enough. Most ALS patients treated by the ALS team experience their life as meaningful, regardless of their degree of neurological dysfunction.

Publication Types:
English Abstract

PMID: 17028632 [PubMed - indexed for MEDLINE]

14: Tidsskr Nor Laegeforen. 2006 Oct 5;126(19):2505.

Tysnes OB.

Nevrologisk avdeling, Haukeland Universitetssjukehus, Norway.
ole-bjorn.tysnes@helse-bergen.no

PMID: 17028627 [PubMed - indexed for MEDLINE]




13: Science. 2006 Oct 6;314(5796):130-3.

Comment in:
Science. 2006 Oct 6;314(5796):42-3.

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic
lateral sclerosis.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J,
Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie
IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM.

Center for Neurodegenerative Disease Research, Department of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104, USA.

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks
of frontotemporal lobar degeneration with ubiquitin-positive inclusions and
amyotrophic lateral sclerosis. Although the identity of the ubiquitinated
protein specific to either disorder was unknown, we showed that TDP-43 is the
major disease protein in both disorders. Pathologic TDP-43 was
hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal
fragments and was recovered only from affected central nervous system regions,
including hippocampus, neocortex, and spinal cord. TDP-43 represents the common
pathologic substrate linking these neurodegenerative disorders.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 17023659 [PubMed - indexed for MEDLINE]

12: Science. 2006 Oct 6;314(5796):42-3.

Comment on:
Science. 2006 Oct 6;314(5796):130-3.

Neurodegenerative diseases. Picking apart the causes of mysterious dementias.

Marx J.

Publication Types:
Comment, News.

PMID: 17023628 [PubMed - indexed for MEDLINE]

11: Mol Diagn Ther. 2006;10(5):281-92.

Plasma and cerebrospinal fluid-based protein biomarkers for motor neuron
disease.

Kolarcik C, Bowser R.

Department of Pathology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261, USA.

Motor neuron diseases (MNDs) and, in particular, amyotrophic lateral sclerosis
(ALS), are a heterogeneous group of neurologic disorders characterized by the
progressive loss of motor function. In ALS, a selective and relentless
degeneration of both upper and lower motor neurons occurs, culminating in
mortality typically within 5 years of symptom onset. However, survival rates
vary among individual patients and can be from a few months to >10 years from
diagnosis. Inadequacies in disease detection and treatment, along with a lack of
diagnostic and prognostic tools, have prompted many to turn to proteomics-based
biomarker discovery efforts. Proteomics refers to the study of the proteins expressed by a genome at a particular time, and the proteome can respond to and reflect the status of an organism, including health and disease states. Although an emerging field, proteomic applications promise to uncover biomarkers critical for differentiating patients with ALS and other MNDs from healthy individuals and from patients affected by other diseases. Ideally, these studies will also provide mechanistic information to facilitate identification of new drug targets for subsequent therapeutic development. In addition to proper experimental design, standard operating procedures for sample acquisition, preprocessing, and storage must be developed. Biological samples typically analyzed in proteomic studies of neurologic diseases include both plasma and cerebrospinal fluid (CSF). Recent studies have identified individual proteins and/or protein panels from blood plasma and CSF that represent putative biomarkers for ALS, although many of these proteins are not unique to this disease. Continued investigations are required to validate these initial findings and to further pursue the role of these proteins as diagnostic biomarkers or surrogate markers of disease progression. Protein biomarkers specific to ALS will additionally function toevaluate drug efficacy in clinical trials and to identify novel targets for drug design. It is hoped that proteomic technologies will soon integrate the basicbiology of ALS with mechanistic disease information to achieve success in the
clinical setting.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 17022691 [PubMed - indexed for MEDLINE]

10: Neuron. 2006 Oct 5;52(1):39-59.

ALS: a disease of motor neurons and their nonneuronal neighbors.

Boillee S, Vande Velde C, Cleveland DW.

Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California, San Diego, La Jolla, California 92093, USA.

Amyotrophic lateral sclerosis is a late-onset progressive neurodegenerative
disease affecting motor neurons. The etiology of most ALS cases remains unknown,
but 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1).
Since sporadic and familial ALS affects the same neurons with similar pathology,
it is hoped that therapies effective in mutant SOD1 models will translate to sporadic ALS. Mutant SOD1 induces non-cell-autonomous motor neuron killing by an unknown gain of toxicity. Selective vulnerability of motor neurons likely arises from a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, excitotoxicity, insufficient growth factor signaling, and inflammation. Damage within motor neurons is enhanced by damage incurred by nonneuronal neighboring cells, via an inflammatory response that accelerates disease progression. These findings validate therapeutic approaches aimed at nonneuronal cells.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17015226 [PubMed - indexed for MEDLINE]

9: Reprod Biomed Online. 2006 Oct;13(4):562-72.

Potential clinical applications using stem cells derived from human umbilical
cord blood.

Ghen MJ, Roshan R, Roshan RO, Blyweiss DJ, Corso N, Khalili B, Zenga WT.

Eden Laboratories Ltd, Frederick House, Frederick Street, PO Box SS-19392,
Nassau, The Bahamas. mghen@edenlaboratories.net

There is an abundance of clinical applications using human umbilical cord blood
(HUCB) as a source for stem cell populations. Other than haematopoietic
progenitors, there are mesenchymal, endothelial stem cells and neuronal
precursors, in varying quantities, that are found in human umbilical cord blood.
These may be useful in diseases such as immune deficiency and autoimmune
disorders. Considering issues of safety, availability, transplant methodology,
rejection and side effects, it is contended that a therapeutic stem cell
transplant, utilizing stem cells from HUCB, provides a reliable repository of
early precursor cells that can be useful in a great number of diverse
conditions. Drawbacks of relatively smaller quantities of mononucleated cells in
one unit of cord blood can be mitigated by in-vitro expansion procedures,
improved in-vivo signalling, and augmentation of the cellular milieu, while
simultaneously choosing the appropriate transplantation site and technique for
introduction of the stem cell graft.

PMID: 17007681 [PubMed - indexed for MEDLINE]

8: Radiology. 2006 Oct;241(1):321-2; author reply 322-4.

Comment on:
Radiology. 2005 Oct;237(1):258-64.

MR imaging of upper motor neuron compromise in amyotrophic lateral sclerosis.

da Rocha AJ, Maia AC Jr, Fonseca RB.

Publication Types:
Comment
Letter

PMID: 16990687 [PubMed - indexed for MEDLINE]

7: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R182-7.

Recent advances in the genetics of amyotrophic lateral sclerosis and
frontotemporal dementia: common pathways in neurodegenerative disease.

Talbot K, Ansorge O.

Department of Physiology, Anatomy and Genetics , University of Oxford, Henry
Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3QX, UK.
kevin.talbot@clneuro.ox.ac.uk

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically
defined by the impairment of the voluntary motor system and ubiquitin-positive
intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD)
is a common form of neurodegenerative dementia and presents with personality
change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of
mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of
ALS and FTD. The identification of two further genetic causes of FTD-U with
(rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for
exploring the pathways associated with ubiquitin-mediated protein mishandling in
FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to
pure FTD-U, may represent a continuous spectrum of ubiquitin-associated
neurodegenerative disease.

Publication Types:
Review

PMID: 16987882 [PubMed - indexed for MEDLINE]

6: NMR Biomed. 2006 Oct;19(6):655-68.

Evaluation of treatment effects in Alzheimer's and other neurodegenerative
diseases by MRI and MRS.

Mueller SG, Schuff N, Weiner MW.

Center of Imaging of Neurodegenerative Diseases, Veterans Administration Medical
Center, Department of Radiology, University of California San Francisco, San
Francisco, CA 94121, USA.

Neurodegeneration refers to a large clinically and pathologically heterogeneous
disease entity associated with slowly progressive neuronal loss in different
anatomical and functional systems of the brain. Neurodegenerative diseases often
affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and
vascular dementia, or different aspects of the motor system, e.g., amyotrophic
lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing
knowledge about the mechanisms leading to neurodegeneration, the development of
treatments able to modify the neurodegenerative process becomes possible for the
first time. Currently, clinical outcome measures are used to assess the efficacy
of such treatments. However, most clinical outcome measures have a low
test-retest reliability and thus considerable measurement variance. Therefore,
large patient populations and long observation times are needed to detect
treatment effects. Furthermore, clinical outcome measures cannot distinguish
between symptomatic and disease-modifying treatment effects. Therefore,
alternative biomarkers including neuroimaging may take on a more important role
in this process. Because MR scanners are widely available and allow for
non-invasive detection and quantification of changes in brain structure and
metabolism, there is increasing interest in the use of MRI/MRS to monitor
objectively treatment effects in clinical trials of neurodegenerative diseases.
Particularly volumetric MRI has been used to measure atrophy rates in treatment
trials of AD because the relationship between atrophic changes and neuron loss
is well established and correlates well with clinical measures. More research is
needed to determine the value of other MR modalities, i.e. diffusion, perfusion
and functional MRI and MR spectroscopy, for clinical trials with neuroprotective
drugs. Copyright 2006 John Wiley & Sons, Ltd.

Publication Types:
Research Support, N.I.H., Extramural

PMID: 16986115 [PubMed - indexed for MEDLINE]

5: Hum Mol Genet. 2006 Oct 15;15(20):2988-3001. Epub 2006 Sep 1.

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal
lobar degeneration.

Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist
S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R,
Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S,
Mesulam M, White CL 3rd, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D,
Hutton M, Rademakers R.

Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo
Road, Jacksonville, FL 32224, USA.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21
nonsense, frameshift and splice-site mutations that cause premature termination
of the coding sequence and degradation of the mutant RNA by nonsense-mediated
decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16950801 [PubMed - indexed for MEDLINE]

4: Neurology. 2006 Oct 10;67(7):1147-50. Epub 2006 Aug 23.

SMN1 gene, but not SMN2, is a risk factor for sporadic ALS.

Corcia P, Camu W, Halimi JM, Vourc'h P, Antar C, Vedrine S, Giraudeau B, de
Toffol B, Andres CR; French ALS Study Group.

INSERM U619, Faculte de Medecine, Tours, France. corcia@med.univ-tours.fr

BACKGROUND: SMN1 gene deletions cause spinal muscular atrophy, and SMN2 gene
deletions have been associated with sporadic lower motor neuron diseases.
OBJECTIVES: To study the frequency of abnormal SMN1 gene copy numbers and to
determine whether SMN2 gene modulates the risk of amyotrophic lateral sclerosis
(ALS) or the duration of evolution. METHOD: The authors studied SMN1 and SMN2
genes in 600 patients with sporadic ALS and 621 controls using a quantitative
PCR method. RESULTS: The authors found an association of ALS with an abnormal
copy number (one or three copies) of SMN1 gene (p < 0.0001) with an OR of 2.8
(1.8 to 4.4, 95% CI). There was no association with SMN2 copy numbers and no
effect of SMN2 copies on the duration of evolution in ALS independently of SMN1
copy number. CONCLUSION: Abnormal SMN1 gene copy numbers are a genetic risk
factor in sporadic amyotrophic lateral sclerosis. There was no modulator effect
of the SMN2 gene.

Publication Types:
Controlled Clinical Trial
Research Support, Non-U.S. Gov't

PMID: 16931506 [PubMed - indexed for MEDLINE]

3: J Biomol Screen. 2006 Oct;11(7):729-35. Epub 2006 Aug 23.

Two approaches to drug discovery in SOD1-mediated ALS.

Broom WJ, Auwarter KE, Ni J, Russel DE, Yeh LA, Maxwell MM, Glicksman M,
Kazantsev AG, Brown RH Jr.

Day Neuromuscular Research Laboratory, MassGeneral Institute for
Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA
02129, USA. wbroom@partners.org

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases;
approximately 25% of these cases are due to mutations in the Cu/Zn superoxide
dismutase gene (SOD1). To date, 105 different mutations spanning all 5 exons
have been identified in the SOD1 gene. Mutant SOD1-associated ALS is caused by a
toxic gain of function of the mutated protein. Therefore, regardless of the
specific mechanism whereby mutant SOD1 initiates motor neuron death, the authors
hypothesize that measures that decrease levels of mutant SOD1 protein should
ameliorate the phenotype in transgenic mice and potentially in patients with
SOD1-mediated disease. They have designed 2 cell-based screening assays to
identify small, brain-permeant molecules that inactivate expression of the SOD1
gene or increase the degradation of the SOD1 protein. Here they describe the
development and optimization of these assays and the results of high-throughput
screening using a variety of compound libraries, including a total of more than
116,000 compounds. The majority of the hit compounds identified that
down-regulated SOD1 were shown to be toxic in a cell-based viability assay or
were nonselective transcription inhibitors, but work is continuing on a number
of nonspecific inhibitors of SOD1 expression. Ultimately, the authors believe
that these 2 cell-based assays will provide powerful strategies to identify
novel therapies for the treatment of inherited SOD1-associated forms of ALS.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16928982 [PubMed - indexed for MEDLINE]

2: Neurosci Lett. 2006 Oct 9;406(3):205-10. Epub 2006 Aug 17.

AIF translocates to the nucleus in the spinal motor neurons in a mouse model of ALS.

Oh YK, Shin KS, Kang SJ.

Department of Molecular Biology, Sejong University, 98 Gunja-Dong, Kwangjin-Gu, Seoul, Republic of Korea.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons in the brain stem and the spinal cords. One of the causes for the familial ALS has been attributed to the mutations in copper-zinc superoxide dismutase (SOD1). Although the toxic function of the mutant enzyme has not been fully understood, the final cell death pathway has been suggested as caspase-dependent. In the present study, we present evidence that the activation of apoptosis inducing factor (AIF) may play a role to induce motor neuron death during ALS pathogenesis. In the spinal cord of SOD1 G93A transgenic mice, expression of AIF was detected in the motor neurons and astrocytes. The level of AIF expression increased as the disease progressed. In the symptomatic SOD1 G93A transgenic mice, AIF released from the mitochondria and translocated into the nucleus in the motor neurons as evidenced by confocal microscopy and biochemical analysis. These results suggest that AIF may play a role to induce motor neuron death in a mouse model of ALS.

Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't

PMID: 16916579 [PubMed - indexed for MEDLINE]

1: J Neurosci Res. 2006 Oct;84(5):980-92.

Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene.

Ohta Y, Nagai M, Nagata T, Murakami T, Nagano I, Narai H, Kurata T, Shiote M, Shoji M, Abe K.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmacy, Okayama University, Okayama, Japan. yasuyuki@cc.okayama-u.ac.jp

We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5 -bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the
number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment. Copyright 2006 Wiley-Liss, Inc.

Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't

PMID: 16902995 [PubMed - indexed for MEDLINE]