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PubMed2005

O triclusters revisited: classical MD and quantum cluster results for glasses of composition (Al(2)O(3))2(SiO(2)).

The (17)O NMR spectrum of CaAl(2)Si(2)O(8) glass shows two types of O sites that are not present in the crystalline material. One of these, with (17)O NMR parameters C(Q) = 2.3 MHz and delta = +20 ppm, has been assigned to a "tricluster" O, a local geometry in which the O is coordinated to three tetrahedrally coordinated atoms, either Al or Si. For crystalline CaAl(4)O(7), a tricluster site (with three Al linkages to O, i.e., OAl(3)) has been characterized experimentally, with a C(Q) of 2.5 MHz and a delta of about +40 ppm. Thus, a C(Q) value of 2.5 MHz or less seems to be a characteristic of such sites, although they may show a range of delta values. However, several different quantum chemical cluster calculations employing energy-optimized geometries for various tricluster species have given C(Q) values considerably larger than that seen experimentally in the CaAl(2)Si(2)O(8) glass (with minimum C(Q) values of 3.0 MHz even for all Al species). We have recently shown that for edge-sharing geometries, in which the tricluster O atoms participate in "two-membered rings" of composition Al(2)O(2), the calculated C(Q) values are considerably lower, in the range identified in the glass. However, such two-membered ring geometries had been observed only in crystalline inorganic alumoxanes. Ab initio MD calculations on related compositions, such as the calcium aluminosilicate, CAS, (CaO)(0.21)(Al(2)O(3))(0.12)(SiO(2))(0.67), show a small percentage of O triclusters, but none in two-membered rings of the Al(2)O(2) type, and the calculated C(Q) values for the triclusters that do exist are higher than seen in the original experiments on CaAl(2)Si(2)O(8) glass and not significantly different from those for two-coordinate O in Si-O-Al sites. However, a classical MD simulation of the structure of glassy aluminum silicate AS2, (Al(2)O(3))2(SiO(2)), gave a predominance of O triclusters within two-membered rings, with structures much like those seen in the alumoxanes. We have now calculated (17)O nuclear quadrupole coupling constants and NMR shielding values for clusters extracted from these simulations, using standard quantum chemical methods. The calculated C(Q) values for these O triclusters are now in the range observed experimentally in the CaAl(2)Si(2)O(8) glass (around 2.3-2.6 MHz) when the tricluster O is surrounded by three Al, two of which are part of an Al(2)O(2) ring. This supports the experimentalists' contention that such tricluster O species do exist and have been seen by (17)O NMR.

Journal Article↗
PubMed2001

Electronic spectroscopy and excited state dynamics of the Al-H2/D2 complex.

The electronic spectra of the Al-H2 and Al-D2 complexes are investigated in a collaborative experimental and theoretical study. The complexes were prepared in a pulsed supersonic beam and detected with laser fluorescence excitation spectroscopy. Transitions to bound vibrational levels in electronic states correlating with the excited-state Al(3d, 4p, 4d) + H2/D2 asymptotes were observed by monitoring emission from lower excited Al atomic levels, formed in the non-radiative decay of the excited complex. Fluorescence depletion has also been used to verify that the observed Al-H2 bands all involve the same molecular carrier. The bands have been assigned to the more strongly bound Al-oH2 and Al-pD2 nuclear spin modifications. In contrast to our previous observations for Al(5s)-H2 [X. Yang and P. J. Dagdigian, J. Chem. Phys., 1998, 109, 8920], for which only one potential energy surface (PES) emanates from the dissociation asymptote, the Lorentzian widths of the different vibrational bands in the 3d, 4p, 4d<--3p transitions vary widely, in some cases allowing resolution of the rotational structure of the bands. With the help of the calculated Al(3p)-oH2/pD2 dissociation energies, binding energies of the observed excited vibronic levels are reported. The mechanism of predissociation is investigated theoretically through ab initio calculation of C2 nu cuts of the excited PESs. It is concluded that predissociation occurs through coupling with the repulsive Al(4s)-H2 PES. With these calculations, a qualitative interpretation of the observed bands could be made.

Journal Article↗
PubMed1999

Effects of AL 107, a novel semisynthetic cardiac glycoside, on the cardiovascular system in anaesthetized beagle dogs with pentobarbital-induced cardiac insufficiency.

The inotropic efficacy, arrhythmogenicity and cardiohaemodynamic properties of AL 107 (3-alpha-methyl-digitoxigenin glucoside, CAS 62190-59-4), a novel cardiac glycoside, were studied in anaesthetized dogs with pentobarbital-induced acute cardiac insufficiency. Three groups of dogs received AL 107, ouabain or verhicle. The cardiac glycosides were infused intravenously in eight increasing dose levels which where given cumulatively. Slope of left ventricular pressure rise (LVdp/dtmax) increased in the AL 107- and ouabain-treated groups. At the end of the 6th dose level ouabain caused a significantly higher LVdp/dtmax (137 +/- 15% of the baseline value taken before induction of insufficiency) than AL 107 (94 +/- 9%). Further increase of the dose resulted in a reduction of LVdp/dtmax in ouabain-treated dogs, whereas AL 107 continuously increased LVdp/dtmax up to the highest dose infused, where 130 +/- 16% of the baseline value was reached. In ouabain-treated dogs, ECG abnormalities accompanied the decrease of LVdp/dtmax whereas ECG-changes did not interfere with the development of left ventricular contractility in AL 107-treated dogs. The 6th dose of ouabain provoked a maximal increase of cardiac output (CO) (up to 107 +/- 8% of baseline values) and stroke volume (SV) (up to 122 +/- 6% of baseline values) which decreased upon further dose elevation. In the dose-range studied AL-107 induced a continuous increase of both parameters which, however, hardly reached the baseline values. ECG abnormalities occurred in both substance-treated groups and showed quantitative but not qualitative differences. The ECG showed rapid recovery after cessation of AL 107 infusion but did not normalize during a postinfusional recovery period of 1 h after treatment with ouabain. In conclusion, AL 107 increased cardiac performance in an acute canine model of cardiac insufficiency. It was slightly less active than ouabain. However, the ECG disorders were more moderate in AL 107--than in ouabain-treated dogs, a difference which was most pronounced with respect to reversibility in the postinfusional period.

Anesthesia↗
PubMed2000

Genetic factors in the early diagnosis of ALS.

The frequency of familial amyotrophic lateral sclerosis (ALS) is usually reported as 5-10% of all ALS cases. This figure is probably an underestimate, primarily due to inadequate recording of family history in the patients' charts, and to the not infrequent occurrence of reduced disease penetrance in pedigrees with familial ALS. The true familial ALS frequency may be at least double this. Familial ALS is heterogenetic. The only known ALS-causing gene is the CuZn-superoxide dismutase gene (CuZn-SOD). Mutations in this gene account for a fifth of all familial ALS cases and a few percent of apparent sporadic ALS cases. Genetic testing for CuZn-SOD mutations can help confirm a diagnosis of ALS, especially in cases with atypical features that have been reported in some cases with CuZn-SOD mutations. Genetic testing should only be performed after thorough clinical examination and in cases with a proven or uncertain family history of ALS. It is not warranted in cases with no proven family history for three generations, unless the patient shows the characteristic phenotype associated with recessive inheritance of the D90A CuZn-SOD mutation.

Gene Frequency↗
PubMed2001

Lasting impact in families after death from ALS.

INTRODUCTION: ALS severely affects families, who have to cope after the patient's death. There is no information on ongoing needs or concerns of families surviving the death of the ALS patient. We wished to survey these needs. METHOD: We developed a written questionnaire which we distributed at a single point in time to 32 patients' families. All patients had been followed in the McMaster University ALS clinic, and had died months to years earlier from ALS. RESULTS: The response rate was excellent (85%). ALS caused lasting emotional and financial hardship in families, and 37% of respondents felt they were coping poorly, sometimes years after the patient's death. This did not clearly relate to the bereavement period, nor to the physical or financial impact of the disease during life. In most cases the disease led to a strengthening of family ties. However, 15% of chief caregivers felt blamed by in-laws for contributing to the death of the patient; in these cases family ties weakened. Less than half of families were still receiving ALS information, although 75% still wished to. About two-thirds of families had ongoing questions about the disease, and a small number remained concerned that they, or their children, would develop the disease. Only a third of families were actively involved in ongoing fund-raising activities. CONCLUSIONS: It is possible to survey ongoing family needs after the death of the ALS patient. ALS causes lasting impact in surviving family members. There are ongoing needs that could be met by ALS clinics, ALS organizations, and healthcare systems, and opportunities for greater involvement of family members in volunteer activities, awareness, and fundraising. Generalization across other healthcare systems, and comparison with other disease states, could be important.

Aged↗
PubMed1982

Intestinal absorption and secretion of radioactive vanadium (48VO3-) in rats and effect of Al(OH)3.

Vanadium in the metavanadate form (VO3-) is a powerful inhibitor of Na+, K+-ATPase. Because of the similarity between the oxy anions of vanadium and phosphorus, it was of interest to see whether Al(OH)3 would restrict the intestinal absorption of vanadium, as it does that of phosphorus. VO3- was extensively bound to a suspension of Al(OH)3 at pH 5-8. Sprague-Dawley rats (180-300 g) were fasted overnight and gavaged with 5 mumol Na3 VO4 in 1.0 ml 0.9% NaCl containing 1 microCi 48V. Control animals (n = 12) simultaneously received 1.0 ml diluent and experimental animals (n = 12) received 1 ml Al(OH))3. Diluent and Al(OH)3 were then given daily for 4 d. Urine and feces were collected separately each day. In control animals total 48V recovery (stool and urine) over 4 d was 86.6 +/- 2.4% of the administered dose. Although Al(OH)3 insignificantly increased total 48V recovery (93.6 +/- 3.2%), it markedly increased excretion of 48V in the stool as compared to the urine (control: stool, 69.1 +/- 1.8%; urine, 12.5 +/- 1.3%; Al(OH)3: stool, 85.7 +/- 1.5%; urine, 7.9 +/- 1.8%). Animals were then sacrificed and tissue uptake of tracer measured. The pattern of unexcreted 48V in tissue of both groups was kidney greater than bone greater than liver greater than intestine greater than muscle, but the tissue levels were uniformly higher in controls than in Al(OH)3-treated animals. The ability of Al(OH)3 to remove endogenous VO3- was also examined. 48V was injected ip (n = 20). Half of the animals received diluent and half received 1.0 ml Al(OH)3 by gavage daily for 4 d. There were no differences in the pattern of 48V tissue distribution and excretion. It is concluded that Al(OH)3 may prevent tissue accumulation of VO3- from dietary sources by reducing intestinal VO3- absorption.

Aluminum Hydroxide↗
PubMed2003

A comparative study of metal levels in leaves of some Al-accumulating Rubiaceae.

Concentrations of Al, Si, Fe, Mn, Cu and Ca were analysed in leaves of ten Rubiaceae species, most of which are Al accumulators, and these were compared with concentrations in one species of Melastomataceae. Quantitative data confirmed the distribution of Al accumulation as previously determined by semi-quantitative tests, and suggest that there is an apparent congruency between the shoot Al concentration and the number of accumulators within a certain genus or tribe. Al accumulators within the Rubiaceae are most characteristic of the Rubioideae subfamily, although a second origin is likely in at least a few members of the tribes Vanguerieae and Alberteae. While the leaf Si concentration in Melastomata malabathricum L. (Melastomataceae) was negligible, all Rubiaceae studied showed relatively high Si levels (mostly >3000 mg kg(-1)). It is hypothesized that an Al-Si complex is formed in the shoot tissues of Al-accumulating Rubiaceae and that this may contribute to Al detoxification. However, the Si : Al mole ratio tended to differ widely among species. There was no significant correlation between Al and the other metals analysed. A remarkably high Mn concentration was found in Coptosapelta olaciformis Elm.

Aluminum↗
PubMed2005

Aluminium resistance requires resistance to acid stress: a case study with spinach that exudes oxalate rapidly when exposed to Al stress.

Spinach is a vegetable with a high oxalate concentration in its tissues. Oxalate efflux from spinach (Spinacia oleracea L. cv. Quanneng) roots was rapidly stimulated (within 30 min) by aluminium (Al) treatment. The efflux was constant within 6 h, but increased with increasing Al concentration. The efflux was confined to the root tip (0-5 mm), which showed a 5-fold greater efflux than the root zone distal to the tip (5-10 mm). Oxalate efflux could not be triggered by treatment with the trivalent cation lanthanum or by phosphorus deficiency, indicating that the efflux was specific to the Al treatment. All this evidence suggested that spinach possesses Al-resistance mechanisms. However, spinach was found to be as sensitive to Al toxicity as the Al-sensitive wheat line ES8, which had no Al-dependent organic acids efflux. The Al accumulated in the apical 5 mm of the roots of spinach which was also similar to that in the Al-sensitive wheat after 24 h treatment with 50 microM AlCl(3), indicating a non-exclusion mechanism. In addition, root elongation in spinach was significantly inhibited at pH 4.5, compared with that at pH 6.5. Based on this evidence, it is concluded that the sensitivity to acid stress in spinach could mask the potential role for oxalate to protect the plant roots from Al toxicity.

Aluminum Chloride↗
PubMed1989

Negative cooperativity of chicken ovotransferrin on Al(III)-binding.

Chicken ovotransferrin, an iron binding protein, has two metal binding sites (amino (N) and carboxy (C) terminal sites). It binds Cu(II), Al(III), Co(II), and other metals, as well as Fe(III). In this study, the selectivity and cooperativity of the N and C sites on Al(III), Co(II), and Tb(III) binding were investigated. Metals were classified into two groups according to their site preference. Co(II) and Al(III) bound to the N site more preferably than to the C site, whereas Tb(III) bound to the C site more preferably. On Fe(III) binding, the binding constant of Fe(III) becomes larger when the other site is already occupied. Thus, positive cooperativity is seen. In the present study, the binding cooperativities of Co(II), Tb(III), and Al(III) as to the N and C sites were investigated. On Co(II) and Tb(III) binding, no cooperativity was observed, as in the case of Cu(II) [Yamamura, T. et al. (1985) in Proteins of Iron Storage and Transport (Spik, G., Montreuil, J., Crichton, R.R., & Mazurier, J., eds.) pp. 53-56, Elsevier Science Publ. B.V., Amsterdam]. In contrast, negative cooperativity was observed on Al(III) binding. Based on a model proposed by Yamamura et al. [Yamamura, T. et al. (1985) ibid.], the ratio of the binding constants, KC/KN, and the stacking coefficient, Kst, were estimated. KC/KN is 2.2 +/- 0.4 for the Tb(III) ion, 0.5 +/- 0.1 for the Co(II) ion, and 0.12 +/- 0.02 for the Al(III) ion. Kst (= 1 in a non-cooperative case) is 0.98 +/- 0.02 for the Tb(III) ion, 1.03 +/- 0.02 for the Co(II) ion, and 0.55 +/- 0.22 for the Al(III) ion.

Aluminum↗
PubMed2000

Acid mist and soil Ca and Al alter the mineral nutrition and physiology of red spruce.

We examined the effects and potential interactions of acid mist and soil solution Ca and Al treatments on foliar cation concentrations, membrane-associated Ca (mCa), ion leaching, growth, carbon exchange, and cold tolerance of red spruce (Picea rubens Sarg.) saplings. Soil solution Ca additions increased foliar Ca and Zn concentrations, and increased rates of respiration early in the growing season (July). Soil Al treatment had a broad impact, reducing foliar concentrations of Ca, Mg, Mn, P and Zn, and resulting in smaller stem diameters, sapling heights and shoot lengths compared with soil treatments with no added Al. Aluminum treatment also reduced respiration when shoots were elongating in July and decreased net photosynthesis at the end of the growing season (September). Three lines of evidence suggest that Al-induced alterations in growth and physiology were independent of foliar Ca status: (1) Ca concentrations in foliage of Al-treated saplings were within the range of sufficiency established for red spruce; (2) mCa concentrations were unaffected by Al treatment; and (3) no Al x Ca interactions were detected. Acid mist treatment increased foliar Fe and K concentrations and increased leaching of Ca, Mg, Mn, Zn, Fe, and Al from foliage. Leaching losses of Ca were more than twice those of the element with the next highest amount of leaching (Zn), and probably led to the reductions in mCa concentration and membrane stability of acid-treated saplings. Acidic mist resulted in enhanced shoot growth, and consistent reductions in foliar cold tolerance in the fall and winter. Of the few significant interactions among treatments, most involved the influence of mist pH and Al treatment on foliar nutrition. In general, reductions in cation concentration associated with Al addition were greater for pH 5.0-treated saplings than for pH 3.0-treated saplings. We propose that H(+)-induced leaching of mCa from mesophyll cells is the mechanism underlying acid-induced reductions in foliar cold tolerance of red spruce.

Journal Article↗
PubMed2003

Growth and nutrient uptake of ectomycorrhizal Pinus sylvestris seedlings in a natural substrate treated with elevated Al concentrations.

Models of the effects of elevated concentrations of aluminum (Al) on growth and nutrient uptake of forest trees frequently ignore the effects of mycorrhizal fungi. In this study, we present novel data indicating that ectomycorrhizal mycelia may prevent leaching of base cations and Al. Mycorrhizal and non-mycorrhizal Pinus sylvestris L. seedlings were grown in sand obtained from the B-horizon of a local forest. In Experiment 1, non-mycorrhizal seedlings and seedlings inoculated with Hebeloma cf. longicaudum (Pers.: Fr.) Kumm. ss. Lange or Laccaria bicolor (Maire) Orton were provided with nutrient solution containing 2.5 mM Al. Aluminum did not affect growth of non-mycorrhizal seedlings or seedlings inoculated with L. bicolor. Seedlings colonized by H. cf. longicaudum had the highest biomass production of all seedlings grown without added Al, but the fungus did not tolerate Al. Shoots of seedlings colonized by L. bicolor had the lowest nitrogen (N) concentrations but the highest phosphorus (P) concentrations of all seedlings. The treatments had small but significant effects on shoot and root Al concentrations. In Experiment 2, inoculation with L. bicolor was factorially combined with the addition of a complete nutrient solution, or a solution lacking the base cations K, Ca and Mg, and solutions containing 0 or 0.74 mM Al. Seedling growth decreased in response to 0.74 mM Al, but the effect was significant only for non-mycorrhizal seedlings. Mycorrhizal seedlings generally had higher P concentrations than non-mycorrhizal seedlings. Aluminum reduced P uptake in non-mycorrhizal plants but had no effect on P uptake in mycorrhizal plants. Mycorrhizal colonization increased the pH of the soil solution by about 0.5 units and addition of Al decreased the pH by the same amount. We conclude that the presence of ectomycorrhizal mycelia decreased leaching of base cations and Al from the soil.

Agaricales↗
PubMed1998

Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS.

Molecular pathology has identified 2 distinct forms of neuronal inclusion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions are skeins or small dense filamentous aggregates which can only be demonstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline conglomerates (HC) are large multifocal accumulations of neurofilaments. Previous reports have failed to clarify the distinction and relationship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and determine the relevance of molecular events in familial cases to the pathogenesis of sporadic disease. We describe the molecular pathology of 5 ALS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were excluded. Hyaline conglomerate inclusions were detected only in the 2 cases with the SOD1 I113T mutation and showed a widespread multisystem distribution. In contrast ALS-type inclusions characterized sporadic cases (70/73) and were restricted to lower motor neurons. Hyaline conglomerates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that HC contain equally abundant phosphorylated and nonphosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immunoreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal column myelin loss. In 4 cases the motor cortex was normal or only minimally affected. This further illustrates the extent to which upper motor neuron damage in ALS is usually a distal axonopathy. Previously reported pathological accounts of SOD1-related familial ALS (FALS) are reviewed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings suggest the possibility that the molecular pathology of neuronal inclusions in ALS indicates 2 distinct pathogenetic cascades.

Aged↗
PubMed1996

The Early Entry of Al into Cells of Intact Soybean Roots (A Comparison of Three Developmental Root Regions Using Secondary Ion Mass Spectrometry Imaging).

Al localization was compared in three developmental regions of primary root of an Al-sensitive soybean (Glycine max) genotype using secondary ion mass spectrometry. In cryosections obtained after a 4-h exposure to 38 [mu]M [Al3+], Al had penetrated across the root and into the stele in all three regions. Although the greatest localized Al concentration was consistently at the root periphery, the majority of the Al in each region had accumulated in cortical cells. It was apparent that the secondary ion mass spectrometry 27Al+ mass signal was spread throughout the intracellular area and was not particularly intense in the cell wall. Inclusion of some cell wall in determinations of the Al levels across the root radius necessitated that these serve as minimal estimates for intracellular Al. Total accumulation of intracellular Al for each region was 60, 73, and 210 nmol g-1 fresh weight after 4 h, increasing with root development. Early metabolic responses to external Al, including those that have been reported deep inside the root and in mature regions, might result directly from intracellular Al. These responses might include ion transport events at the endodermis of mature roots or events associated with lateral root emergence, as well as events within the root tip.

Journal Article↗
PubMed2006

TEM and HREM study of Al3Zr precipitates in an Al-Mg-Si-Zr alloy.

The structure of Al(3)Zr precipitates in Al-1.0Mg-0.6Si-0.5Zr (in wt.%) alloy was investigated using conventional transmission electron microscopy (TEM) and high-resolution TEM (HREM). After annealing of the alloy in the temperature range 450-540 degrees C, spherical precipitates of metastable L1(2)-Al(3)Zr phase appeared nearly homogeneously within the matrix, and elongated particles were found at grain boundaries. L1(2)-structured Al(3)Zr were about 20-30 nm in diameter and coherent with the matrix. Inside some of them, planar faults parallel to {100} planes were revealed by use of HREM. Most probably, these faults are an indication of the transition stage of transformation to the stable D0(23)-type Al(3)Zr phase. The elongated precipitates (about 100 nm) were identified as D0(22)-type Al(3)Zr. Energy-dispersive X-ray analysis showed that they contain, apart from Al, mainly Zr with small amounts of Si. The substitution of Al by Si increased the stability of the D0(22)-Al(3)Zr as compared with D0(23)-Al(3)Zr.

Journal Article↗
PubMed1997

AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton.

Previous experiments identified AL-1 as a glycosylphosphatidylinositol (GPI)-linked ligand for the Eph-related receptor, REK7, and showed that a REK7-IgG fusion protein blocks axon bundling in co-cultures of cortical neurons on astrocytes, suggesting a role for REK7 and AL-1 in axon fasciculation. Subsequent identification of RAGS, the chick homologue of AL-1, as a repellent axon guidance molecule in the developing chick visual system led to speculation that AL-1, expressed on astrocytes, provides a repellent stimulus for cortical axons, inducing them to bundle as an avoidance mechanism. Using a growth cone collapse assay to test this hypothesis, we show that a soluble AL-1-IgG fusion protein is a potent collapsing factor for embryonic rat cortical neurons. The response is strongly correlated with REK7 expression, implicating REK7 as a receptor mediating AL-1-induced collapse. Morphological collapse is preceded by an AL-1-IgG-induced reorganization of the actin cytoskeleton that resembles the effects of cytochalasin D. This suggests a pathway whereby REK7 activation by AL-1 leads to perturbation of the actin cytoskeleton, possibly by an effect on actin polymerization, followed by growth cone collapse. We further show that AL-1-IgG causes collapse of rat hippocampal neurons and rat retinal ganglion cells. These data suggest a role for REK7 and AL-1 in the patterning of axonal connections in the developing cortex, hippocampus and visual system.

Actins↗
PubMed2006

Identification of potential CSF biomarkers in ALS.

BACKGROUND: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis. OBJECTIVE: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects. METHODS: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry-directed peptide sequencing. RESULTS: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF. CONCLUSION: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.

Adult↗
PubMed2006

Elevated serum angiogenin levels in ALS.

BACKGROUND: The role of hypoxia responsive genes in the pathogenesis of ALS was first suggested when deletions of the hypoxia-responsive element of vascular endothelial growth factor (VEGF) promoter caused a motor neuron disease phenotype in mice. The discovery of ALS-associated mutations in ANG, a hypoxia responsive gene coding for the protein angiogenin, has further supported this pathogenic mechanism in human ALS. In endothelium, angiogenin can regulate expression of VEGF. To date, the patterns of serum angiogenin expression among patients with ALS have not been assessed. METHODS: Serum angiogenin and VEGF levels were quantified at diagnosis in 79 patients with definite or probable ALS and 72 healthy controls, using a quantitative sandwich enzyme-linked immunoassay. RESULTS: Patients with ALS exhibited higher serum angiogenin (p = 0.006) but not VEGF (p = 0.55) levels than matched control subjects. Subgroup analysis showed a greater elevation in angiogenin levels for spinal- (p < 0.001) than bulbar- (p = 0.11) onset ALS vs controls. At 12 months, angiogenin levels remained elevated. No correlation was noted between angiogenin and VEGF levels (r = -0.08, p = 0.49) in ALS patient serum. CONCLUSION: These data suggest a modest elevation in serum angiogenin in ALS at diagnosis. Further investigation will be required to assess the utility of serum angiogenin as a biomarker for ALS and as a predictor of disease progression.

Amyotrophic Lateral Sclerosis↗
PubMed1999

1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla.

OBJECTIVE: To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease. BACKGROUND: 1H-MRSI can detect N-acetylaspartate + N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology. METHODS: Ten patients with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine-phosphocreatine and compared between groups. RESULTS: Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = -0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53). CONCLUSION: There is in vivo 1H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.

Adult↗