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Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis
Abstract and Figures
Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H(+) concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.
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... Increased glycogen has been reported in the spinal cords of ALS patients and SOD1 G93A mice (Dodge et al., 2013;Li et al., 2019). In fixed spinal sections from ALS patients, periodic acid-Schiff (PAS) staining showed glycogen in motor neurons and glia of the gray matter as well as white matter glia (Dodge et al., 2013). ...
... Increased glycogen has been reported in the spinal cords of ALS patients and SOD1 G93A mice (Dodge et al., 2013;Li et al., 2019). In fixed spinal sections from ALS patients, periodic acid-Schiff (PAS) staining showed glycogen in motor neurons and glia of the gray matter as well as white matter glia (Dodge et al., 2013). In the same report, increased glycogen levels in the spinal cord and brainstem were observed in the end stage but not in symptomatic SOD1 G93A mice. ...
... Therefore, glial cells and metabolic pathways are being actively investigated as therapeutic modulators of the disease (Cassina et al., 2021). In the current study, using both biochemical quantification and immunostaining with a glycogen antibody that is more specific than PAS staining used by previous groups (Dodge et al., 2013;Li et al., 2019), we reported elevated glycogen throughout the brainstem and spinal cord at all stages of ALS progression in the SOD1 G93A model. This glycogen is associated with reactive astrocytes. ...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1G93A mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1G93A mice with reduced glycogen synthesis (SOD1G93A GShet mice). SOD1G93A GShet mice had a significantly longer life span than SOD1G93A mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1G93A mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.
... The loss of Sod1 was associated with abnormal lipid metabolism [16,17], and SOD1 human polymorphisms were also linked to incidences of diabetes and obesity [51][52][53][54]. Besides, Sod1-G93A mutant mice exhibited hypolipidemia with lowered LDL/HDL ratio and promoted lipolysis with pathological acidosis [55,56], while the Sod1-G93A ALS mutant mice exhibited reduced insulin-stimulated glucose uptake in skeletal muscle [57]. Similarly, knockout of YWHAZ also led to increased lipolysis with decreased visceral adipose accumulation [25]. ...
... Similarly, knockout of YWHAZ also led to increased lipolysis with decreased visceral adipose accumulation [25]. Our discoveries of PPIs' (SOD1 and YWHAE or YWHAZ) impact on lipid metabolism could provide new clues to those unsettled issues or unexplained phenotypes [25][26][27][55][56][57]. Because 14-3-3 proteins have recently been linked to ALS [58][59][60], our finding on altered cellular lipid metabolism by disrupted PPIs between SOD1 and YWHAE or YWHAZ may reveal a latent factor for the onset and development of ALS. ...
Copper–zinc superoxide dismutase 1 (SOD1) has long been recognized as a major redox enzyme in scavenging superoxide radicals. However, there is little information on its non-canonical role and metabolic implications. Using a protein complementation assay (PCA) and pull-down assay, we revealed novel protein–protein interactions (PPIs) between SOD1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) or epsilon (YWHAE) in this research. Through site-directed mutagenesis of SOD1, we studied the binding conditions of the two PPIs. Forming the SOD1 and YWHAE or YWHAZ protein complex enhanced enzyme activity of purified SOD1 in vitro by 40% (p < 0.05) and protein stability of over-expressed intracellular YWHAE (18%, p < 0.01) and YWHAZ (14%, p < 0.05). Functionally, these PPIs were associated with lipolysis, cell growth, and cell survival in HEK293T or HepG2 cells. In conclusion, our findings reveal two new PPIs between SOD1 and YWHAE or YWHAZ and their structural dependences, responses to redox status, mutual impacts on the enzyme function and protein degradation, and metabolic implications. Overall, our finding revealed a new unorthodox role of SOD1 and will provide novel perspectives and insights for diagnosing and treating diseases related to the protein.
... Notably, defects in glucose metabolism are a common and early event across all forms of ALS (Pradat et al., 2010). Specifically, reductions in glucose uptake and in the expression of glucose transporters have been described numerous times in ALS patients and in brain and spinal cord (SPC) from animal models analyzed at both pre-and post-symptomatic stages (Tefera et al., 2021); increased glycogen deposits in postmortem spinal cord ALS sections (Dodge et al., 2013); reduction in insulin sensitivity (Reyes et al., 1984); and increased circulation of fatty acids in the serum of ALS patients (Pradat et al., 2010), although the source of these defects is unclear. ...
... Moreover, the decreased use of pyruvate as a mitochondrial fuel source, and the reductions in LDH activity [lactate®pyruvate], could explain the high levels of lactate (and glucose) in the blood of ALS patients(Pradat et al., 2010;Siciliano et al., 2001). Furthermore, under conditions of low glucose utilization, excess glucose can be channeled through alternative, non-ATP-producing pathways, such as the formation of advanced glycation end products, synthesis of hexosamine, and astrocytic storage of glycogen, all of which are upregulated in ALS(Dodge et al., 2013;Juranek et al., 2015; Moll et al., 2020). Finally, a shift towards the use of FAs could also underlie the high levels of free FAs and triglyceride-rich lipoproteins found in blood and tissue samples from ALS patients(Area-Gomez et al., 2021;Dorst et al., 2011; Mariosa et al., 2017), and the observation that high-fat diets slow the progression of the disease(Mattson et al., 2007; Zhao et al., 2012). ...
Mitochondria-associated ER membranes (MAM) are transient functional domains in the endoplasmic reticulum (ER) in close apposition to mitochondria involved in multiple metabolic functions, including the regulation of mitochondria functionality. Specifically, MAM interactions with mitochondria contribute to the regulation of mitochondrial dynamics, calcium transference between both organelles and the composition of mitochondrial membranes. In addition, recent data indicate that alterations in MAM-mitochondria contacts are associated with impairments in glucose metabolism and insulin resistance phenotypes, but the mechanism behind these defects is unknown. Human embryonic stem cell (ESC)-derived motor neurons (hMNs) and mouse models with pathogenic mutations in superoxide dismutase 1 (SOD1) have been shown to present with a progressive disruption of MAM structure and function, as it occurs in other models of amyotrophic lateral sclerosis (ALS). In this work, we have found that impairments in the activation of MAM in the context of SOD1 mutations, hinder the use of glucose-derived pyruvate as a mitochondrial fuel and trigger a shift in mitochondrial substrates from pyruvate to fatty acids. We also show that, over time, this change in mitochondrial fuels induces significant alterations in mitochondrial electron flow and in the active/de-active (A/D) status of complex I in mutant hMNs and spinal cord tissues, but not in brain. Our data agree with a role for MAM in the maintenance and regulation of cellular glucose metabolism and the selection of mitochondrial substrates and suggest that MAM disruption in ALS could be the underlying cause of the bioenergetic deficits observed in the disease.
... Reduced glucose metabolism is observed in the motor-sensory cortex of ALS patients and the frontal lobes, striatum, and thalamus of FTD patients, including in asymptomatic carriers of the ALS/FTD-linked C9orf72 mutation [32][33][34] . Glycogen, the storage form of glucose, is elevated in ALS mice and patients' spinal cord tissues 35,36 . Moreover, mitochondrial dysfunction is a pathological hallmark of ALS/FTD and is mechanistically associated with several genetic forms of the disease, including those linked to SOD1, TDP-43, FUS, CHCHD10, and C9orf72 [37][38][39][40][41][42] . ...
... Brain glycolysis is usually reduced during normal aging or in NDDs 31,82 . Moreover, abnormal glycogen deposits in the human brain are observed with aging and in multiple NDDs, including ALS, Alzheimer's disease, Parkinson's disease, and Lafora disease 35,79,[83][84][85] . Recent studies have indicated that upregulated glycolysis, achieved by either a high-glucose diet or genetic or pharmacological activation of glycolytic enzymes, might mitigate the disease phenotype in animal models or patients with NDDs, including ALS, Parkinson's disease, and Huntington's disease [86][87][88] . ...
Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy deficiency regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules induced by energy deficiency under physiological conditions and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy deficiency induced the rapid formation of energy deficiency-induced stress granules (eSGs) independently of eIF2α phosphorylation, whereas moderate energy deficiency delayed the clearance of conventional SGs. The formation of eSGs or the clearance of SGs was regulated by the mTOR-4EBP1-eIF4E pathway or eIF4A1, involving assembly of the eIF4F complex or RNA condensation, respectively. In neurons or brain organoids derived from patients carrying the C9orf72 repeat expansion associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the eSG formation was enhanced, and the clearance of conventional SGs was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that disruptions in energy-controlled granule dynamics may contribute to the pathogenesis of relevant diseases.
... Transcription and splicing of nuclear-encoded mitochondrial protein genes similar changes in substrate uptake and use 65,129,130,161,162 and changes in mitochondrial function 151,161,[163][164][165][166] are becoming well understood. Regarding the clinical relevance of these findings, the breadth of mitochondrial alterations that are proposed to lead to bioenergetic failure in preclinical models have also been consistently observed in the brain, spinal cord and skeletal muscle of people living with ALS 163,[167][168][169][170][171][172][173][174][175][176][177][178][179][180] . ...
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.
... We found in the truncated TDP43 cases, defects in the metabolism of the glucoside salicin, likely caused by loss of alphaglucosidase (GAA) expression. Reduction in GAA activity has been observed in the spinal cord of the SOD1 mouse model (Dodge et al., 2013). These data indicate a common mechanism of dysfunction between genetic sub-groups of the disease. ...
A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.
... It has therefore been proposed that bioenergetic failure is one of the critical factors behind MN degeneration [8][9][10][11][12]. In support of this hypothesis, abnormal morphologies of mitochondria and disrupted function have been reported from postmortem samples of ALS patients and are an early marker in several rodent ALS models [6,11,[13][14][15][16] and iPSC-derived motoneurons [10,[17][18][19][20]. Changes in global metabolism and the ability to catabolize glucose by MN correlate with the severity of ALS progression [21,22]. ALS-causing mutations in FUS were recently reported to disrupt several energy-demanding processes in iPSC-derived MNs, such as neuronal firing rates and axonal transport [20,23,24]. ...
Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms.
... It has been therefore proposed that bioenergetic failure is one of the critical factors behind MN degeneration [8][9][10][11][12]. In support of this hypothesis, abnormal morphologies of mitochondria and disrupted function have been reported from postmortem samples of ALS patients and are an early marker in a number of rodent ALS models [6,11,[13][14][15][16] and in iPSC-derived motoneurons [10,[17][18][19][20]. Changes in global metabolism and ability to catabolize glucose by MN correlate with the severity of ALS progression [21,22]. ALS-causing mutations in FUS were recently reported to disrupt several energy demanding processes in iPSC-derived MNs such as neuronal firing rates and axonal transport [20,23,24]. ...
Motoneurons are one of the highest energy demanding cell types and a primary target in Amyo-trophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without current-ly available effective treatments. Disruption of mitochondrial ultra-structure, transport and metabo-lism is a commonly reported phenotype in ALS models and can critically affect survival and proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression are not fully understood yet. Here we utilize hiPCS derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in Fused in Sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons is accompanied by an overall upregulation of mitochondrial components and significant increase in metabolic rates that corresponds to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of disease motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mi-tochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts metabolic states of motoneurons and makes them more susceptible to further neurodegener-ative mechanisms.
... Human and mouse studies have shown alterations in carbohydrate, amino acid, and lipid metabolism within the serum and cerebral spinal fluid [13][14][15]. It is reported that altered metabolites in the ALS-like SOD1 G93A model are associated with a progressive state of acidosis [16]. Thus, understanding the metabolomics and intestinal changes will be important for the neuron pathogenesis in ALS. ...
Microbial metabolites affect the neuron system and muscle cell functions. Amyotrophic lateral sclerosis (ALS) is a multifactorial neuromuscular disease. Our previous study has demonstrated elevated intestinal inflammation and dysfunction of the microbiome in patients with ALS and an ALS mouse model (human-SOD1G93A transgenic mice). However, the metabolites in ALS progression are unknown. Using an unbiased global metabolomic measurement and targeted measurement, we investigated the longitudinal changes of fecal metabolites in SOD1G93A mice over the course of 13 weeks. We further compared the changes of metabolites and inflammatory response in age-matched wild-type (WT) and SOD1G93A mice treated with the bacterial product butyrate. We found changes in carbohydrate levels, amino acid metabolism, and the formation of gamma-glutamyl amino acids. Shifts in several microbially contributed catabolites of aromatic amino acids agree with butyrate-induced changes in the composition of the gut microbiome. Declines in gamma-glutamyl amino acids in feces may stem from differential expression of gamma-glutamyltransferase (GGT) in response to butyrate administration. Due to the signaling nature of amino acid-derived metabolites, these changes indicate changes in inflammation, e.g., histamine, and contribute to differences in systemic levels of neurotransmitters, e.g., γ-Aminobutyric acid (GABA) and glutamate. Butyrate treatment was able to restore some of the healthy metabolites in ALS mice. Moreover, microglia in the spinal cord were measured by IBA1 staining. Butyrate treatment significantly suppressed the IBA1 level in the SOD1G93A mice. Serum IL-17 and LPS were significantly reduced in the butyrate-treated SOD1G93A mice. We have demonstrated an inter-organ communications link among microbial metabolites, neuroactive metabolites from the gut, and inflammation in ALS progression. The study supports the potential to use metabolites as ALS hallmarks and for treatment.
Neurotransmission is shaped by extracellular pH. Alkalization enhances pH sensitive transmitter release and receptor activation, whereas acidification inhibits these processes and can activate acid-sensitive conductances in the synaptic cleft. Previous work has shown that the synaptic cleft can either acidify due to synaptic vesicular release, and/or alkalize due to Ca ²⁺ extrusion by the plasma membrane ATPase (PMCA). The direction of change differs across synapse types. At the mammalian neuromuscular junction (NMJ), the direction and magnitude of pH transients in the synaptic cleft during transmission remain ambiguous. We set out to elucidate the extracellular pH transients that occur at this cholinergic synapse under near physiological conditions and identify their sources. We monitored pH-dependent changes in the synaptic cleft of the mouse levator auris longus (LAL) using viral expression of the pseudo-ratiometric probe pHusion-Ex in the muscle. Using mice from both sexes, a significant and prolonged alkalization occurred when stimulating the connected nerve for 5s at 50Hz, which was dependent on postsynaptic intracellular Ca ²⁺ release. Sustained stimulation for a longer duration (20s at 50 Hz) caused additional prolonged net acidification at the cleft. To investigate the mechanism underlying cleft alkalization, we used muscle-expressed GCaMP3 to monitor the contribution of postsynaptic Ca ²⁺ . Activity-induced liberation of intracellular Ca ²⁺ in muscle positively correlated with alkalization of the synaptic cleft, whereas inhibiting PMCA significantly decreased the extent of cleft alkalization. Thus, cholinergic synapses of the mouse NMJ typically alkalize due to cytosolic Ca ²⁺ liberated in muscle during activity, unless under highly strenuous conditions where acidification predominates.
SIGNIFICANCE STATEMENT:
Changes in synaptic cleft pH alter neurotransmission, acting on receptors and channels on both sides of the synapse. Synaptic acidification has been associated with a myriad of diseases in the central and peripheral nervous system. Here, Durbin et al. report that in near-physiological recording conditions the cholinergic neuromuscular junction shows use-dependent bidirectional changes in synaptic cleft pH: immediate alkalinization, and a long-lasting acidification under prolonged stimulation. These results provide further insight into physiologically relevant changes at cholinergic synapses that have not been defined previously. Understanding and identifying synaptic pH transients during and after neuronal activity provides insight into short-term synaptic plasticity synapses and may identify therapeutic targets for diseases.
Os autores analisam, por técnica cromatográfica, as concentrações de glicose no cérebro de camundongos inoculados com L.CR de 4 pacientes com ELA. Foi encontrada redução na, concentração do carboidrato no material estudado, sugerindo a presença de fator extrínseco veiculado pelo LCR.
Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by the unremitting degeneration of motor neurons. Multiple processes involving motor neurons and other cell types have been implicated in its pathogenesis. Neural stem cells (NSCs) perform multiple actions within the nervous system to fulfill their functions of organogenesis and homeostasis. We test the hypothesis that transplanted, undifferentiated multipotent migratory NSCs may help to ameliorate an array of pathological mechanisms in the SOD1(G93A) transgenic mouse model of ALS. On the basis of a meta-analysis of 11 independent studies performed by a consortium of ALS investigators, we propose that transplanted NSCs (both mouse and human) can slow both the onset and the progression of clinical signs and prolong survival in ALS mice, particularly if regions sustaining vital functions such as respiration are rendered chimeric. The beneficial effects of transplanted NSCs seem to be mediated by a number of actions including their ability to produce trophic factors, preserve neuromuscular function, and reduce astrogliosis and inflammation. We conclude that the widespread, pleiotropic, modulatory actions exerted by transplanted NSCs may represent an accessible therapeutic application of stem cells for treating ALS and other untreatable degenerative diseases.
The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow-metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS.
The purpose of this study was to determine which pulmonary function variables best predicted the potential for prolonging survival of individuals with amyotrophic lateral sclerosis (ALS) by the use of physical medicine respiratory muscle aid alternatives to tracheostomy for ventilatory support and airway suctioning. The records of 27 such ALS ventilator users with less than 15 minutes of ventilator-free breathing time for a mean +/- standard deviation of 23.7 +/- 20.3 months (range, 1 to 65) were reviewed. All patients underwent measurements of vital capacity (VC), maximum insufflation capacity (MIC), MIC VC difference, forced expiratory volumes, and peak cough expiratory flows (PCEF) every 1 to 6 months, depending on rate of disease progression, until requiring 24-hour ventilatory support. The ability to generate assisted PCEF in excess of 3L/sec and the ability to hold an insufflation deeper than the VC were associated with the capacity to prolong survival by methods other than tracheostomy, whereas the extent of decrease in VC and autonomous breathing ability were not. Because the PCEF and MIC VC difference correlate with bulbar muscle function, it can be concluded that the ability to use 24-hour ventilatory support by noninvasive means is a function of residual bulbar muscle strength and is independent of VC or the extent of need for ventilatory support. Properly equipped and trained, some ALS patients can use noninvasive respiratory muscle aids to delay or eliminate the need for tracheostomy.
Objective: This study determines whether acid-base data obtained in the emergency department correlate with outcome from major vascular injury. Design: Observational, retrospective record review of trauma patients requiring vascular repair (torso or extremity, January 1988 to December 1997). Data included age, Injury Severity Score, injury mechanism, survival, laboratory profiling, calculated anion gap, strong ion difference, and strong ion gap. Patients were divided into survivors and nonsurvivors with comparison by Student's t-test; significance was assumed for p less than or equal to .05. Multivariate logistic regression was used for further analysis of univariate predictors of mortality, and receiver operator characteristic curves were generated for mortality from each variable. Setting: Urban level I trauma facility. Patients: Trauma patients requiring vascular repair of torso or extremity injury. Interventions: None. Measurements and Main Results: Both nonsurvivors (n = 64) and survivors (n = 218) were similar with respect to age (31 +/- 9 vs. 31.5 +/- 10.5, p = 0.15) and injury mechanics (81% penetrating in survivors vs. 83% penetrating in nonsurvivors, p = .71). Nonsurvivor Injury Severity Score exceeded that of survivors (27.5 +/- 7.8 vs. 12.4 +/- 9.4, p < .001). Nonsurvivor pH (7.06 +/- 0.15 vs. 7.34 +/- 0.08, p < .001) and apparent strong ion difference (31.38 +/- 4.39 vs. 37.53 +/- 3.86, p < .001) were significantly lower, whereas nonsurvivor standard base excess (-17.9 +/- 5.1 vs. -2.9 +/- 4.4 mEq/L, p < .001), lactate (11.1 +/- 3.6 vs. 3.6 +/- 1.5 mmol/L, p < .001), anion gap (28.2 +/- 4.1 vs. 15.6 +/- 3.1, p < .001), and strong ion gap (10.8 +/- 3.2 vs. 2.4 +/- 1.8, p < .001) were higher. All but one nonsurvivor had initial emergency department pH less than or equal to7.26, standard base excess less than or equal to -7.3 mEq/L, lactate less than or equal to5 mmol/L, and strong ion gap less than or equal to5 mEq/L. All of the acid-base descriptors were strongly associated with outcome, but the strong ion gap discriminated most strongly with an area under the receiver operator characteristic of 0.991 (95% confidence interval, 0.972-0.998). Conclusions: The initial emergency department acid-base variables of pH, base deficit, lactate, anion gap, apparent strong ion difference, and strong ion gap discriminate survivors from nonsurvivors of major vascular injury. The strong ion gap is most strongly predictive of mortality following major vascular trauma.
Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca2+ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1G93A ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.
More than 20 years ago Stewart proposed a method for acid–base analysis moving from a new definition of neutrality, acidity and alkalinity. 10 years later Figge defined more precisely the quantitative role of plasmatic nonbicarbonate buffers. Scientific literature studying this physicochemical approach to acid–base balance found controversial results. The aim of this article is to review the basic principles of the approach to acid–base developed by Stewart and Figge. The definitions of apparent and effective strong ion difference (SID) and of strong ion gap (SIG) will be also reviewed considering the findings of the scientific literature regarding these two main parameters related to this approach. Several clinical conditions of acid–base imbalances will be reviewed using the physicochemical approach described by Stewart. He identified the independent variables determining pH; they include SID, carbon dioxide partial pressure and the serum concentration of weak acids. SIG reflects the contribution of unidentified anions to SID. The physicochemical approach to acid–base developed by Stewart and Figge provides more details about complex acid–base abnormalities than does the classic approaches developed by Henderson–Hasselbach and Siggaard–Andersen. However the prognostic role of SID and SIG is still not well established. Moreover, the Stewart and Figge approach requires complicated calculations at the bedside and a simpler adjustment of the anion gap for albumin concentration may result in the same clinical conclusions as the physicochemical approach. Even if the pure Stewart approach to acid–base is difficult to apply in daily clinical practice and its simplifications seem more practical, it is noteworthy that Stewart improved significantly the approach to acid–base abnormalities by providing a better understanding of many acid–base imbalances.
The diuretic amiloride has recently proven neuroprotective in models of cerebral ischemia, a property attributable to the drug's inhibition of central acid-sensing ion channels (ASICs). Given that Parkinson's disease (PD), like ischemia, is associated with cerebral lactic acidosis, we tested amiloride in the MPTP-treated mouse, a model of PD also manifesting lactic acidosis. Amiloride was found to protect substantia nigra (SNc) neurons from MPTP-induced degeneration, as determined by attenuated reductions in striatal tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry, as well as smaller declines in striatal DAT radioligand binding and dopamine levels. More significantly, amiloride also preserved dopaminergic cell bodies in the SNc. Administration of psalmotoxin venom (PcTX), an ASIC1a blocker, resulted in a much more modest effect, attenuating only the deficits in striatal DAT binding and dopamine. These findings represent the first experimental evidence of a potential role for ASICs in the pathogenesis of Parkinson's disease.