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Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis
Abstract
Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.
To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes.
In a cross-sectional study, we compared Hcy, B(12), and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center.
Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] micromol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels >or= 11.6 micromol/L] with the bottom tertile [Hcy levels < 9.2 micromol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] micromol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r(2) = 0.18; p = 0.01).
Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.
... Other po phisms of genes encoding the paraoxonases (PON 1, 2, 3) that convert HCY to homo acid have also been reported [29]. In comparison with controls, ALS patients pres creased folate levels in plasma [30] and increased levels of HCY in cerebrospina plasma and serum [26,[30][31][32] (Figure 2). Importantly, HCY levels in ALS seem po correlated with the rate of disease progression [30]. ...
... Other po phisms of genes encoding the paraoxonases (PON 1, 2, 3) that convert HCY to homo acid have also been reported [29]. In comparison with controls, ALS patients pres creased folate levels in plasma [30] and increased levels of HCY in cerebrospina plasma and serum [26,[30][31][32] (Figure 2). Importantly, HCY levels in ALS seem po correlated with the rate of disease progression [30]. ...
... In comparison with controls, ALS patients pres creased folate levels in plasma [30] and increased levels of HCY in cerebrospina plasma and serum [26,[30][31][32] (Figure 2). Importantly, HCY levels in ALS seem po correlated with the rate of disease progression [30]. Like in patients, decreased le folic acid were reported in the plasma, cerebral cortex, and spinal cord of middlestage SOD1 G93A mouse model of ALS, along with reduced levels of 5-MTHF at earli points [33]. ...
The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual’s lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.
... Association of FA, D-serine and HCSA with ALS, their production by gut microbial species and mechanism of transport from gut to brain. Transporter not yet identified [54][55][56][57][58][59] FA is a small molecule that is an environmental pollutant and is also generated during metabolism, through the one-carbon cycle [60]. FA can induce neurotoxicity by its ability to form cross-linking with DNA, proteins and lipid molecules [43]. ...
... Hyperhomocysteinemia is classified as either moderate (15-30 µmol/L), intermediate (30-100 µmol/L) or severe (>100 µmol/L) [102]. Several studies have reported high blood plasma Hcy levels in patients with ALS, with levels ranging from 11 to 46 µmol/L [54,55]. MS-targeted metabolomics have also identified significantly higher levels of Hcy in the plasma of pa-tients with ALS compared to healthy controls [56,57]. ...
... As already mentioned, ALS patients have higher Hcy levels compared to age-and sex-matched controls [55]. Higher levels of Hcy were also shown to be correlated with ALS disease progression [99]. ...
Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.
... Is likely to reduce the risk of ALS [12,13,[19][20][21][22][23][24][25] Vitamin B7 (biotin) ...
... Is likely to reduce the risk of ALS [10,12,23,24,[33][34][35][36][37][38][39][40] Vitamin B12 (cyanocobalamin) Participation in the regulation of the folate cycle (regulation of homocysteine levels); cofactor of vitamin B9 (folic acid); participation in the regulation of amino acids and fatty acids (pro-pionic acid); participation in the regulation of growth and differentiation of neurons (active influence on cell division); participation in the regulation of the formation of the myelin sheath; influence on cognitive and emotional-volitional functions; participation in the regulation of the balance function; participation in the conversion of folic acid derivatives necessary for the synthesis of DNA and RNA nucleotides; participation in the regeneration of methionine; participation in the metabolism of polyunsaturated fatty acids with an odd number of carbon atoms; influence on the exchange of amino acids with a branched side chain (methionine, isoleucine, trionine, and valine); participation in the synthesis of adrenaline, acetylcholine; influence on the level of cholesterol in the blood; regulation of CNS excitability; participation in the formation of erythrocytes; slowing down the aging process and protection against oncopathology. ...
... The authors concluded that a vitamin B6 deficiency may play a significant role in the etiology of ALS. Additionally, this article considers elevated plasma homocysteine levels in ALS patients [24] as a risk factor for ALS. In turn, vitamin B6 converts homocysteine into sulfuric amino acids [25], which may play a protective role in this neurodegenerative disease ( Figure 4). ...
Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression.
Methods:
We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010-2020.
Discussion:
We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development.
Conclusion:
The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.
... Estudos indicam aumento da HCT em pacientes com esclerose lateral amiotrófica (ELA). 22,23 Esse aumento pode se correlacionar com a progressão da doença, sendo independente dos níveis de folato ou vitamina B 12 . 23 A HCT é capaz de causar a morte do neurônio motor por excitotoxicidade glutamatérgica com influxo de cálcio. ...
... 22,23 Esse aumento pode se correlacionar com a progressão da doença, sendo independente dos níveis de folato ou vitamina B 12 . 23 A HCT é capaz de causar a morte do neurônio motor por excitotoxicidade glutamatérgica com influxo de cálcio. 24 Ademais, neurônios motores com mutação da SOD (superóxido dismutase), responsável pela forma mais comum de ELA familiar, parecem ser mais suscetíveis ao dano causado por altos níveis de HCT. ...
... 24 Ademais, neurônios motores com mutação da SOD (superóxido dismutase), responsável pela forma mais comum de ELA familiar, parecem ser mais suscetíveis ao dano causado por altos níveis de HCT. 23 ...
RESUMO Objetivo: Realizar uma revisão sobre o metabolismo do aminoá-cido sulfurado homocisteína, analisando como elevações de seus níveis séricos se correlacionam com a fisiopatologia das mais diver-sas doenças neurológicas, assim como sobre o tratamento da hiper-homocisteinemia. Método: Revisão não sistemática de artigos que abordassem o papel da homocisteína associado a doenças neuro-lógicas. Foi priorizada a utilização de artigos que apresentassem no título as palavras-chave "homocisteína" ou "hiper-homocisteinemia" , associadas a palavras-chave contendo as enfermidades neurológi-cas de maior prevalência como acidente vascular cerebral, doença de Alzheimer, doença de Parkinson e outras. Foram utilizadas as bases de dados do PubMed, Lilacs e Google Scholar. Resultados: Foram utilizados 35 artigos em inglês e 2 artigos em português para a confecção desta revisão. Conclusão: A homocisteína se encontra elevada em associação com as mais diversas doenças neurológicas. Contudo, em muitas delas não está estabelecido se esse aumento é um achado secundário ou se representa um papel da homocisteína na patogênese dessas enfermidades. Mais estudos são necessários para estabelecer o papel da homocisteína em situações neurológi-cas. O tratamento da hiper-homocisteinemia é fácil, sendo feito com reposição de vitamina B 12 e, principalmente, de folatos. Palavras-chave: Homocisteína, S-adenosil-homocisteína, metioni-na, doenças neurológicas. ABSTRACT Objective: Review the metabolism of sulfur amino acid homocystei-ne and how elevation of its serum levels is correlated with the patho-physiology of several neurological diseases, as well as the treatment of hyperhomocysteinemia. Method: A non-systematic review of articles discussing the role of homocysteine associated with neuro-logical diseases was performed. The use of articles that presented in the title the keywords "homocysteine" or "hyperhomocysteinemia" associated with keywords containing the most prevalent neurologi-cal disorders such as stroke, Alzheimer's disease, Parkinson's disease and others were preferred. The search was underdone through PubMed, Google Scholar and Lilacs databases. Results: There were selected 35 articles in English and 2 articles in Portuguese in this this review. Conclusion: High levels of homocysteine are associated with various neurological disorders. However, in many of these are not established whether this increase is a consequence of these disorders or if homocysteine plays a role in the pathogenesis of these diseases. More studies are needed to establish the participation of homocysteine in neurological disorders. The treatment of hyperho-mocysteinemia is easy, being done with replacement of vitamin B 12 and especially folate.
... EAR L RES INTRODUCTION Homocysteine (Hcy) is an intermediary metabolite of amino acid, methionine, during methylation. Elevated plasma level of homocysteine (eHcy) have been observed in many neurologic and psychiatric disorders including stroke, [1,2] cognitive impairment, dementia, [3,4] Alzheimer's disease, [5,6] Parkinson's disease, [6,7] amyotrophic lateral sclerosis, [8] depression, [6,[9][10][11][12] schizophrenia and bipolar disorders and in an animal model, [13,14] indicating eHcy may adversely cause central nervous system dysfunction. [15] Whether eHcy interferes with central conduction as the pathophysiologic background relevant to the central processing slowness is unknown. ...
... Laboratory data included mean corpuscular volume of red blood cells, glucose, creatinine, glycosylated hemoglobin, thyroid stimulating hormone, lipids and liver function panels; inflammatory and infectious studies including erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rapid plasma reagin, lyme titers, hepatitis profile, and human immunodeficiency virus. [8] Subjects with an isolated eHcy who completed evoked potential studies were included. Subjects with an identifiable etiology, other than eHcy, such as deficiency of vitamin B12 and/or folic acid, metabolic, toxic, endocrinologic, infectious, inflammatory, renal or liver diseases were excluded. ...
... [4,[37][38][39] Elevated plasma level of homocysteine has been observed in a number of neurological disorders including stroke, [1,2] Alzheimer's disease, [5] Parkinson's disease, [7] and amyotrophic lateral sclerosis. [8] In addition, eHcy may also play a role in psychiatric disorders, such as depression, [6,[9][10][11][12] bipolar disorders and schizophrenia. [13,14] Importantly, eHcy has been linked to cognitive impairment and dementia. ...
... Extremely high HCY levels (up to 200 µM) has been found in some patients with disrupted HCY metabolism, and is believed to be at the root of certain vascular disorders including stroke and coronary occlusions (Kang et al., 1992;Stanger et al., 2009). According to a number of studies, abnormally elevated levels of HCY in plasma and cerebrospinal fluids correlate with amyotrophic lateral sclerosis (ALS), a motor neuronal disease that causes muscle degeneration (Zoccolella et al., 2008(Zoccolella et al., , 2010Levin et al., 2010;Valentino et al., 2010;Veeranki and Tyagi, 2013). Inherited deficiency of the enzyme methylenetetrahydrofolate reductase (MTHFR), transforming HCY into methionine through remethylation, is associated with severe muscular hypotonia (Huemer et al., 2015). ...
... However, the role of HCY in ALS where the impairment of the neuromuscular transmission is one of the early and leading symptoms of the disease is consistently discussed. Thus, many studies reported the high level of HCY in ALS (Zoccolella et al., 2008(Zoccolella et al., , 2010Levin et al., 2010;Valentino et al., 2010;Veeranki and Tyagi, 2013). In particular, high levels of HCY in both plasma and cerebrospinal fluids were found to correlate with ALS muscle degeneration (Zoccolella et al., 2008;Valentino et al., 2010). ...
... Thus, many studies reported the high level of HCY in ALS (Zoccolella et al., 2008(Zoccolella et al., , 2010Levin et al., 2010;Valentino et al., 2010;Veeranki and Tyagi, 2013). In particular, high levels of HCY in both plasma and cerebrospinal fluids were found to correlate with ALS muscle degeneration (Zoccolella et al., 2008;Valentino et al., 2010). However, conflicting data should also be mentioned. ...
Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.
... EAR L RES INTRODUCTION Homocysteine (Hcy) is an intermediary metabolite of amino acid, methionine, during methylation. Elevated plasma level of homocysteine (eHcy) have been observed in many neurologic and psychiatric disorders including stroke, [1,2] cognitive impairment, dementia, [3,4] Alzheimer's disease, [5,6] Parkinson's disease, [6,7] amyotrophic lateral sclerosis, [8] depression, [6,[9][10][11][12] schizophrenia and bipolar disorders and in an animal model, [13,14] indicating eHcy may adversely cause central nervous system dysfunction. [15] Whether eHcy interferes with central conduction as the pathophysiologic background relevant to the central processing slowness is unknown. ...
... Laboratory data included mean corpuscular volume of red blood cells, glucose, creatinine, glycosylated hemoglobin, thyroid stimulating hormone, lipids and liver function panels; inflammatory and infectious studies including erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rapid plasma reagin, lyme titers, hepatitis profile, and human immunodeficiency virus. [8] Subjects with an isolated eHcy who completed evoked potential studies were included. Subjects with an identifiable etiology, other than eHcy, such as deficiency of vitamin B12 and/or folic acid, metabolic, toxic, endocrinologic, infectious, inflammatory, renal or liver diseases were excluded. ...
... [4,[37][38][39] Elevated plasma level of homocysteine has been observed in a number of neurological disorders including stroke, [1,2] Alzheimer's disease, [5] Parkinson's disease, [7] and amyotrophic lateral sclerosis. [8] In addition, eHcy may also play a role in psychiatric disorders, such as depression, [6,[9][10][11][12] bipolar disorders and schizophrenia. [13,14] Importantly, eHcy has been linked to cognitive impairment and dementia. ...
Aim: Elevated plasma level of homocysteine (eHcy) is a recognized risk factor for dementia. However, whether the central conduction is affected in patients with an isolated eHcy is unknown. In this study, we addressed whether central conduction is altered in adults with eHcy. Methods: Evoked potential studies including somatosensory (SSEP), visual (VEP) and brainstem auditory evoked potentials (BAEP), were performed to evaluate central conduction in patients with isolated eHcy. Results: Nine SSEP, 7 VEP, and 6 BAEP were studied in 9 patients with eHcy (age: 63.3 ± 7.5 years old, mean ± standard deviation, male/female: 4/5). SSEP with median nerve stimulation was delayed in peak latency of N9 (5/9/55.6%, abnormal/total subjects/percentage), N13 (7/9/77.8%), N20 (6/9/66.7%), and/or interpeak latency of N9-N13 (5/9/55.6%), N13-N20 (5/9/55.6%), and N9-N20 (4/9/44.4%). There was one delayed P100 latency (1/7/14.3%) in 7 VEP. BAEP was within normal limits in all the 6 subjects tested. Conclusion: Our pilot study provided neurophysiologic evidence of central conduction slowness in patients with eHcy, which may be due to a large diameter fiber dysfunction within the somatosensory, but not the visual and auditory, white matter pathway. The central conduction slowing in eHcy may be relevant to the pathophysiologic background for slowing the central processing.
... HHcy also affects ion channels, inducing intracellular calcium in ux associated with mitochondrial dysregulation, DNA damage, and cell death [91][92][93]. Studies on ALS have reported HHcy in patients plasma and cerebrospinal uids [94,95], discussed as a factor in the predisposition of motor neurons to the process of excitotoxicity and oxidative stress, due to interactions in glutamatergic receptors, which causes higher sensitivity in the release process of glutamate neurotransmitters [94,96]. Moreover, the increased Hcy level in the bloodstream could contribute to muscle denervation and neurodegeneration, given that the concentration of this amino acid is ten times higher in the bloodstream of ALS patients than in their central nervous system [95]. ...
... HHcy also affects ion channels, inducing intracellular calcium in ux associated with mitochondrial dysregulation, DNA damage, and cell death [91][92][93]. Studies on ALS have reported HHcy in patients plasma and cerebrospinal uids [94,95], discussed as a factor in the predisposition of motor neurons to the process of excitotoxicity and oxidative stress, due to interactions in glutamatergic receptors, which causes higher sensitivity in the release process of glutamate neurotransmitters [94,96]. Moreover, the increased Hcy level in the bloodstream could contribute to muscle denervation and neurodegeneration, given that the concentration of this amino acid is ten times higher in the bloodstream of ALS patients than in their central nervous system [95]. ...
Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurodegenerative disease without a definitive diagnostic test and effective treatment. A plethora of studies suggest that genetic factors play an important role in ALS development, and potentially link folate pathway dysregulation to disease pathogenesis. This study aims to evaluate folate dysregulation due to MTHFR C677T polymorphism and other factors such as sociodemographic and clinical, to better elucidate the involvement of these factors in ALS pathogenesis, and to investigate possible biomarkers for use as disease diagnostics or prognostics. This hospital-based case-control study analyzed 101 patients diagnosed with ALS and 119 considered healthy, with no suspicion or diagnosis of neurodegenerative disease. Blood samples were collected, stored, and underwent DNA extraction. Clinical and sociodemographic data from patients were collected through a questionnaire, as well as consultation of medical records. Genotypic analyses were performed using PCR-RFLP, and statistical analysis of clinical and genotypic data was conducted with SPSS software, version 23. The results show a higher presence of the mutant genotype (p = 0.02) in the case group, and suggest that mutant allele (T) is a risk factor for ALS susceptibility (OR = 1.54; 95% CI = 1.05–2.29; p = 0.03). Mutant genotype (T/T) interacts with both demographics (White p = 0.005 / Brown p = 0,001) and clinical factors (Physical activity p = 0.006) as risk factors for ALS. Also, a significant difference in alcohol consumption (p = 0.001) between the case and control group was observed. Moreover, a statistical trend towards faster disease progression and death was observed for patients with the mutant allele (T) (p = 0.06). Thus, the results of this study suggest that folate deficiency due to MTHFR C677T polymorphism is implicated in ALS through pathogenic mechanisms and interaction with other risk factors, resulting in faster disease progression and early death.
... La homocisteína resultante puede ser remetilada para producir metionina o puede ser convertida en cistationina por la cistationina β-sintetasa, enzima que utiliza piridoxina (vitamina B6) como co-factor, como parte de la ruta de la trans-sulfuración que finaliza con la síntesis de glutatión. (5,15) Papel del metabolismo del folato en enfermedades neurodegenerativas Se han establecido asociaciones entre distintos factores vinculados al metabolismo del folato y varias enfermedades neurodegenerativas, entre las que se encuentran la enfermedad de Alzheimer, (3,16,17) de Parkinson, (18) el Temblor Esencial, (19) la Esclerosis Lateral Amiotrófica, (12,20) y enfermedades poliglutamínicas como la enfermedad de Huntington (21,22) y la Ataxia Espinocerebelosa tipo 2. (4) Entre las evidencias que sustentan estas asociaciones, se relacionan la ocurrencia de alteraciones en los niveles de folatos y en otros metabolitos derivados del metabolismo del folato, y el vínculo entre variantes alélicas en genes codificantes de enzimas clave en el metabolismo del folato y el riesgo o gravedad clínica de estas enfermedades. ...
... En estos pacientes también se observó que los niveles de folato sanguíneo estaban disminuidos, al parecer como respuesta compensatoria ante la elevación de los eventos citotóxicos asociados a la acumulación de homocisteína. (20) También se ha reportado una significativa disminución en las concentraciones de 5-metiltetrahidrofolato a nivel de plasma, médula espinal y corteza cerebral, desde etapas presintomáticas en un modelo murino transgénico SOD1G93A de la ALS, y se propuso que la disminución en la actividad de la MTHFR pudiera estar relacionada con variantes genéticas en el gen SOD1, o en otro gen asociado a la patogenia de esta enfermedad. (12) Adicionalmente, se ha demostrado que la homocisteína es tóxica para neuronas motoras y la metil-cianocobalamina puede rescatar neuronas motoras de la apoptosis inducida por homocisteína, en cultivos de células NSC-34D resultantes de la fusión entre células neuronas motoras y células de neuroblastoma. ...
Introducción:
Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales.
Objetivo:
Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas.
Material y métodos:
Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios.
Desarrollo:
Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas.
Conclusiones:
El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades.
... Intensive efforts have been dedicated towards finding biomarkers of ALS aiming to diagnose the disease in early stages. Recently some studies have shown altered levels of homocysteine (Hcy) in biological fluids of patients with ALS [5][6][7]. Hcy is a non-proteinogenic sulfurcontaining amino acid, which plays an important role in living organisms. Its metabolism is intermediate to re-methylation to methionine (Met) and transsulfuration to cysteine (Cys) via cystathionine pathway [8]. ...
... On the other hand, plasma levels of Met and Hcy did not show a significant difference between controls and patients, which is in disagreement with previously published work. However, patients and controls were not perfectly matched in terms of age, and this might have contributed for not detecting differences on plasma levels of these amino acids [5,7]. ...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons, leading to muscle atrophy, paralysis, and death caused by respiratory failure or infectious complications. Altered levels of homocysteine, cysteine, methionine, and glutamic acid have been observed in plasma of ALS patients. In this context, a method for determination of these potential biomarkers in plasma by capillary electrophoresis tandem mass spectrometry (CE-MS/MS) is proposed herein. Sample preparation was carefully investigated, since sulfur-containing amino acids may interact with plasma proteins. Owing to the non-thiol sulfur atom in methionine, it was necessary to split sample preparation into two methods: i) determination of homocysteine and cysteine as S-acetyl amino acids; ii) determination of glutamic acid and methionine. All amino acids were separated within 25 min by CE-MS/MS using 5 mol L⁻¹ acetic acid as background electrolyte and 5 mmol L⁻¹ acetic acid in 50% methanol/H2O (v/v) as sheath liquid. The proposed CE-MS/MS method was validated, presenting RSD values below 6% and 11% for intra- and inter-day precision, respectively, for the middle concentration level within the linear range. The limits of detection ranged from 35 (homocysteine) to 268 nmol L⁻¹ (glutamic acid). The validated method was applied to the analysis of plasma samples from a group of healthy individuals and patients with ALS, showing the potential of glutamic acid and homocysteine metabolites as biomarkers of ALS.
... Six acids (urate, lactate, oxaloacetate, pentothenate, 2hydroxybutyrate, and 3-phenylpropionate), five alkaloids (caffeine, paraxanthine, theobromine, theophylline, and betaine), two lipids (1-palmitoleoylglycerophosphocholine and stearoyl sphingomyelin), homocysteine, amine, mannose, and riluzole were determined in plasma of patients having ALS disease (Lawton et al., 2014;Zoccolella et al., 2008). Among those, amine and lactate, as well as the amino acids, phenylalanine and tyrosine, glucose, acetone, and inositol were determined in CSF of ALS patients (Blasco et al., 2015;Gray et al., 2015;Toczylowska et al., 2013). ...
... When the expression patterns (i.e., up-or downregulation) of metabolites were examined, we observed that the majority of the ALS biomarkers (riluzole, 1-palmitoleoylglycerophosphocholine, phenylalanine, glucose, tyrosine, ketone, oxaloacetate, mannose, 2-hydroxybutyrate, pentothenate, homocysteine, formate, b-hydroxybutyrate, inositol, stearoyl sphingomyelin, sphinganine-1-phosphate, lactate, and acetone) were over-expressed in the diseased state; whereas N-acetyl derivatives, 3-phenylpropionate, amine, betaine, and urate levels were decreased. In addition, low levels of alkaloids (caffeine, paraxanthine, theobromine, and theophylline), and hippurate were observed in ALS patients (Blasco et al., 2015;Botosoa et al., 2012;Gray et al., 2015;Kumar et al., 2010;Lawton et al., 2012Lawton et al., , 2014Toczylowska et al., 2013;Zoccolella et al., 2008). ...
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) lack robust diagnostics and prognostic biomarkers. Metabolomics is a postgenomics field that offers fresh insights for biomarkers of common complex as well as rare diseases. Using data on metabolite-disease associations published in the previous decade (2006-2016) in PubMed, ScienceDirect, Scopus, and Web of Science, we identified 101 metabolites as putative biomarkers for these three neurodegenerative diseases. Notably, uric acid, choline, creatine, L-glutamine, alanine, creatinine, and N-acetyl-L-aspartate were the shared metabolite signatures among the three diseases. The disease-metabolite-pathway associations pointed out the importance of membrane transport (through ATP binding cassette transporters), particularly of arginine and proline amino acids in all three neurodegenerative diseases. When disease-specific and common metabolic pathways were queried by using the pathway enrichment analyses, we found that alanine, aspartate, glutamate, and purine metabolism might act as alternative pathways to overcome inadequate glucose supply and energy crisis in neurodegeneration. These observations underscore the importance of metabolite-based biomarker research in deciphering the elusive pathophysiology of neurodegenerative diseases. Future research investments in metabolomics of complex diseases might provide new insights on AD, PD, and ALS that continue to place a significant burden on global health.
... Methylcobalamin (vitamin B 12 ) acts as a methyl donor for homocysteine remethylation with neuroprotective properties by decreasing the levels of neuronal homocysteine. 125 Moreover, methylcobalamin activates extracellular signal-regulated kinases 1 and 2 and Akt, favoring neuronal survival. 126 Preclinical studies indicated that this compound has antiglutamatergic properties. ...
Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.
... HHcy is related in patients with both MS (Besler and Comoğlu, 2003;Vrethen et al., 2003) and ALS (Zoccolella et al., 2008;Zoccolella et al., 2010). The elevation of this neurotoxic compound is also described in other neurodegenerative diseases, such as Parkinson's (Postuma and Lang, 2004) and Alzheimer's (Ng et al., 2018), and the main responsible for this condition is the low enzymatic activity of MTHFR (Brustolin et al., 2010). ...
... In vitro and in vivo studies revealed the neuroprotective effects of high-dose methylcobalamin (vitamin B12) in neurodegenerative diseases, such as ALS [179,180]. It acts as a coenzyme by donating methyl in homocysteine remethylation reaction and prevents neuronal degeneration by reducing the levels of homocysteine, the deposit which relates to neuronal injury in ALS patients [181,182]. In addition, experimental studies described that methylcobalamin protects neural cells against glutamate neurotoxicity [183], and induces nerve regeneration [184]. ...
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies,
glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly re
duces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib’s mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.
... Chronically high values of plasma Hcy (HHcy) has been associated with numerous health issues such as cognitive impairment (Marengoni et al., 2004), neurological disorders (Gu et al., 2012;Valentino et al., 2010;Zoccolella et al., 2008), bone resorption (Álvarez-Sánchez et al., 2018), and higher risk of mortality (Wong et al., 2013). High levels of Hcy, called hyperhomocysteinemia (HHcy), has also been recently linked to poorer physical performances (Kado et al., 2002;Kuo et al., 2007;van Schoor et al., 2012;Vidoni et al., 2017Vidoni et al., , 2018 and frailty (Álvarez-Sánchez et al., 2020;Wong et al., 2013). ...
Background
Homocysteine (Hcy) has been associated with several health problems, including reduced physical capacity. No study appears to have looked at the role of Hcy values longitudinally on physical capacity deterioration in older adults. The objective is to examine cross-sectional and prospective associations between Hcy values and frailty in the elderly and investigate Hcy potential association with the onset of frailty.
Methods
769 community-dwelling older adults from the MAPT study were recruited for this study. Total Hcy was measured at baseline. Frailty was evaluated at 5 different collection timepoints: baseline, 6-month, 1-, 2-, and 3-year using a frailty index (FI) composed of 19 items. Linear regressions adjusted for all the confounders (age, gender, educational level, MAPT group allocation and Omega-3) were performed to examine the cross-sectional associations of homocysteine values with the FI. A cox model was used to test the association of Hcy with the onset of frailty. Results.
Mean Hcy values (15.9 ± 5.6 μmol\L) were obtained from 769 community-dwelling adults (75.7 ± 4.6 years old). After adjustments, a significant (β = 0.002, (00002–0.003)) and positive association between baseline Hcy values and FI was found (ß = 0.002). Additionally, higher values of Hcy were associated with a worsening of FI after 3 years (ß = 0.002, p = 0.003). A significant association between baseline Hcy values and the likelihood of developing frailty was discovered by incident event analysis (HR: 1.04 (1.01–1.06), p = 0.004).
Conclusion
High levels of Hcy are associated with the fragility process in community-dwelling older adults.
... 18,19 In fact, plasma homocysteine levels are reported to be elevated in patients with ALS. 20 The current trial showed that plasma homocysteine levels indeed significantly decreased with methylcobalamin. On the other hand, changes in plasma homocysteine levels were not correlated with those in ALSFRS-R scores in the treatment period. ...
Importance:
The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent.
Objective:
To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset.
Design, setting, and participants:
This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo.
Interventions:
Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks.
Main outcomes and measures:
The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.
Results:
A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups.
Conclusions and relevance:
Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period.
Trial registration:
ClinicalTrials.gov Identifier: NCT03548311.
... It is difficult at present to speculate upon the reason for the increased HCSA but not of HCA in ALS. It may be that the increased HCSA arise by increased oxidation of homocysteine, which is known to be elevated in patients with ALS [16]; it may be that the activity of oxidases that subsequently convert HCSA to HCA is decreased in ALS. In studies where brain extracts were incubated with [ 35 S]homocysteine and its derivatives examined by pre-column o-phthalaldehyde derivatisation followed by HPLC, only a slow nonenzymic increase in HCSA was detected, whereas the level of HCA was below the limit of sensitivity [15]. ...
b> Objectives: Excitotoxicity is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). One possible source of excitotoxicity is the presence of sulphur amino acids (SAAs). In the brain of subjects with ALS, there are increased levels of taurine. In the metabolism of methionine to taurine, excitatory sulphur amino acids (SAAs) are formed. These could potentially contribute to excitotoxicity in ALS. The present study has examined whether plasma levels of SAAs in 38 ALS patients differ from those of 30 healthy controls. Methods: Plasma levels of SAAs were measured by liquid chromatography mass spectrometry. Results: There were no significant changes in plasma cysteic acid, cysteine sulfinic acid, and homocysteic acid in ALS patients compared to healthy subjects. Significant elevations in plasma homocysteinesulfinic acid (HCSA) levels ( p < 0.0001) were observed in the ALS patients (75.91 ± 15.38 nM) compared to healthy controls (54.06 ± 8.503 nM); 50% of the ALS patients had HCSA levels that were 1.5–2-folds higher than those of controls. Plasma levels of HCSA differed significantly ( p = 0.0440) between patients with bulbar onset and spinal onset (68.57 ± 14.20 vs. 79.30 ± 14.95 nM, respectively). Conclusion: HCSA is elevated in the blood of subjects with ALS. Since HCSA can be transported from the blood to the CNS by active transport, has neurotransmitter properties, and can activate synaptic receptors including NMDAR and metabotropic glutamate receptor, it is possible that increases in HCSA could influence glutamatergic neurotransmission and potentially contribute to excitotoxicity in some ALS patients.
... Homocysteine is metabolised either by the trans-sulfuration pathways which requires pyridoxine as a cofactor, or the remethylation pathways which requires folate and vitamin B12 together as a cofactor [19,20]. The correlation between the levels of Hcy and vitamins B12 and B6 is of clinical relevance as reported in ALS patients [21]. [22]. ...
... These are beneficial against a series of ischemic and degenerative conditions, being able to observe how anthocyanin supplementation counteracts the inflammatory response to stress conditions Hornedo-Ortega et al., 2018). At the same time, polyphenols, together with B vitamins (folic acid, vitamin B6, and vitamin B12), which are also found in large quantities in this diet, decrease homocysteine concentrations that are elevated in patients with Alzheimer's disease (Zoccolella et al., 2008). ...
Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease which is pathogenically based on the mitochondrial alteration of motor neurons, causing progressive neuron death. While ALS is characterized by enormous oxidative stress, the Mediterranean diet has been seen to have high antioxidant power. Therefore, the aim of this study is to determine how the Mediterranean diet can improve mitochondrial activity, establishing the specific nutrients and, in addition, observing the pathogenic mechanisms related to the disease that would achieve this improvement. To this end, a comprehensive review of the literature was performed using PubMed. KBs have been observed to have a neuroprotective effect to improve energy balance, increasing survival and the number of motor neurons. This ketogenesis can be achieved after following a Mediterranean diet which is associated with great benefits in other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS. These benefits are due to the high antioxidant power especially based on polyphenols contained mainly in olive oil, wine, nuts, or berries. In short, KBs could be considered as a promising option to treat ALS, representing an alternative source to glucose in motor neurons by providing neuroprotection. In addition, treatment results can be improved as ketogenesis can be achieved (increase in KBs) by following a Mediterranean diet, thanks to the high antioxidant properties which, at the same time, would improve the high oxidative stress that characterizes the disease.
... In a pre-symptomatic mouse model of ALS and also in some patients of ALS a condition of inflammation in the areas of motor neuron loss was found which was detected by increased levels of cytokines in serum and cerebrospinal fluid of some ALS patients [46][47][48]. Apeland, et al. Own matched control based study Drugs such as phenytoin, primodine, and phenobarbital belonging to anti-epileptics category share a link with high plasma homocysteine and low folate levels in adult patients. ...
Excessive level of Homocysteine (Hcy) is considered a neurotoxin since it has a very deleterious effect on the nervous system. It is a sulfur-containing amino acid that is reversibly formed and secreted during metabolism. Pre-clinically and clinically, Hcy exhibits several neurological mechanisms that have been reported in the pathogenesis of Alzheimer's disease, stroke, Parkinson's disease, multiple sclerosis, epilepsy, neuronal cell death, and amyotrophic lateral sclerosis. Homocysteine may promote Alzheimer's disease by more than one mechanism, including oxidative stress, neuronal cell damage, tau phosphorylation, enhancement of beta-amyloid aggregation, and hyperactivation of NMDA receptor. Moreover, it increases the production of chemokines by stimulation of nuclear factor-kappa B. It is well known that the use of levodopa diminishes the symptoms of Parkinson's disease but also lead to an elevation in the level of homocysteine. In this review, we highlight the associate relationship between hyperhomocysteinemia and neurological disorders by discussing its neurodegenerative effects.
... HHcy has been associated with severe skeletal muscle dysfunction, but the precise mechanism(s) is still unknown (Brustolin et al. 2010;Kanwar et al. 1976;Kolling et al. 2013;Majumder et al. 2017;Miller et al. 2000;Valentino et al. 2010;Veeranki et al. 2015;Voskoboeva et al. 2018;Zoccolella et al. 2008). Children born with very high levels of Hcy, i.e., HHcy due to deficiency of functional CBS gene (CBS −/− ), show severe muscle myopathy and die shortly after birth, but heterozygous for CBS mutation (CBS +/− ) children can survive (Voskoboeva et al. 2018). ...
Elevated homocysteine (Hcy), i.e., hyperhomocysteinemia (HHcy) causes skeletal muscle myopathy. Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER)-stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is increasingly recognized as a potent anti-oxidant, anti-apoptotic/necrotic/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less H2S, making them vulnerable to Hcy-mediated cellular damage. Many studies reported bidirectional regulation of ER-stress in apoptosis through JNK activation, and concomitant attenuation of cell proliferation and protein synthesis via PI3K/AKT axis. Whether H2S mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative/ER-stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how H2S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H2S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy.
... HHcy has been associated with severe skeletal muscle dysfunction, but the precise mechanism(s) is still unknown (Brustolin et al. 2010;Kanwar et al. 1976;Kolling et al. 2013;Majumder et al. 2017;Miller et al. 2000;Valentino et al. 2010;Veeranki et al. 2015;Voskoboeva et al. 2018;Zoccolella et al. 2008). Children born with very high levels of Hcy, i.e., HHcy due to deficiency of functional CBS gene (CBS −/− ), show severe muscle myopathy and die shortly after birth, but heterozygous for CBS mutation (CBS +/− ) children can survive (Voskoboeva et al. 2018). ...
Elevated homocysteine (Hcy), i.e., hyperhomocysteinemia (HHcy), causes skeletal muscle myopathy. Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER) stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is increasingly recognized as a potent anti-oxidant, anti-apoptotic/necrotic/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less H2S, making them vulnerable to Hcy-mediated cellular damage. Many studies have reported bidirectional regulation of ER stress in apoptosis through JNK activation and concomitant attenuation of cell proliferation and protein synthesis via PI3K/AKT axis. Whether H2S mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative/ER stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how H2S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H2S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy.
... There are also several other drivers like age, sex, physical activity, alcohol intake, certain medications, and different disease conditions (such as type 2-diabetes) that can also modulate the functioning Met cycle leading to an increased total Hcy concentration in the blood (Diakoumopoulou et al. 2005). Hyperhomocysteinemia (HHcy) has been associated with severe skeletal muscle dysfunction (Brustolin et al. 2010;Kanwar et al. 1976;Kolling et al. 2013;Majumder et al. 2017;Miller et al. 2000;Valentino et al. 2010;Veeranki et al. 2015;Voskoboeva et al. 2018;Zoccolella et al. 2008), but the precise mechanism(s) is still unknown. Previous studies found that HHcy causes endothelial cell (EC) injury (Wang et al. 1997), inhibition of EC proliferation (Zou et al. 2011), reduction of bioavailability of vasoregulatory mediators (nitric oxide and endothelin) (Upchurch et al. 1997), and induction of oxidative/ER-stress Tyagi et al. 2005;Werstuck et al. 2001). ...
Neoangiogenesis is a fundamental process which helps to meet energy requirements, tissue growth, and wound healing. Although previous studies showed that Peroxisome proliferator‐activated receptor (PPAR‐γ) regulates neoangiogenesis via upregulation of vascular endothelial growth factor (VEGF), and both VEGF and PPAR‐γ expressions were inhibited during hyperhomocysteinemic (HHcy), whether these two processes could trigger pathological effects in skeletal muscle via compromising neoangiogenesis has not been studied yet. Unfortunately, there are no treatment options available to date for ameliorating HHcy‐mediated neoangiogenic defects. Hydrogen sulfide (H2S) is a novel gasotransmitter that can induce PPAR‐γ levels. However, patients with cystathionine‐β‐synthase (CBS) mutation(s) cannot produce a sufficient amount of H2S. We hypothesized that exogenous supplementation of H2S might improve HHcy‐mediated poor neoangiogenesis via the PPAR‐γ/VEGF axis. To examine this, we created a hind limb femoral artery ligation (FAL) in CBS+/− mouse model and treated them with GYY4137 (a long‐acting H2S donor compound) for 21 days. To evaluate neoangiogenesis, we used barium sulfate angiography and laser Doppler blood flow measurements in the ischemic hind limbs of experimental mice post‐FAL to assess blood flow. Proteins and mRNAs levels were studied by Western blots and qPCR analyses. HIF1‐α, VEGF, PPAR‐γ and p‐eNOS expressions were attenuated in skeletal muscle of CBS+/− mice after 21 days of FAL in comparison to wild‐type (WT) mice, that were improved via GYY4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐FAL CBS+/− mice compared to WT mice and these effects were ameliorated by GYY4137. Moreover, we found that plasma nitrite levels were decreased in post‐FAL CBS+/− mice compared to WT mice, which were mitigated by GYY4137 supplementation. These results suggest that HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing PPAR‐γ/VEGF axis and that GYY4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of HHcy conditions. Neoangiogenesis is a fundamental process of human health to satisfy energy requirements, tissue growth, and wound healing. Our results suggest that HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signals through PPAR‐γ axis and GYY4137 may be beneficial to alleviate these effects.
... A study revealed that patients with ALS having a normal lipid profile have a better survival rate than patients with dyslipidemia. Hypercholesterolemia is considered as one of the major factors in the treatment of ALS [14][15][16][17] . ...
World Health Organization estimated cardiovascular disease as the major cause of mortality in recent decades. Dyslipidemia or hyperlipidemia is the root cause of most of the cardiovascular diseases like atherosclerosis, stroke and myocardial infarction. Different factors like age, genetic and life style contribute to the development of these conditions worldwide. Considering the therapeutic perspective, most countries prescribe statin-based drugs for dyslipidemic and cardiovascular patients. In this review we discuss the mechanism of statin action, the prescribed dosage levels in different countries, the variants of statins and the adverse effects of statins in the patients. This review also focuses on therapeutic approaches using different phytochemicals for dyslipidemia conditions without any adverse effects and also describes how phytochemicals are advantageous over statins.
... Recently, involvement of H 2 S as an astroglial mediator of motor neuron damage in Amyotrophic lateral sclerosis (ALS) has been shown [32]. It has been demonstrated that Hcy levels are significantly increased in plasma and cerebrospinal fluid of patients with ALS [33,34]. However, the influence of elevated Hcy and endogenous H 2 S levels on Hcy-induced behavioral and neurochemical deficits has not been clearly investigated. ...
Hyperomocysteinemia (HHcy) has been associated with mild cognitive impairment and dementia. Hydrogen sulfide (H 2 S) has been suggested to be an endogenous modulator of neuro-nal functions. However, the effect and mechanisms involved in beneficial effect of H 2 S has not been investigated in homo-cysteine (Hcy)-induced cognitive deficits. This study has been designed to evaluate the effect of exogenous H 2 S on behav-ioral deficits and neurochemical alterations in HHcy animals. Hcy levels were significantly elevated in plasma, cortex, and hippocampus of Hcy administered animals. A progressive decline in memory functions and increased anxiolytic behavior was observed in HHcy animals. This was accompanied by decrease in endogenous H 2 S levels along with decreased activity of cystathionase (CSE) and cystathionine b-synthase (CBS). However, a significant increase in CSE and CBS mRNAs was observed. In addition, the catecholamine and serotonin levels were reduced and the activity of monoamine oxidase A and B were increased in brain regions of HHcy animals. Hae-matoxylin and eosin staining revealed higher number of pyknotic cells in brain regions of HHcy animals. H 2 S administration was found to lower elevated plasma and brain Hcy levels. The activities of CBS, CSE, and levels of H 2 S were restored in HHcy animals administered H 2 S. Exogenous H 2 S also ameliorated behavioral deficits accompanied by significant increase in catecholamines. Histological analysis revealed normal cell morphology in Hcy-treated animals supplemented with H 2 S. These results clearly demonstrate that the protective effect of H 2 S on Hcy-induced cognitive deficits is mediated through increased catecholamine and H 2 S levels thereby suggesting its beneficial role in preventing HHcy-induced neuro-degeneration.
... Blood homocysteine levels are also elevated in patients with progressive supranuclear palsy and amyotrophic lateral sclerosis (ALS) (Levin et al. 2010), more markedly so in ALS patients with a shorter time to diagnosis. Higher levels may be linked to a more rapid disease progression (Zoccolella et al. 2008). ...
... Several small-scale cross-sectional studies showed increased serum homocysteine levels in patients with ALS [74]. A single study demonstrated elevated CSF homocysteine concentrations in ALS patients [75]. ...
The use of nutrients for the purposes improving health and preventing and treating diseases has been the focus of attention for a very long time not only in the scientific area but also in the general public. Although the efforts were generally unfruitful from the perspective of neurologic disorders, the interest to the subject is escalating at an enormous rate, primarily as a combined result of commercial marketing strategies and demand from patients/public for the alleviation of neurologic problems where conventional treatments do not provide satisfactory results in general. This chapter, expectedly, cannot cover every aspect of neuronutrition. We will primarily summarize the evidence regarding the mostly studied neuro-nutraceuticals, including antioxidant vitamins, vitamin D, polyphenolic compounds, and cellular energy modulators. We will also provide information on neuronutritional aspects of stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, amyotrophic lateral sclerosis, and migraine.
... The vitamin B12-linked folate and methionine cycles are also implicated in ALS through multiple previous studies. For example, homocysteine is increased in the plasma and CSF of ALS patients (92,107,109), whereas carnitine (80) and methionine (41) are decreased in the plasma of ALS patients. Furthermore, folic acid supplementation is neuroprotective (105), S-adenosylmethionine delays disease onset (87) and carnitine decreases disease progression and increases survival (49) in a mouse model for ALS. ...
Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. In order to gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top-ranked findings from six genome-wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho-GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate and methionine; and (3) ribonucleoprotein granule functioning and axonal transport. Interestingly, estradiol signaling is functionally involved in all three cascades and as such an important mediator of the molecular ALS landscape. Furthermore, epidemiological findings together with an analysis of possible gender effects in our own cohort of sporadic ALS patients indicated that estradiol may be a protective factor, especially for bulbar-onset ALS. Taken together, our molecular landscape of ALS suggests that abnormalities within three interconnected molecular processes involved in the functioning and maintenance of motor neuron axons are important in the etiology of ALS. Moreover, estradiol appears to be an important modulator of the ALS landscape, providing important clues for the development of novel disease-modifying treatments. This article is protected by copyright. All rights reserved.
... Similarly, showed in a study that Hcy affects fatty acid oxidation of energy metabolism in skeletal muscle via PGC-1a specific protein nitrotyrosylation and reduce its association with PPARg . On the other hand many neurological disorders like amyotrophic lateral sclerosis (ALS) and multiple sclerosis which affect muscle degeneration are also connected to HHcy [Zoccolella et al., 2008;Valentino et al., 2010;Zoccolella et al., 2012]. HHcy also leads to significantly lower physical functions by deteriorating skeletal muscle functions in older people comparing to age matched healthy subjects [Kado et al., 2002], which might suggests that ageing is one of the potential factor to be consider in this process [Westerblad et al., 2010]. ...
A detrimental consequence of hypermethylation is hyperhomocysteinemia (HHcy), that causes oxidative stress, inflammation and matrix degradation, which leads to multi-pathology in different organs. Although, it is well known that hypermethylation leads to overall gene silencing and hypomethylation leads to overall gene activation, the role of such process in skeletal muscle dysfunction during HHcy condition is unclear. In this study, we emphasized the multiple mechanisms including epigenetic alteration by which HHcy causes skeletal muscle myopathy. This review also highlights possible role of methylation, histone modification and RNA interference in skeletal muscle dysfunction during HHcy condition and potential therapeutic molecules, putative challenges, and methodologies to deal with HHcy mediated skeletal muscle dysfunction. We also highlighted that B vitamins (mainly B12 and B6) with folic acid supplementation, could be useful as an adjuvant therapy to reverse these consequences associated with this HHcy conditions in skeletal muscle. However, we would recommend to further study involving long-term trials could help to assess efficacy of the use of these therapeutic agents. This article is protected by copyright. All rights reserved.
... 9 Numerous environmental factors may contribute to oxidative stress and preclude a discussion of the direct alteration of oxidative stress status. For example some studies found increased concentrations of homocysteine in ALS correlated with progression, 10 alterations of vitamin and metals levels, 11 all mechanisms able to modify oxidative status of patients. Inflammation, another major pathophysiological process involved in ALS, has been reported by fundamental studies of cultured cells, animal models and clinical studies in humans. ...
Background:
Pathophysiological mechanisms that contribute to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) include oxidative stress and inflammation. We conducted a preliminary study to explore these mechanisms, to discuss their link in ALS, and to determine the feasibility of incorporating this combined analysis into current biomarkers research.
Methods:
We enrolled 10 ALS patients and 10 controls. We measured the activities of glutathione peroxidase, glutathione reductase, superoxyde dismutase (SOD), and the levels of serum total antioxidant status (TAS), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and glutathione status (e.g. glutathione disulfide, GSSG/reduced glutathione, GSH). We analysed the concentrations of homocysteine, several cytokines, vitamins and metals by standard methods used in routine practice.
Results:
There was a significant decrease in TAS levels (p=0.027) and increase in 8-OHdG (p=0.014) and MDA (p=0.011) levels in ALS patients. We also observed a significantly higher GSSG/GSH ratio (p=0.022), and IL-6 (p=0.0079) and IL-8 (p=0.009) concentrations in ALS patients. Correlations were found between biological and clinical markers (homosysteine vs. clinical status at diagnosis, p=0.02) and between some biological markers such as IL-6 vs. GSSG/GSH (p=0.045) or SOD activity (p=0.017).
Conclusion:
We confirmed the systemic alteration of both the redox and the inflammation status in ALS patients, and we observed a link with some clinical parameters. These promising results encourage us to pursue this study with collection of combined oxidative stress and inflammatory markers.
... Apart from haemostatic disturbances, higher Hcy levels are observed in a few neurological diseases, such as Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis [17,18,19], for which vascular component is not commonly considered an important etiologic factor. Reason for Hcy neurotoxicity derives from excitotoxic stress induced by Hcy after its interaction with metabotropic and/or ionotropic glutamate receptors [20,21]. ...
Homocysteine (Hcy) is an excitotoxic amino acid. It is potentially possible to prevent Hcy-induced toxicity, including haemostatic impairments, by antagonizing glutaminergic receptors. Using impedance aggregometry with arachidonate and collagen as platelet agonists, we tested whether the blockade of platelet NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors with their inhibitors: MK-801 (dizocilpine hydrogen maleate, [5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine), CNQX (7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile) and UBP-302 (2-{[3-[(2S)-2-amino-2-carboxyethyl]-2,6-dioxo-3,6-dihydropyrimidin 1(2H)-yl]methyl}benzoic acid) may hamper Hcy-dependent platelet aggregation. All the tested compounds significantly inhibited Hcy-augmented aggregation of blood platelets stimulated either with arachidonate or collagen. Hcy stimulated the generation of superoxide anion in whole blood samples in a concentration-dependent manner; however, this process appeared as independent on ionotropic glutamate receptors, as well as on NADPH oxidase and protein kinase C, and was not apparently associated with the extent of either arachidonate- or collagen-dependent platelet aggregation. Moreover, Hcy acted as a significant fluidizer of surface (more hydrophilic) and inner (more hydrophobic) regions of platelet membrane lipid bilayer, when used at the concentration range from 10 to 50 µmol/l. However, this effect was independent on the Hcy action through glutamate ionotropic receptors, since there was no effects of MK-801, CNQX or UBP-302 on Hcy-mediated membrane fluidization. In conclusion, Hcy-induced changes in whole blood platelet aggregation are mediated through the ionotopic excitotoxic receptors, although the detailed mechanisms underlying such interactions remain to be elucidated.
... Other studies quantifying specific metabolites (instead of a full metabolome analysis) showed elevated plasma levels of patient homocysteine [92] and NAA [93]. However, both reports concluded that the results were preliminary. ...
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that primarily affects motor neurons and is accompanied by sustained unregulated immune responses, but without clear indications of the ultimate causative mechanisms. The identification of a diverse array of ALS phenotypes, a series of recently discovered mutations, and the links between ALS and frontotemporal degeneration have significantly increased our knowledge of the disease. In this review we discuss the main features involved in ALS pathophysiology in the context of recent advances in 'omics' approaches, including genomics, proteomics, and others. We emphasize the pressing need to combine clinical imaging with various different parameters taken from omics fields to facilitate early, accurate diagnosis and rational drug design in the treatment of ALS. ALS, or amyotrophic lateral sclerosis, is a progressive neurodegenerative disease that affects motor neurons. There is no cure for ALS. Although ALS is a brain disease closely related to Parkinson's, Alzheimer's, and Huntington's diseases, so far the complex descriptions of ALS-associated damage have not clarified the ultimate causative mechanisms.Current interventions are the result of unintentional discoveries or the non-specific application of cell-based therapies whose effects are not completely understood. However, research on ALS is currently thriving and the body of knowledge on the subject has increased remarkably in recent years.The emergence of functional immunomics for ALS from established omics technologies are opening new therapeutic avenues based on the smart manipulation of the immune system.Molecular imaging in the field of ALS is evolving. Thus, a combination of omics technologies and clinical imaging may very well be the key for breaking-down ALS.
... Finally, MeCbl lowers plasma homocysteine levels (14). Plasma homocysteine levels are elevated in PALS with a shorter time to diagnosis (15) and homocysteine can be toxic to motor neurons in culture (7). ALSUntangled assigns a TOE 'Mechanism' grade of A based on this information (Table I). ...
Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate’s impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate’s impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.
Background and Aim
Recreational use of nitrous oxide (N 2 O) has been associated with the development of severe nitrous oxide‐induced neuropathy (N 2 On). Follow‐up of these patients poses challenges, and their clinical progression remains largely unknown. The identification of prognostic factors is made difficult by the lack of standardized longitudinal assessments in most studies. The objective was to document the course of neuropathy through systematic follow‐up assessments in N 2 On patients to identify prognostic factors for persistent disability after 6 months.
Methods
We gathered demographic, clinical, biological, and electrophysiological data from N 2 On patients hospitalized in the Referral center in Marseille, both at baseline and during a standardized follow‐up assessment at 6 months.
Results
We retrospectively included 26 N 2 On patients (mean age 22.6 ± 4.4). Significant improvements were observed in all main clinical scores including Rankin, ONLS, and MRC testing ( p < .01). Electrophysiological studies (EDX) revealed a predominantly motor neuropathy with marked reduction in CMAP in the lower limbs at baseline, and no significant improvement in motor parameters ( p = .543). Rankin score at 6 months correlated with the initial weekly N 2 O consumption ( r = .43, p = .03) and the CMAP sum score in the lower limbs at the first EDX ( r = −.47, p = .02). Patients with and without myelitis showed similar Rankin and ONLS score after 6 months.
Interpretation
The clinical course generally improved favorably at 6 months with notable amelioration in the primary disability scores, sensory deficits, and ataxia. However, distal motor impairment associated with peripheral neuropathy persisted, with distal axonal loss emerging as the main prognostic factor for long‐term disability in these young patients.
Prebiotics are non-digestible ingredients that exert significant health-promoting effects on hosts. Galactooligosaccharides (GOS) have remarkable prebiotic effects and structural similarity to human milk oligosaccharides. They generally comprise two to eight sugar units, including galactose and glucose, which are synthesized from substrate lactose by microbial β-galactosidase. Enzyme sources from probiotics have received particular interest because of their safety and potential to synthesize specific structures that are particularly metabolized by intestinal probiotics. Owing to advancements in modern analytical techniques, many GOS structures have been identified, which vary in degree of polymerization, glycosidic linkage, and branch location. After intake, GOS adjust gut microbiota which produce short chain fatty acids, and exhibit excellent biological activities. They selectively stimulate the proliferation of probiotics, inhibit the growth and adhesion of pathogenic bacteria, alleviate gastrointestinal, neurological, metabolic and allergic diseases, modulate metabolites production, and adjust ion storage and absorption. Additionally, GOS are safe and stable, with high solubility and clean taste, and thus are widely used as food additives. GOS can improve the appearance, flavor, taste, texture, viscosity, rheological properties, shelf life, and health benefits of food products. This review systemically covers GOS synthesis, structure identifications, metabolism mechanisms, prebiotic bioactivities and wide applications, focusing on recent advances.
Objective:
To investigate the differences of the level of homocysteine (Hcy) between ALS patients and controls.
Methods:
PubMed, EMBASE, OVID, and other databases were searched systematically up to October 2022 for relevant reports about the level of Hcy, folic acid, and vitamin B12 (VB12) among ALS patients. Two reviewers screened and selected the titles and abstracts of the studies independently during the database searches and performed full-text reviews and extracted available data. The MD (mean difference) and 95%CI (credibility interval) of the level of Hcy, folic acid, and VB12 between ALS group and control group were calculated.
Results:
Pooled results of nine studies including 812 ALS patients and 2632 controls showed that the MD in plasma levels of HCY between ALS patients and controls was 1.56 (95%CI: - 0.07, 3.19) μmol/L with remarkable heterogeneity (I2 = 94%). The mean CSF levels of Hcy among ALS patients were significantly higher than that of controls (MD: 0.23, 95%CI: 0.21, 0.24 μmol/L) with no significant heterogeneity (I2 = 0%). No significant difference in the plasma level of folic acid (MD: - 0.52, 95%CI: - 1.89, 0.84 ng/mL) or VB12 (MD: - 9.76, 95%CI: - 83.41, 63.89) was found between ALS patients and controls.
Conclusion:
There was no significant difference in the plasma level of Hcy, folic acid, or VB12 between ALS patients and controls. The CSF level of Hcy among ALS population was remarkably higher than that among controls. Vitamin supplements including folate and VB12 might be recommended to ALS patients with the complication of deficiencies.
Objective The present study was to investigate the significance of creatinine, uric acid, creatine kinase, total cholesterol, triglyceride, HCY (Homocysteine), and cystatin C in neurological function and progression rate of amyotrophic lateral sclerosis. Methods According to the diagnostic criteria of EI-Escorial (2000), 103 patients with ALS were enrolled. All patients were given corresponding serological tests at the initial diagnosis. The Revised ALS Functional Rating Scale (ALSFRS-R) and Disease Progression Rate (DPR) were evaluated. The detected indexes in blood tests included creatinine, uric acid, creatine kinase, total cholesterol, triglycerides, homocysteine, and cystatin C. All data were input into the computer, and the data analysis was performed by SPSS22.0 statistical software. Results 1. There were significant differences in creatinine, uric acid, creatine kinase,
total cholesterol, HCY and cystatin C between the two groups ( P <0.05). The levels of uric acid and creatinine of ALS group were lower than those of the control group, and the levels of creatine kinase, total cholesterol, triglyceride, HCY and cystatin C were higher than that in the control group.
2. The results from correlation analysis demonstrated that there was a significant correlation between ALSFRS-R and creatinine ( P <0.01), the correlation coefficient was 0.567 (positive correlation); There was also a significant correlation between DPR and creatinine ( P <0.01), and the correlation coefficient was -0.808 (negative correlation). The correlations of DPR with triglyceride and total cholesterol were significantly negative correlated ( P <0.05), with -0.201 and -0.210 of correlation coefficients, respectively. The remaining indexes did not show any correlation with ALSFRS-R and DPR.
Conclusions 1. Uric acid and creatinine of ALS patients were lower than that in healthy people. Creatine kinase, triglyceride, total cholesterol, HCY, and cystatin C in ALS patients were higher than those in health controls. There were significant metabolic abnormalities in ALS patients.
2. Creatinine level is an independent risk factor affecting ALSFRS-R. The creatinine and total cholesterol levels are also the independent risk factors affecting DPR. Creatinine and total cholesterol levels could be used as reliable indicators to evaluate the ALSFRS-R and DPR of ALS patients.
Aims
Homocysteine has been linked to neurodegeneration and motor function impairments. In the present study, we evaluate the effect of chronic mild hyperhomocysteinemia on the motor behavior (motor coordination, functional performance, and muscular force) and biochemical parameters (oxidative stress, energy metabolism, gene expression and/or protein abundance of cytokine related to the inflammatory pathways and acetylcholinesterase) in the striatum and cerebellum of Wistar male rats.
Main methods
Rodents were submitted to one injection of homocysteine (0.03 μmol Hcy/g of body weight) between 30th and 60th postnatal days twice a day. After hyperhomocysteinemia induction, rats were submitted to horizontal ladder walking, beam balance, suspension, and vertical pole tests and/or euthanized to brain dissection for biochemical and molecular assays.
Key findings
Chronic mild hyperhomocysteinemia did not alter motor function, but induced oxidative stress and impaired mitochondrial complex IV activity in both structures. In the striatum, hyperhomocysteinemia decreased TNF-α gene expression and increased IL-1β gene expression and acetylcholinesterase activity. In the cerebellum, hyperhomocysteinemia increased gene expression of TNF-α, IL-1β, IL-10, and TGF-β, while the acetylcholinesterase activity was decreased. In both structures, hyperhomocysteinemia decreased acetylcholinesterase protein abundance without altering total p-NF-κB, NF-κB, Nrf-2, and cleaved caspase-3.
Significance
Chronic mild hyperhomocysteinemia compromises several biochemical/molecular parameters, signaling pathways, oxidative stress, and chronic inflammation in the striatum and cerebellum of rats without impairing motor function. These alterations may be related to the mechanisms in which hyperhomocysteinemia has been linked to movement disorders later in life and neurodegeneration.
We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age‐related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease.
Abstract
Neurodegenerative diseases are progressive diseases, affecting many people in today. Due to unknown underlying mechanisms, many studies have been carried out about this subject. in this review, folate's role and mechanism of action on the these diseases were investigated. Folate takes place in the single carbon cycle that is necessary for vital methylation reactions in the body and its deficiency causes neurological results has provided connection with neurodegenerative diseases. in many studies, individuals with neurodegenerative diseases have high level of homocysteine level due to low folate level, have been attracteed attention. studies have shown that folate metabolism doesn't have ability to directly generate neurodegenerative diseases, but it pave the way for it's formation and enables it to progress. in this review, it is aimed to explain folate metabolism and it's role in the pathogenesis of neurodegenerative diseases. Folat Metabolizmasının Nörodejeneratif Hastalıklardaki Rolü ÖZ Nörodejeneratif hastalıklar, günümüzde çok sayıda insanı etkileyen, ilerleyici hastalıklardır. Oluşum mekanizmaları tam olarak bilinmediğinden bu konuda birçok çalışma yapılmaktadır. Bu derlemede folat metabolizmasının bu hastalıklar üzerindeki rolü ve etki mekanizmaları incelenmiştir. Folatın vücutta hayati önem taşıyan metilasyon reaksiyonları için gerekli tek karbon döngüsünde yer alması ve eksiliğinin nörolojik sonuçlar oluşturması nörodejeneratif hastalıklar ile bağlantı kurulmasını sağlamıştır. Yapılan birçok çalışmada nörodejeneratif hastalıklara sahip bireylerde folat düzeyinin düşüklüğüne bağlı homosistein seviyesindeki yükseklik dikkat çekmiştir. Yapılan çalışmalar folat metabolizmasının direkt nörodejeneratif hastalık oluşturma yeteneğine sahip olmadığını ancak oluşumuna ortam hazırladığını ve ilerlemesini sağladığını göstermiştir. Bu derlemede folat metabolizmasını ve nörodejeneratif hastalıkların patogenezindeki rolünü kapsamlı bir şekilde açıklamak hedeflenmiştir. Anahtar kelimeler: Folat, folat metabolizması, alzheimer hastalığı, parkinson hastalığı, huntington hastalığı, amyotrofik lateral skleroz hastalığı
Objectives
Homocysteine (Hcy) has been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). Although the CSF Hcy changes were explored in patients with ALS previously, the outcomes were inconsistent, and the permeability of the blood-brain barrier (BBB) may involve in the process. The aim of this study was to investigate the relationship between concentration of Hcy and BBB integrity indicated by CSF/serum albumin ratio (Qalb).MethodsCSF and plasma/serum levels of Hcy, folate, and vitamin B12 and other biochemical biomarkers such as albumin, β2-microglobulin, high sensitive-C reactive protein (hs-CRP), microalbumin, immunoglobulin G (IgG), IgM, IgA, and complement 3 and 4 were analyzed in all 31 ALS patients and 34 controls. Routine CSF analysis including cells/leukocytes count, total protein, glucose, and chlorides were also performed.ResultsCSF Hcy levels (0.50 ± 0.46 vs 0.25 ± 0.27 μmol/L) and Qalb (8.09 ± 3.03 vs 6.39 ± 2.21) were significantly higher in the ALS group than that in controls (P < 0.05). The generalized linear mixed model analysis showed that the CSF Hcy was positively correlated with Qalb in ALS patients (P < 0.05).ConclusionsBBB permeability is increased in ALS patients. CSF Hcy level is associated with BBB integrity. Qalb is a significantly independent predisposing factor for CSF Hcy.
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is an incurable neurodegenerative condition, characterized by the loss of upper and lower motor neurons. It affects 1–1.8/100,000 individuals worldwide, and the number of cases is projected to increase as the population ages. Thus, there is an urgent need to identify both therapeutic targets and disease-specific biomarkers–biomarkers that would be useful to diagnose and stratify patients into different sub-groups for therapeutic strategies, as well as biomarkers to follow the efficacy of any treatment tested during clinical trials. There is a lack of knowledge about pathogenesis and many hypotheses. Numerous “omics” studies have been conducted on ALS in the past decade to identify a disease-signature in tissues and circulating biomarkers. The first goal of the present review was to group the molecular pathways that have been implicated in monogenic forms of ALS, to enable the description of patient strata corresponding to each pathway grouping. This strategy allowed us to suggest 14 strata, each potentially targetable by different pharmacological strategies. The second goal of this review was to identify diagnostic/prognostic biomarker candidates consistently observed across the literature. For this purpose, we explore previous biomarker-relevant “omics” studies of ALS and summarize their findings, focusing on potential circulating biomarker candidates. We systematically review 118 papers on biomarkers published during the last decade. Several candidate markers were consistently shared across the results of different studies in either cerebrospinal fluid (CSF) or blood (leukocyte or serum/plasma). Although these candidates still need to be validated in a systematic manner, we suggest the use of combinations of biomarkers that would likely reflect the “health status” of different tissues, including motor neuron health (e.g., pNFH and NF-L, cystatin C, Transthyretin), inflammation status (e.g., MCP-1, miR451), muscle health (miR-338-3p, miR-206) and metabolism (homocysteine, glutamate, cholesterol). In light of these studies and because ALS is increasingly perceived as a multi-system disease, the identification of a panel of biomarkers that accurately reflect features of pathology is a priority, not only for diagnostic purposes but also for prognostic or predictive applications.
Objective
To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).
Methods
373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset).
Results
No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months’ duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups.
Conclusion
Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.
Trial registration number
NCT00444613 .
La carence en vitamine B12 est fréquente chez les sujets âgés et produit un vieillissement cérébral par des mécanismes malconnus. La vitamine B12 joue un rôle majeur dans les régulations épigénomiques dépendantes de la S-adénosyl méthionine (SAM). Nous avons établi un modèle de cellules neuronales dopaminergiques NIE115 carencé en vitamine B12 par l'expression stable d'une protéine chimère : la transcobalamine-oléosine (TO) réduisant la disponibilité cellulaire en B12, la SAM et la prolifération cellulaire. La protéine chimère oléosine-transcobalamine (OT) ne lie pas la B12 et constitue un contrôle. Les cellules TO ont une diminution B12-dépendante de la déacétylase SIRT1 (sirtuin1) et un stress du réticulum endoplasmique (RE) avec une augmentation des transducteurs transmembranaires, une diminution des protéines chaperonnes et une augmentation des marqueurs pro-apoptotiques. La diminution de l'expression de SIRT1 déclenche le stress du RE en réponse au stress nutritionnel. Cette diminution produit une augmentation de HSF1 acétylé diminuant l'expression des protéines chaperons. L'ajout de B12, des activateurs de SIRT1 et HSF1, la surexpression de SIRT1 et HSF1 réduisent le stress du RE. Dans les cellules contrôles, le traitement par la thapsigargin, l'inhibition de SIRT1 et HSF1 induisent également un stress du RE réversible en présence de B12. Le traitement des cellules OT par Adox (inhibiteur des méthyltransférases) induit les mêmes effets que la carence. En conclusion, la carence en B12 induit un stress du RE via la diminution de SIRT1 et l'augmentation de HSF1 acétylé, l'ajout de B12 induit des effets neuro-protecteurs sur les cellules soumises à un stress du RE. Ces résultats suggèrent d'évaluer les effets des agonistes de SIRT1 sur les complications cérébrales de la carence
Homocysteine (Hcy) has been shown to have a neurotoxic effect on ischemic brain cells; however, the underlying mechanisms remain incompletely understood. Here, we examined whether Hcy treatment influences mitochondria injury, oxidative stress, and mitochondrial STAT3 (mitoStat3) expression in rat ischemic brain. Our results demonstrated that Hcy treatment aggravated the damage of mitochondrial ultrastructure in the brain cortex and the dentate gyrus region of the hippocampus after focal cerebral ischemia. An elevated Hcy level was also accompanied by the significant inhibition of mitochondrial complex I–III enzymatic activities in addition to an increase in cytochrome c release. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) content and mitoStat3 protein phosphorylation level were increased in Hcy-treated animals, whereas AG490, a Jak2 inhibitor, inhibited mitoStat3 phosphorylation as well as 8-OHdG levels induced by Hcy. In vitro studies revealed that Hcy also markedly increased reactive oxygen species (ROS) and mitoStat3 levels. In addition, the inhibition of pSTAT3 reduced Hcy-mediated increase in ROS levels, whereas quenching ROS using the ROS inhibitor glutathione ethyl ester inhibited Hcy-mediated pSTAT3 overactivation in Neuro2a cells. These findings suggest that the development of therapies that interfere with the ROS/pSTAT3 pathway may be helpful for treating cerebral infarction-related diseases associated with Hcy.
Given the severity of their illness and lack of effective disease-modifying agents, it is not surprising that most patients with amyotrophic lateral sclerosis (ALS) consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation, and energy healing. This article reviews these in detail. The authors also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy, and shared decision making. Finally, the authors review a program called ALSUntangled, which uses shared decision making to review alternative therapies for ALS.
High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS.
After initial diagnosis of the disease at the postnatal age of 3-4weeks, wobbler mice received methylcobalamin (3 or 30mg/kg, n=10/group) or vehicle (n=10), daily for 4weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group).
In comparison with vehicle, mice treated with ultra-high dose (30mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle.
Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.
Copyright © 2015. Published by Elsevier B.V.
The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the within-person SD was 0.93 micromol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentrations were inversely related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35) concentrations. Median tHcy concentrations were approximately 1 micromol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetrahydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on single tHcy measurements may underestimate the magnitude of any risk associations with disease by 10-15%.
Excitotoxicity, autoimmunity and free radicals have been postulated to play a role in the pathomechanism of amyotrophic lateral sclerosis (ALS), the most frequent motor neuron disease. Altered calcium homeostasis has already been demonstrated in Cu/Zn superoxide dismutase transgenic animals, suggesting a role for free radicals in the pathogenesis of ALS, and in passive transfer experiments, modeling autoimmunity. These findings also suggested that yet-confined pathogenic insults, associated with ALS, could trigger the disruption of calcium homeostasis of motor neurons. To test the possibility that excitotoxic processes may also be able to increase calcium in motor neurons, we applied the glutamate analogue DL-homocysteic acid to the spinal cord of rats in vivo and analyzed the calcium distribution of the motor neurons over a 24-h survival period by electron microscopy. Initially, an elevated cytoplasmic calcium level, with no morphological sign of degeneration, was noticed. Later, increasing calcium accumulation was seen in different cellular compartments with characteristic features of alteration at different survival times. This calcium accumulation in organelles was paralleled by their progressive degeneration, which culminated in cell death by the end of the observation time. These findings confirm that increased calcium also plays a role in excitotoxic lesion of motor neurons, in line with previous studies documenting the involvement of calcium ions in motor neuronal injury in other models of the disease as well as elevated calcium in biopsy samples from ALS patients. We suggest that intracellular calcium might be responsible for the interplay between the different pathogenic processes resulting in a uniform clinicopathological picture of the disease.
Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.
Hyperhomocysteinemia is an established risk factor for atherosclerosis, thrombosis and other vascular diseases. Homocysteine auto-oxidation is considered to be crucially involved in the pathogenesis of these diseases. However, the question remains to be elucidated whether vitamin deficiency and homocysteine accumulation are causal for disease development or rather comprise a secondary phenomenon. Most diseases accompanied by hyperhomocysteinemia are also associated with ongoing activation of the immune system. In vitro experiments show homocysteine to accumulate in stimulated peripheral blood mononuclear cells. In patients with coronary heart disease, with rheumatoid arthritis and in patients with dementia, an association between cellular immune activation and homocysteine metabolism is found. Homocysteine concentrations not only correlate inversely with folate concentrations, they also show a positive relationship with concentrations of immune activation markers like neopterin. Moreover, in patients with various kinds of dementia, increased concentrations of serum peroxides, homocysteine and neopterin correlate with each other. Studies support a role of immune system activation in the development of hyperhomocysteinemia. Stimulation and proliferation of immune cells may lead to the production of reactive oxygen species that may oxidize antioxidants and oxidation-sensitive B-vitamins. An enhanced demand for antioxidants as well as folate and vitamin B12 may develop, together with hyperhomocysteinemia, despite sufficient dietary intake.
Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor alpha (TNF-alpha) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.
A rapid, isocratic high-performance liquid chromatographic (HPLC) method is described for the determination of total homocysteine levels in human serum. Prior to reversed-phase HPLC analysis, the serum thiols were derivatized with SBD-F (ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulphonate), a thiolspecific fluorogenic probe which is commercially available. Retention of SBD-homocysteine was sensitive to pH, and a mobile phase pH of 2.1 ensured baseline separation of serum thiols within 6 min. The method is simple, sensitive, reproducible (between-run coefficient of variation of 6.6%) and very suitable for routine determination of serum homocysteine levels in a clinical pathology laboratory.
In a previous study, we reported increased NOS expression in the astrocytes in the spinal cord of SOD mutant transgenic mice that are used as ALS animal model. Recently, Messmer and Brune suggested that nitric oxide-induced apoptosis is intimately related with p53-dependent signaling pathway, and de la Monte et al. reported increased p53-immunoreactivity in the spinal cord of ALS patients. In the present study, we performed immunocytochemical studies to investigate the changes of p53-immunoreactivity in the brains of the mutant transgenic mice expressing a human Cu/Zn SOD mutation. Immunocytochemistry showed intensely stained p53-IR glial cells with the appearance of astrocytes in all levels of the spinal cord of the mutant transgenic mice, but no p53-IR glial cells were observed in the spinal cord of the control mice. P53-IR astrocytes were also detected in the brain stem of the mutant transgenic mice. In the medulla, they were observed in the medullary reticular formation, hypoglossal nucleus, vestibular nucleus, dorsal motor nucleus of the vagus and nucleus ambiguus. In the pons, their presences were noted in the pontine reticular formation, and trigeminal and facial nuclei. In the midbrain, astrocytes were detected in the mesencephalic reticular formation, red nucleus and periaqueductal gray matter. In the cerebellum, intensely stained p53-IR astrocytes were detected in the intracerebellar nuclei. In contrast to the mutant transgenic mice, no p53-IR astrocytes were detected in the brain stem and spinal cord of the control mice. Further multidisciplinary investigations involving p53-mediated cellular damage and pathogenesis of ALS are needed to clarify the importance of these results.
Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.
Taken together, impairment, disability and handicap changes define the stages of ALS in a manner similar to the interaction between the Kurtzke Functional Scales and the Kurtzke Expanded Disability Status Scale in multiple sclerosis (MS).20 Further research is required to dissect the relative contributions of impairment, disability and handicap to the clinical state of the patient and, in turn, the effect of this clinical state on the well-being of the patient.
Accurate information on prognosis of ALS is useful to patients, families, and clinicians.
In a population-based study of ALS in western Washington, the authors assembled a cohort of 180 patients with incident ALS between 1990 and 1994. Information on potential prognostic factors was collected during an in-person interview. Patients also completed the Medical Outcomes Study Short Form 36 (SF-36). Vital status through December 1999 was known for all patients.
Median survival was 32 months from onset of symptoms and 19 months from diagnosis. The 5-year survival after diagnosis was 7%. Older age and female sex were strongly associated with poor survival. In multivariable Cox proportional hazards regression models, factors significantly and independently associated with a worse prognosis included older age, any bulbar features at onset, shorter time from symptom onset to diagnosis, lack of a marital partner, and residence in King County. Recursive partitioning identified age, time from symptom onset to diagnosis, and marital status as the strongest predictors of survival. Good summary scores for physical health on the SF-36, but not for mental health, were significantly associated with longer survival than poor scores.
These findings are consistent with other population-based studies of ALS and confirm its pernicious nature. Older age, female sex, any bulbar features at onset, short time from symptom onset to diagnosis, lack of a marital partner, and disease severity are key prognostic factors. Serial measurement of severity would likely improve predictions.
In the present study, we used the transgenic mice expressing a human Cu/Zn SOD mutation (SOD1(G93A)) as an in vivo model of ALS and performed immunohistochemical studies to investigate the changes of homocysteine in the central nervous system of symptomatic transgenic mice. In control and presymptomatic transgenic mice, homocysteine-immunoreactive astrocytes were not detected in any region. In symptomatic transgenic mice, homocysteine-immunoreactive astrocytes were distributed in the spinal cord, brainstem and cerebellar nuclei of transgenic mice. In the hippocampal formation of transgenic mice, pyramidal cells in the CA1-3 regions and granule cells in the dentate gyrus showed homocysteine immunoreactivity. The present study provides the first in vivo evidence that homocysteine immunoreactive astrocytes were found in the central nervous system of symptomatic SOD(G93A) transgenic mice, suggesting that reactive astrocytes may play an important role in the pathogenesis and progress of ALS. This study also suggests that increased expression of homocysteine in the hippocampal neurons might reflect a role of homocysteine in an abnormality of hippocampal function of ALS.
The cytoarchitecture and cellular signaling mechanisms of the nervous system are complex, and this complexity is reflected at the molecular level with more genes being expressed in the nervous system than in any other tissue. Gene expression and protein function in neural cells can be regulated by methylation and acetylation. Studies of mice deficient in enzymes that control DNA methylation and of animals with a dietary deficiency of folate have established critical roles for methylation in development of the nervous system. Various neuronal proteins including histones and tubulin are regulated by acetylation which appears to serve important functions in the development, stability and plasticity of neuronal networks. Some inherited neurological disorders have recently been linked to mutations in genes that regulate DNA methylation, and alterations in DNA and protein methylation and/or acetylation have been documented in studies of age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Manipulations of methylation and acetylation can affect the vulnerability of neurons to degeneration and apoptosis in experimental models of neurodegenerative disorders, suggesting a contribution to altered methylation and acetylation to the disease processes. Interestingly, dietary factors that influence DNA methylation may affect the risk of neurodegenerative disorders, for example, individuals with low dietary folate intake are at increased risk of Alzheimer's and Parkinson's diseases.
We used the SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS) and performed immunohistochemical studies to investigate whether alpha-synuclein is involved in the pathogenesis of ALS. In the spinal cord of transgenic mice, immunohistochemistry showed intense staining of alpha-synuclein mainly in the anterior horn. In the hippocampus of transgenic mice, differential increases in the staining density of alpha-synuclein were observed. In the cerebellar cortex of transgenic mice, the prominent immunostaining of alpha-synuclein was found in the molecular and granular layers. The present study provides the first in vivo evidence that alpha-synuclein immunoreactivity was increased in the central nervous system of SOD(G93A) transgenic mice, suggesting that alpha-synuclein might play an important role in the pathogenesis of ALS. However, the functional implications of these increases require elucidation.
Background:
A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer's disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible.
Recent developments:
A recent prospective study (S Seshadri and colleagues N Engl J Med; 2002 346: 476-83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification. WHERE NEXT? 25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.
About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.
Folate deficiency induces neurotoxicity by multiple routes, including increasing cytosolic calcium and oxidative stress via increasing levels of the neurotoxin homocysteine (HC), and inducing mitochondrial and DNA damage. Because some of these neurotoxic effects overlap with those observed in motor neuron disease, we examined the impact of folate deprivation on dorsal root ganglion (DRG) neurons in culture. Folate deprivation for 2 h increased cytosolic calcium and reactive oxygen species (ROS) and impaired mitochondrial function. Treatment with nimodipine [an L voltage-sensitive calcium channel (LVSCC) antagonist], MK-801 (an NMDA channel antagonist) and thapsigarin (an inhibitor of efflux of calcium from internal stores) indicated that folate deprivation initially induced calcium influx via the LVSCC, with subsequent additional calcium derived from NMDA channels and internal stores. These compounds also reduced ROS and mitochondrial degeneration, indicating that calcium influx contributed to these phenomena. Calcium influx was prevented by co-treatment with 3-deaza-adenosine, which inhibits HC formation, indicating that HC mediated increased cytosolic calcium following folate deprivation. Nimodipine, MK-801 and thapsigargin had similar effects following direct treatment with HC as they did following folate deprivation. These findings support the idea that folate deprivation and HC treatment can compromise the health of DRG neurons by perturbing calcium homeostasis.
Epidemiologic evidence has linked elevation of serum homocysteine to an increased risk of coronary artery disease, stroke, and dementia. An increase in homocysteine levels in Parkinson disease (PD) recently has been discovered. Although B vitamin status and genetic factors are important modifying influences determining the degree of this elevation, the main cause appears to be therapy with L-dopa. It has been suggested that breakdown of L-dopa by catechol-O-methyltransferase results in increased homocysteine formation. Therefore, there are reasons to suggest that management of PD may render patients at increased risk of stroke, heart disease, dementia, and even accelerated nigral degeneration. At present, no controlled prospective studies have evaluated this phenomenon, although they are ongoing.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
- B R Brooks
- R G Miller
- M Swash
- T L Munsat