vitamin-b-12 and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials.. In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS.. Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.

Topics: Amyotrophic Lateral Sclerosis; Biomarkers; Clinical Trials as Topic; Frontotemporal Dementia; Humans; Hydroxylamines; Memantine; Neuroprotective Agents; Riluzole; Superoxide Dismutase; Vitamin B 12

Topics: Amyotrophic Lateral Sclerosis; Disease Progression; Early Medical Intervention; Humans; Palliative Care; Treatment Outcome; Vitamin B 12; Vitamin B Complex

Vitamin B(12)(vB(12)) deficient is regarded as iatrogenic in some cases. Although the recommended oral intake of vB(12) has been determined, administration of vB(12) exceeding the recommended dose could have multiple pharmacological effects. "Ultra-high dose" vB(12) therapy has been used for peripheral neuropathy and amyotrophic lateral sclerosis, suggesting its promising neuroprotective effects.

Topics: Amyotrophic Lateral Sclerosis; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Peripheral Nervous System Diseases; Treatment Outcome; Vitamin B 12

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Weakness may begin in the legs, hands, proximal arms, or pharynx. The course is relentless and progressive without remissions, relapses, or even stable plateaus. There is no effective drug therapy for ALS, although riluzole has been shown to prolong life in sufferers, without tracheostomy. A vitamin B12 analog, methylcobalamin, has a protective effect on cultured cortical neurons against glutamate-induced cytotoxicity. We have shown the ultra-high-dose methylcobalamin (25 mg/day i.m.) slows down the progressive reduction of the CMAP (compound muscle action potential) amplitudes in ALS in the short term (4 weeks). The latencies of SSR (sympathetic skin response) were shorter after treatment (50 mg/day i.v., 2 weeks). In the long-term effect of methylcobalamin (50 mg/day i.m., twice a week), the survival time (or the period to become respirator-bound) was significantly longer in the treated group than in the untreated. Larger-scale randomized double blind trial was started in Japan in order to evaluate the long-term efficacy and the safety of ultra-high-dose methylcobalamin for sporadic or familial cases of ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Progression; Double-Blind Method; Glutamic Acid; Humans; Pulse Therapy, Drug; Randomized Controlled Trials as Topic; Rats; Time Factors; Vitamin B 12

Controversy regarding amyotrophic lateral sclerosis (ALS) concerns aspects of relatively little consequence (such as the role of lead intoxication or trauma in the pathogenesis of the disease) and others of greater relevance, particularly the two following questions regarding treatment options: 1) Are we in a new era of therapy for ALS? Prior to the 1990's no controlled study showed consistent benefit from any of the treatments tried. We have now had announcements of benefit for four entirely different agents: riluzole, insulin-like growth hormone, brain derived neurotrophic hormone and gabapentin. The benefit, at most, is marginal or questionable. The effect is of statistical significance but of little clinical relevance, and 2) what is the role of peripheral nerves in ALS? The syndrome of multifocal motor neuropathy and conduction block (MMNCB) shares some clinical data (active tendon jerks in weak, wasted and fasciculating muscles) and pathological features (anterior horn cell loss and glions) with "typical" ALS. This is relevant because MMNCB is reversible with immunoglobulin therapy. The rigid separation between ALS (a disease of the motor neuron perikaryon) and MMNCB (a disease of the motor neuron axon) is no longer tenable.

Topics: Amyotrophic Lateral Sclerosis; Chelation Therapy; Humans; Peripheral Nerves; Thiamine; Venoms; Vitamin B 12

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.. To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset.. 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.. Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks.. The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.. 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.. 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.. ClinicalTrials.gov Identifier: NCT03548311.

Topics: Amyotrophic Lateral Sclerosis; Double-Blind Method; Humans; Male; Middle Aged; Treatment Outcome; Vital Capacity; Vitamin B 12

High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.

Topics: Amyotrophic Lateral Sclerosis; Double-Blind Method; Humans; Japan; Prospective Studies; Vitamin B 12

To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).. 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).. 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.. 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.. NCT00444613.

Topics: Aged; Amyotrophic Lateral Sclerosis; Double-Blind Method; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Respiration, Artificial; Survival Rate; Vitamin B 12

To develop a symptomatic treatment for amyotrophic lateral sclerosis, we compared the effects of ultrahigh-dose and low-dose (25 and 0.5 mg/day, intramuscularly, for 14 days) methylcobalamin on averaged compound muscle action potential amplitudes (CMAPs) in a double-blind trial. No significant changes in CMAP amplitude were found in 12 patients who had the low-dose treatment at either 2 or 4 weeks after start of treatment. By contrast, 12 patients assigned to the ultrahigh-dose group demonstrated a significant increase at 4 weeks. This method may provide a clinically useful measure to improve or retard muscle wasting, if a larger extended trial fulfills its promise.

Topics: Action Potentials; Adult; Aged; Amyotrophic Lateral Sclerosis; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Treatment Outcome; Vitamin B 12

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 (Q. CSF Hcy levels (0.50 ± 0.46 vs 0.25 ± 0.27 μmol/L) and Q. BBB permeability is increased in ALS patients. CSF Hcy level is associated with BBB integrity. Q

Topics: Amyotrophic Lateral Sclerosis; Blood-Brain Barrier; Folic Acid; Homocysteine; Humans; Vitamin B 12

Topics: Amyotrophic Lateral Sclerosis; Humans; Motor Neurons; Vitamin B 12

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 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks 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 (30 mg/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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Muscle Strength; Neuroprotective Agents; Vitamin B 12

We have previously demonstrated that the concentration of normal prion proteins (PrP(C)) is increased in the serum and cerebrospinal fluid (CSF) of rats deficient in vitamin B(12) (cobalamin, Cbl). In this study, we investigated whether similar increases also occur in the serum and CSF of patients deficient in Cbl (Cbl-D), and whether the increase in serum levels can be corrected by Cbl therapy. The study involved two sample populations. The first consisted of 45 patients (13 patients with pernicious anemia [PA], 19 with other forms of anemia, and 13 healthy controls); and the second, 68 patients (five with subacute combined degeneration [SCD], 18 with amyotrophic lateral sclerosis, 22 with multiple sclerosis [MS], and 23 neurological controls). Serum PrP(C) levels were measured using an enzyme-linked-immunosorbent-assay before as well as after Cbl therapy. The mean serum PrP(C) levels in patients with PA were significantly higher than those of the controls (p=0.0017) but normalized after Cbl therapy; there was no significant change in the patients with other forms of anemia. Mean CSF PrP(C) levels in the patients with SCD were significantly higher than in the neurological controls (p<0.03). The serum and CSF PrP(C) levels of patients with PA and those with SCD were correlated significantly with serum (p=0.004) and CSF (p=0.0018) Cbl levels. In patients with MS, CSF PrP(C) concentrations were significantly lower than those of the controls regardless of their CSF Cbl levels. We found a correlation between Cbl and PrP(C) levels in the serum and CSF of Cbl-D patients, which suggests that Cbl may regulate the PrP(C) levels in the serum and CSF in humans.

Topics: Adult; Amyotrophic Lateral Sclerosis; Analysis of Variance; beta-Thalassemia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Neurologic Examination; Prions; Statistics as Topic; Subacute Combined Degeneration; Vitamin B 12; Vitamin B Complex

To investigate the relationship between plasma level of homocysteine (Hcy) and amyotrophic lateral sclerosis (ALS).. The differences of Hcy, Vitamin B(12), and folate levels between 150 outpatients with ALS and 137 age and sex matched controls were compared in a cross-sectional study.. Compared with the healthy controls, patients with ALS had a higher plasma Hcy level [(18.47 ± 13.09) µmol/L vs (11.91 ± 5.37) µmol/L, P < 0.001] and a lower folate level [(8.39 ± 4.45) ng/ml vs (10.38 ± 5.01) ng/ml, P < 0.001]. In a logistic regression model using ALS as a dependent variable, plasma level of Hcy was significantly associated with ALS. A trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI) was also found [Hcy levels (20.73 ± 15.79) µmol/L with ODI < 19 months vs (16.41 ± 9.73) µmol/L with ODI ≥ 19 months, P = 0.035].. Plasma Hcy level is significantly increased in patients with ALS. The individuals with shorter time to diagnosis present higher Hcy level, suggesting that it may associate with the progression pace of ALS.

Topics: Adult; Amyotrophic Lateral Sclerosis; Case-Control Studies; Female; Folic Acid; Homocysteine; Humans; Male; Middle Aged; Vitamin B 12

Increasing evidence suggests that elevated levels of homocysteine (Hcy) and methylmalonate (MMA) may be involved in the pathogenesis of neurodegenerative diseases.. The urine levels of MMA and serum levels of Hcy as well as folic acid and vitamin B(12) were measured in patients suffering from the distinct neurodegenerative diseases progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), and compared to age- and gender-matched control subjects.. We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8, ALS 13.9, control 11.2 micromol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7, control 1.8 mg/g) in all patient groups in comparison with controls. Levels of Hcy and MMA did not differ significantly between the neurodegenerative diseases.. Our findings might imply that Hcy and MMA are released as a consequence of neurodegeneration regardless of the underlying cause and serve as surrogate markers of neurodegeneration. Alternatively they might be directly implicated in the pathogenesis of these diseases. Since elevated levels of both Hcy and MMA are neurotoxic, further studies might investigate the effect of vitamin therapy on disease progression.

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Case-Control Studies; Female; Folic Acid; Homocysteine; Humans; Male; Matched-Pair Analysis; Methylmalonic Acid; Middle Aged; Parkinson Disease; Reference Values; Supranuclear Palsy, Progressive; Vitamin B 12

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.

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Biomarkers; Central Nervous System; Comorbidity; Cross-Sectional Studies; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Male; Middle Aged; Nerve Degeneration; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity; Up-Regulation; Vitamin B 12

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.

Topics: Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Folic Acid; Gas Chromatography-Mass Spectrometry; Homocysteine; Inflammation; Mice; Mice, Transgenic; Motor Neurons; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rotarod Performance Test; Spinal Cord; Superoxide Dismutase; Vitamin B 12; Vitamin B Complex

High serum vitamin B12 concentrations have been reported in patients with hepatic disease, disseminated neoplasia, myeloproliferative disorders, and hypereosinophilic syndromes. We recently discovered an extraordinarily increased vitamin B12 concentration in a patient without these underlying conditions.. Affinity and size-exclusion chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and ELISA methods were used to determine the cause of the increased vitamin B12 concentrations in this patient's serum.. The protein G column eluates from 2 apparently healthy volunteers and 2 patients with recent vitamin B12 treatment for anemia had vitamin B12 concentrations of <74 pmol/L, whereas the vitamin B12 concentration in the protein G column eluate from the patient was 7380 pmol/L. The elution profile from size-exclusion chromatography of vitamin B12-binding proteins in the patient's serum revealed an abnormal vitamin-B12-binding protein. SDS-PAGE analysis of the concentrated eluates from the protein G column, under reducing conditions, revealed an additional band with an apparent molecular mass of 76 kDa, which was not present in control column eluates. MALDI-TOF MS identified this band as an IgM heavy chain. By use of a modified ELISA, we determined that the IgM present in the patient's eluates was associated with the IgG to form IgG-IgM immune complexes.. This case demonstrates the unusual circumstance of a patient with markedly increased vitamin B12 concentrations attributed to immune complexes composed of IgG, IgM, and vitamin B12 and illustrates techniques that can be used to identify this occurrence.

Topics: Amyotrophic Lateral Sclerosis; Antibodies, Blocking; Antibodies, Heterophile; Antigen-Antibody Complex; Chromatography; Clinical Laboratory Techniques; Dementia; False Positive Reactions; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Vitamin B 12

Topics: Amyotrophic Lateral Sclerosis; Catatonia; Erectile Dysfunction; Fatigue; Hemiplegia; Humans; Male; Mental Disorders; Neuritis; Paralysis; Spinal Cord; Thiamine; Trigeminal Neuralgia; Vitamin B 12; Vitamin B Complex

Topics: Amyotrophic Lateral Sclerosis; Corrinoids; Hematinics; Humans; Sclerosis; Vitamin B 12

Topics: Amyotrophic Lateral Sclerosis; Corrinoids; Hematinics; Humans; Sclerosis; Vitamin B 12; Vitamin B Complex