Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.

BACKGROUND AND OBJECTIVES: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS. METHODS: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival. RESULTS: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up. DISCUSSION: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

Neuroprotective agents target molecular mechanisms of disease in ALS.

Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review neuroprotective agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure-activity relationships, with the overall goal of creating a screening strategy for further clinical application.

Biochemical alterations associated with ALS.

Our objective was to identify metabolic pathways affected by ALS using non-targeted metabolomics in plasma, comparing samples from healthy volunteers to those from ALS patients. This discovery could become the basis for the identification of therapeutic targets and diagnostic biomarkers of ALS. Two distinct cross-sectional studies were conducted. Plasma was collected from 62 (Study 1) and 99 (Study 2) participants meeting El Escorial criteria for possible, probable, or definite ALS; 69 (Study 1) and 48 (Study 2) healthy controls samples were collected. Global metabolic profiling was used to detect and evaluate biochemical signatures of ALS. Twenty-three metabolites were significantly altered in plasma from ALS patients in both studies. These metabolites include biochemicals in pathways associated with neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction, all of which are proposed disease mechanisms in ALS. The data also suggest possible hepatic dysfunction associated with ALS. In conclusion, the data presented here provide insight into the pathophysiology of ALS while suggesting promising areas of focus for future studies. The metabolomics approach can generate novel hypotheses regarding ALS disease mechanisms with the potential to identify therapeutic targets and novel diagnostic biomarkers.

A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis.

Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations.

Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects.

Coenzyme Q10 (CoQ(10)), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntington's disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ(10) dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ(10) in HD and healthy subjects. Twenty-eight subjects (20 HD, 8 healthy) enrolled in a 20-week open-label trial. Subjects started on 1,200 mg/day of CoQ(10), increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ(10) blood levels. Twenty-three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ(10). The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 µg/mL (baseline, n = 28), 5.59 ± 2.24 µg/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 µg/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 µg/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36 µg/mL (3,600 mg/day, week 20, n = 20). CoQ(10) was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned.

Arimoclomol: a potential therapy under development for ALS.

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.

Vitamin E intake and risk of amyotrophic lateral sclerosis.

Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.