Literature Review and Commentary

By Alan R. Gaby, MD

Can Diet Help Prevent Age-Related Cognitive Decline?

The association between long-term intake of vegetables and fruits and late-life subjective cognitive function (SCF) was examined in a prospective cohort study of 27,842 male healthcare professionals (aged 40-75 years; mean age, 51 years at baseline in 1986). Average dietary intake was calculated from food frequency questionnaires collected every four years until 2002. SCF was assessed twice (2008 and 2012) using a six-item questionnaire, and the average of the two scores was categorized as good, moderate, or poor. Higher intakes of total vegetables, total fruits, and fruit juice were each significantly associated with lower odds of having moderate or poor SCF, after adjustment for major non-dietary factors and total energy intake. The association with total fruit intake was weaker after further adjustment for major dietary factors. In this model, the multivariate odds ratio for vegetable intake (top vs. bottom quintile) was 0.83 for moderate SCF (p for trend < 0.001) and 0.66 for poor SCF (p for trend < 0.001). For orange juice, compared with less than one serving per month, daily consumption was associated with a lower odds of poor SCF (0.53; p for trend < 0.001).

Comment: In this study, higher consumption of vegetables, orange juice, and possibly total fruit were each associated with a lower risk of age-related cognitive decline. While observational studies cannot prove causation, a number of nutrients found in vegetables and fruits (such as magnesium and B vitamins) are known to play an important role in cognitive function. In addition, fruits and vegetables contain abundant amounts of beta-carotene. In a randomized controlled trial, supplementation with 50 mg of beta-carotene every other day for 18 years slowed the rate of age-related cognitive decline, compared with placebo, in middle-aged and elderly male physicians.¹ That amount of beta-carotene can be readily obtained by consuming a diet high in vegetables and fruits.

Yuan C, et al. Long-term intake of vegetables and fruits and subjective cognitive function in US men. Neurology. 2019;92:e63-e75.

Is Thiamine Useful for Essential Tremor?

Two patients (aged 73 and 75 years, respectively) with essential tremor and a normal plasma thiamine concentration experienced rapid and marked improvement after beginning treatment with thiamine at a dose of 100 mg intramuscularly twice a week. At the time this report was written, thiamine treatment had been continued for approximately three years, and the improvements were maintained.

Comment: Essential tremor (also called benign tremor or familial tremor) is a slowly progressive disorder characterized by a tremor of the upper extremities and occasionally other parts of the body. A tremor is considered essential if is not associated with known causes such as Parkinson’s disease, vitamin B₁₂ deficiency, hyperthyroidism, stroke, use of certain medications, or consumption of (or withdrawal from) alcohol. Essential tremor is inherited in some cases and occurs randomly in other cases.²

The doctor who wrote this report has also reported that high-dose thiamine (given orally or intramuscularly) is beneficial for a wide range of other neurological conditions, including Parkinson’s disease, spinocerebellar ataxia type 2, Friedreich’s ataxia, myotonic dystrophy, fibromyalgia, and fatigue associated with multiple sclerosis or following a stroke. The patients who improved did not typically have thiamine deficiency before receiving high-dose thiamine. There has been no confirmation from other investigators with regard to most of these clinical observations. Follow-up studies by other research groups would therefore be welcomed.

Costantini A. High-dose thiamine and essential tremor. BMJ Case Rep. 2018;2018:bcr-2017-223945.

Docosahexaenoic Acid for Attention-Deficit/Hyperactivity Disorder

Fifty children (aged 7-14 years) with attention-deficit/hyperactivity disorder (ADHD) who were not taking psychotropic medication were randomly assigned to receive, in double-blind fashion, 500 mg per day of docosahexaenoic acid (DHA) from an algal source or placebo for six months. The primary outcome measure was the change in the ADHD rating scale IV Parent Version-Investigator (ADHD-RS-IV) after four and six months. There was no significant difference between groups with respect to the primary outcome measure. With regard to secondary outcome measures, compared with placebo, there were small but statistically significant positive effects of DHA on psychosocial functioning, emotional problems, and focused attention. No significant side effects were reported.

Comment: Studies on the effect of omega-3 fatty acids (eicosapentaenoic acid [EPA], DHA, or both) in children with ADHD have produced conflicting results. A meta-analysis of 10 randomized controlled trials found that omega-3 fatty acid supplementation resulted in a small but statistically significant improvement of ADHD symptoms.³ The effect of such treatment presumably depends both on the patient’s habitual intake of omega-3 fatty acids (from fish and other sources) and on individual differences in fatty acid metabolism. One study in which the combination of EPA and DHA was ineffective was conducted in Japan, where fish consumption is high and children were probably already consuming abundant amounts of omega-3 fatty acids.⁴ The available evidence suggests that supplementation with DHA or the combination of EPA and DHA may provide modest benefits in children with ADHD, particularly those with low dietary intake of omega-3 fatty acids.

Crippa A, et al. Behavioral and cognitive effects of docosahexaenoic acid in drug-naive children with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial. Eur Child Adolesc Psychiatry. 2019;28::571-583.

High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis

Three hundred seventy-three patients with definite or probable amyotrophic lateral sclerosis (ALS), with disease duration of 36 months or less were randomly assigned to receive placebo or 25 or 50 mg of methylcobalamin intramuscularly twice a week for 3.5 years. The study was apparently single-blind, and the injections were given in such a way that the patients and their caregivers could not see the red color of the active treatment. The primary endpoints were the time to the composite outcome of death or full ventilation support, and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to the end of the trial. Two hundred sixty patients completed the trial. There was a nonsignificant trend toward a beneficial effect of both doses of methylcobalamin for each of the two primary endpoints. In post hoc analysis, when considering only those patients who had been diagnosed early (i.e., they entered the study 12 months or less after the onset of symptoms), methylcobalamin-treated patients had a longer median time to the primary event (p < 0.025) and less decrease in the median ALSFRS-R score (p < 0.025), compared with those who received placebo. No significant adverse effects were observed.

Comment: These results suggest that high-dose vitamin B₁₂ in the form of methylcobalamin may prolong survival and slow disease progression in patients in the early stages (but not the later stages) of amyotrophic lateral sclerosis. The mechanism of action is not known, although vitamin B₁₂ is known to play an important role in the functioning of the brain and central nervous system.

Kaji R, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry. 2019;90:451-457.

N-Acetylcysteine and Bipolar Disorder

Eighty patients with bipolar disorder (type I or II) with a current depressive episode lasting at least four weeks, who were being treated with antidepressants, antipsychotics, and/or other psychotropic medication were randomly assigned to receive, in double-blind fashion, 1.5 g of N-acetylcysteine (NAC) twice a day or placebo for 20 weeks. The primary outcome measure was the change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment period. The mean MADRS score at baseline was 30.1 and 28.8 in the NAC and placebo groups, respectively. The mean decrease in the MADRS score at 20 weeks was 13.8 in the NAC group and 13.2 in the placebo group (p = 0.88 for the difference in the change between groups).

Comment: This study failed to confirm the results of a previous trial conducted by the same research group, in which NAC given as an adjunct to conventional medication improved symptoms of depression in patients with bipolar disorder.⁵ The conflicting results might be explainable at least in part by the large placebo response in the present study. In the earlier study, the MADRS score decreased in the placebo group by 21%, as compared with a 55.6% decrease in the present study. A large placebo response in the new study may have made it difficult for the active treatment to demonstrate efficacy.

Ellegaard PK, et al. The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study. J Affect Disord. 2019;245:1043-1051.

Acetyl-L-Carnitine for Dementia Associated with Cerebrovascular Disease

Fifty-six Korean patients (mean age, 73 years) with dementia associated with cerebrovascular disease were randomly assigned to receive, in double-blind fashion, 500 mg of acetyl-L-carnitine (ALC) three times per day or placebo for 28 weeks. The primary outcome measure was the Korean version of Montreal Cognitive Assessment (MoCA-K). The mean MoCA-K score increased (improved) from 17.3 to 17.6 in the ALC group and decreased from 16.7 to 15.9 in the placebo group (p = 0.01 for the difference in the change between groups). ALC was well tolerated.

Comment: ALC is structurally similar to acetylcholine and functions as a cholinergic neurotransmitter. In addition, as a source of L-carnitine, ALC may help prevent the decline in brain mitochondrial function that typically occurs with age. In studies in rodents, ALC counteracted the age-related decrease of several receptors in the central nervous system. In randomized controlled trials, administration of ALC in doses of 1.5 g to 3.0 g per day for periods of six weeks to 12 months improved various measures of cognitive function in elderly people with mild-to-moderate age-related cognitive decline.⁶ ALC has also been reported in double-blind trials to slow the deterioration of mental function in patients with Alzheimer’s disease.^{7 8 9} The results of the present study indicate that ALC can also prevent the progression of dementia associated with cerebrovascular disease.

Yang Y, et al. A multicenter, randomized, double-blind, placebo-controlled clinical trial for efficacy of acetyl-L-carnitine in patients with dementia associated with cerebrovascular disease. Dement Neurocogn Disord. 2018;17:1-10.

Acetyl-L-Carnitine for Carpal Tunnel Syndrome

Eighty-two patients with carpal tunnel syndrome of mild-to-moderate severity in a total of 120 hands received acetyl-L-carnitine (ALC) for 120 days (500 mg twice a day intramuscularly for 10 days followed by the same dose orally for 110 days). Seventy-three patients completed the trial. Compared with baseline, a significant improvement was seen in the mean sensory conduction velocity of the median nerve and in symptoms as assessed by the Boston Carpal Tunnel Questionnaire (p < 0.0001 for each). A significant improvement was also seen in nine measures of pain as assessed by the Neuropathic Pain Symptom Inventory (p < 0.0001).

Comment: ALC is known to exert a neuroprotective effect in patients with various types of peripheral neuropathy. ALC has also been shown in animal studies to have an anti-nociceptive effect (i.e., it blocks the perception of pain by sensory neurons). In the present study, treatment with ALC was associated with both subjective and objective improvement in patients with carpal tunnel syndrome. Controlled trials are needed to rule out the possibility of a placebo effect.

Cruccu G, et al. L-Acetyl-carnitine in patients with carpal tunnel syndrome: effects on nerve protection, hand function and pain. CNS Drugs. 2017;31:1103-1111.

Coenzyme Q10 for Nephrotic Syndrome

A four-year-old girl was diagnosed with glomerulopathy (proteinuria with hypercholesterolemia) at two years of age. Treatment with glucocorticoids produced no improvement, and subsequent treatment with cyclosporine A resulted in only partial remission. She was found to have a mutation in a coenzyme Q complex gene (a CoQ6 defect). Previously described patients with this mutation typically had sensorineural deafness and various neurologic abnormalities in addition to progressive steroid-resistant nephrotic syndrome, and almost half of them died in early childhood. This patient in this report did not have any of those manifestations. She was treated with coenzyme Q10 at a dose of 30 mg per kg of body weight per day. Within one month she was in complete remission, which enabled reduction and discontinuation of cyclosporine A over a three-month period.

Comment: Mutations of various CoQ genes are associated with steroid-resistant nephrotic syndrome, with or without neurologic or other manifestations. The dramatic response to coenzyme Q10 in the present report raises the possibility that other patients with steroid-resistant nephrotic syndrome have an unrecognized defect of a CoQ gene. The authors of this report suggested that practitioners should consider genetic testing and/or an empirical trial of coenzyme Q10 supplementation in all patients with steroid-resistant nephrotic syndrome, regardless of whether or not they have other manifestations of a defective CoQ gene.

Stanczyk M, et al. CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy – a case report. Pediatr Nephrol. 2018;33:2383-2387.