Benfotiamine

Literature Review and Commentary

By Alan R. Gaby, MD

Does Aluminum Cause Alzheimer’s Disease?

The authors of this study previously developed a method for non-invasive measurement of bone aluminum concentrations using an in vivo neutron activation analysis technique. Among 15 patients (mean age, 80.2 years) with mild-to-moderate Alzheimer’s disease, the mean aluminum concentration in bone was 12.5 µg per g of calcium, as compared with 2.7 µg/g (p = 0.02) in 15 control subjects (mean age, 75 years). The mean serum aluminum concentration was nonsignificantly higher by 5% in the patients than in the controls. Although the ratio of aluminum to calcium in bone increased with increasing age, the older age of the patients appeared to account for only a very small proportion of the difference in aluminum-to-calcium ratio between groups.

Comment: Several lines of evidence suggest that aluminum exposure contributes to the pathogenesis of Alzheimer’s disease.¹ In some, but not all, studies aluminum concentrations in brain tissue were significantly higher in patients with Alzheimer’s disease than in healthy controls and patients with other types of senile dementia (alcoholic, vascular, or multi-infarct). In patients with Alzheimer’s disease, foci of aluminum were found in a high proportion of neurons that contained neurofibrillary tangles (a pathological change in the brain that is associated with Alzheimer’s disease). In observational studies, higher dietary aluminum intake or higher aluminum concentrations in drinking water were associated with increased risk of developing Alzheimer’s disease. In addition, injection of aluminum into the brain of rabbits produced neurofibrillary tangles in cerebral neurons. Moreover, treatment with the aluminum-chelating drug, deferoxamine, significantly decreased the rate of functional deterioration in patients with Alzheimer’s disease.

In the present study, the aluminum-to-calcium ratio in bone was significantly higher in patients with Alzheimer’s disease than in controls, whereas serum aluminum levels did not differ significantly between groups. Since bone is a major storage site for aluminum (whereas only small amounts are found in serum), the results of this study support previous evidence that aluminum exposure is associated with an increased risk of Alzheimer’s disease.

Sources of aluminum exposure include beverage cans; aluminum cookware; municipal water supplies that add aluminum compounds to help remove particulate matter; food additives present in processed cheese, baking powder, and other foods; and aluminum-containing antacids and antiperspirants

Mohseni HK, et al. A pilot study measuring aluminum in bone in Alzheimer’s disease and control subjects using in vivo neutron activation analysis. J Alzheimers Dis. 2016;53:933-942.

Thiamine Derivative Possibly Beneficial for Alzheimer’s Disease

Five Chinese patients with mild-to-moderate Alzheimer’s disease received 300 mg per day of benfotiamine for 18 months. All patients showed improvements in cognitive function, as determined by the Mini-Mental Status Examination (MMSE), with an average increase of 3.2 points at month 18 (from 17.0 to 20.2). The maximum score on the MMSE is 30, with 24-30 indicating normal cognitive function, 19-23 indicating mild cognitive impairment, and 10-18 indicating moderate cognitive impairment.

Comment: Benfotiamine (S-benzoylthiamine-O-monophosphate) is a lipid-soluble derivative of thiamine that has been reported to be more bioavailable than water-soluble thiamine. This compound has been used with some success to treat diabetic neuropathy. The results of the present study suggest that benfotiamine can produce modest improvement in cognitive function in patients with mild-to-moderate Alzheimer’s disease. Controlled trials are needed to rule out the possibility of a placebo effect.

Pan X, et al. Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer’s disease. Neurosci Bull. 2016;32:591-596.

Vitamin B₁₂ Deficiency and Neurological Symptoms in Infants

Vitamin B₁₂ status was assessed in 121 infants in Sweden who were hospitalized between 2004 and 2012 with severe neurological symptoms at less than one year of age. Vitamin B₁₂ deficiency was defined as low serum cobalamin and/or increased homocysteine and/or increased methylmalonic acid levels. Infants found to be deficient received vitamin B₁₂ replacement therapy. Thirty-five infants (29%) had vitamin B₁₂ deficiency, which was diagnosed at an average age of 1.7 months. Seizures, apnea, and other apparent life-threatening events were common symptoms. After vitamin B₁₂ replacement therapy, neurological development was normal.

Comment: The results of this study demonstrate that vitamin B₁₂ deficiency is common in infants presenting with severe neurological symptoms such as seizures and apparent life-threatening events, and that these abnormalities can be corrected by vitamin B₁₂ supplementation. While an elevated homocysteine level in adults indicates folate deficiency more often than vitamin B₁₂ deficiency, a high homocysteine level in infants has been found in most cases to be due to vitamin B₁₂ deficiency. In a previous study, 81 of 105 children presenting with feeding difficulties, subtle neurologic signs, or delayed psychomotor development had an elevated plasma homocysteine concentration. Seventy-nine of the 81 infants thought to have vitamin B₁₂ deficiency were randomly assigned to receive, in double-blind fashion, a single intramuscular injection of hydroxocobalamin (400 µg) or a sham injection (placebo). The median improvement in motor function (as determined by the Alberta Infants Motor Scale) was significantly greater in the vitamin B₁₂ group than in the placebo group. In addition, a higher proportion of infants in the B₁₂ group than in the placebo group showed improvement in regurgitations (69% vs. 29%; p = 0.003).² Vitamin B₁₂ deficiency should therefore be considered in the differential diagnosis of both severe and mild neurological and developmental abnormalities in infants.

Irevall T, et al. B12 deficiency is common in infants and is accompanied by serious neurological symptoms. Acta Paediatr. 2017;106:101-104.

Omega-3 Fatty Acids for Age-Related Cognitive Decline

Two hundred forty Chinese individuals (mean age, 74.5 years) with mild cognitive impairment were randomly assigned to receive, in double-blind fashion, 2 g per day of docosahexaenoic acid (DHA) or placebo (corn oil) for 12 months. Compared with placebo, DHA significantly improved scores in the Full-Scale Intelligence Quotient, Digit Span, and other measures of cognitive function, and significantly decreased the loss of hippocampal volume (as determined by MRI).

Comment: Omega-3 fatty acids (i.e., eicosapentaenoic acid [EPA] and DHA) play a role in normal brain function. In the present study, supplementation with DHA prevented the deterioration of cognitive function and slowed the progression of hippocampal atrophy in elderly Chinese individuals with mild cognitive impairment. Some previous studies using DHA or the combination of DHA and EPA found results similar to those of the current study. In other research, however, these omega-3 fatty acids did not slow the progression of age-related cognitive decline. Further research is needed to determine which patients are most likely to benefit from DHA or fish oil. However, considering the other reported benefits of DHA/EPA (e.g., anti-inflammatory and cardioprotective effects), it would be reasonable to include these fatty acids as part of a comprehensive treatment plan for patients with mild cognitive impairment.

Zhang YP, et al. Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with mild cognitive impairment: a 12-month randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2017;55:497-507.

N-Acetylcysteine for Substance Abuse Associated with Posttraumatic Stress Disorder

Thirty-five military veterans (34 male; mean age, 49 years) with the combination of substance use disorder (SUD) and posttraumatic stress disorder (PTSD) were randomly assigned to receive, in double-blind fashion, 2,400 mg per day of N-acetylcysteine (NAC) or placebo for eight weeks. All patients received cognitive-behavioral therapy for SUD. Twenty-seven patients (77%) completed the trial. Mean severity of PTSD symptoms improved to a significantly greater extent with NAC than with placebo (32% vs. 3%; p < 0.05). Mean amount of drug craving also improved to a significantly greater extent with NAC than with placebo (81% vs. 32%; p < 0.05). However, alcohol and drug use did not differ significantly between groups.

Comment: Glutamate synapses in the nucleus accumbens region of the brain are involved in both PTSD and SUD, which are conditions that frequently occur together. The presence of a subnormal concentration of glutamate in the nucleus accumbens may increase compulsive or addictive behaviors and heighten cravings. Treatment with NAC has been shown to increase glutamate concentrations in the nucleus accumbens, and NAC has been used successfully to treat addictions to tobacco, marijuana, and gambling. The results of the present study suggest that NAC, when used in combination with psychotherapy, is also beneficial in the treatment of PTSD coexisting with SUD.

Back SE, et al. A double-blind, randomized, controlled pilot trial of N-acetylcysteine in Veterans with posttraumatic stress disorder and substance use disorders. J Clin Psychiatry. 2016;77:e1439-e1446.

Magnesium Deficiency and Depression

Sixty Iranian patients (mean age, 32 years) with depression and hypomagnesemia (serum magnesium < 1.8 mg/dl) were randomly assigned to receive, in double-blind fashion, 500 mg per day of magnesium oxide or placebo for eight weeks. At the end of the trial, serum magnesium was normal in 88.5% of the patients in the magnesium group and in 48.1% of those in the placebo group. The mean percent improvement in the Beck Depression Inventory-II score was significantly greater in the magnesium group than in the placebo group (62% vs. 41%; p = 0.02).

Comment: Depression is one of the known manifestations of magnesium deficiency. The results of the present study confirm previous observations that magnesium supplementation can improve symptoms of depression in patients with hypomagnesemia. Magnesium is primarily an intracellular ion, and a normal serum magnesium concentration does not rule out magnesium deficiency. The gold standard for assessing magnesium status is an intravenous magnesium load test, which involves intravenous administration of magnesium followed by the measurement of magnesium output in a 24-hour urine sample. This test is cumbersome and is rarely performed in clinical practice. Red blood cell and white blood cell magnesium levels do not appear to be reliable indicators of magnesium status. Risk factors for magnesium deficiency include excessive alcohol intake; use of thiazide diuretics, loop diuretics, or proton pump inhibitors; diseases that cause malabsorption or malnutrition; and chronic stress. Considering the difficulty of identifying mild-to-moderate magnesium deficiency with standard laboratory tests, a trial of magnesium supplementation would be reasonable for depressed patients with risk factors for magnesium deficiency, even if the serum magnesium concentration is normal.

Rajizadeh A, et al. Effect of magnesium supplementation on depression status in depressed patients with magnesium deficiency: A randomized, double-blind, placebo-controlled trial. Nutrition. 2017;35:56-60.

Vitamin D for Restless Legs Syndrome

The median serum 25-hydroxyvitamin D level in 12 Saudi Arabian adults (mean age, 38 years) with restless legs syndrome was 8.7 ng/ml (range, 5.4-23 ng/ml). Patients with a 25-hydroxyvitamin D level below 20 ng/ml were treated with oral vitamin D (28,000 IU per week) or parenteral vitamin D (200,000 IU per month) for three-to-eight months, until the 25-hydroxyvitamin D level became normal. The mean severity of restless legs syndrome improved by 62%.

Comment: The results of this study suggest that vitamin D supplementation can improve symptoms of restless legs syndrome in people with very low serum 25-hydroxyvitamin D levels. Controlled trials are needed to rule out a placebo effect. In addition, further research is needed to determine whether vitamin D supplementation would be beneficial for individuals with moderately low or normal 25-hydroxyvitamin D levels.

Wali S, et al. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath. 2015;19:579-583.

Probiotic Improves Gingivitis During Pregnancy

Forty-five women with gingivitis in the third trimester of pregnancy were randomly assigned to receive, in double-blind fashion, one probiotic lozenge or one placebo lozenge twice a day until delivery (approximately seven weeks of treatment). Each probiotic lozenge (Prodentis; BioGaia AB, Lund, Sweden) contained at least 10⁸ colony-forming units each of Lactobacillus reuteri ATCC PTA 5289 and L. reuteri DSM 17938. At baseline, the mean Gingival Index and mean Plaque Index did not differ significantly between groups. At reevaluation within two days after delivery, both of these parameters were significantly lower (better) in the probiotic group than in the placebo group (p < 0.0001 for each comparison). The mean improvement in the Gingival Index was 80% in the probiotic group and 22% in the placebo group. The mean improvement in the Plaque Index was 71% in the probiotic group 25% in the placebo group.

Comment: In this study, treatment with lozenges containing a proprietary blend of two strains of L. reuteri improved pregnancy-associated gingivitis. The product used in this study is apparently not sold in the United States, although vendors on sites such as Amazon and eBay offer to ship it from other countries to the U.S. L. reuteri DSM 17938 is sold in the US under the name Gerber Soothe Colic Drops. It is not known whether this strain would be effective against gingivitis when used alone, but L. reuteri DSM 17938 has been found in controlled trials to be useful for preventing and treating infantile colic and for preventing dental caries in children.

Schlagenhauf U, et al. Regular consumption of Lactobacillus reuteri-containing lozenges reduces pregnancy gingivitis: an RCT. J Clin Periodontol. 2016;43:948-954.