Batya Swift Yasgur, MA, LSW
September 17, 2020
Investigators at the University of Vienna in Austria explored the hypothesis that the accumulation of iron in the brain is caused by a breakdown of the blood-brain barrier (BBB) attributable to thiamine depletion induced by alcohol consumption.
If the hypothesis proves to be true, it could inform "the emergence of possible new therapeutic approaches in the treatment of cognitive decline in AUD [alcohol use disorder] patients, raising hope for the question of preventing, or at least limiting, the progression of alcohol-related dementia," first author Stephan Listabarth and colleagues write.
The study was published online August 18 in Alzheimer's and Dementia.
A 'Key Stimulus'
"Strong evidence" points to an increase in the burden of dementia that corresponds to increased alcohol consumption, and "presenile cognitive decline is a very common consequence of AUD," the authors note.
The underlying pathophysiologic pathways that may be responsible for the neurodegenerative effects of alcohol are "not fully understood." Some evidence points to the possibility that brain iron overload (BIO) may play a role in cognitive deterioration and that thiamine depletion, which is a "common concomitant feature" of AUD patients, may be a "key stimulus" for BIO, the authors suggest.
To investigate this hypothesis, the authors conducted a literature review. Although they found that the role and significance of BIO in alcohol-related dementia have not been thoroughly researched, they did find studies that examined BIO in other neurodegenerative diseases, as well as studies that point to the consequences of thiamine deficiency.
Iron overload is associated with iron-dependent necrosis, as well as oxidative stress and the activation of microphages. The accumulation of iron and other metals in the brain appears to be associated with the development of Alzheimer's disease by affecting plaque deposit of β-amyloid protein.
In addition, BIO has been implicated in neurodegeneration associated with diseases that involve the accumulation of iron in the brain.
The authors identified one study that utilized fMRI to compare 20 patients with AUD to matched control persons. That study found significant iron accumulation in the brains of AUD patients, particularly in the striatum, globus pallidus, and cerebellar dentate nucleus.
These brain regions are associated with the "strongest age-dependent" iron accumulation in healthy people. The authors describe them as the "hot spots of physiological brain iron accumulation." Even in healthy individuals, "high striatal iron was found to be a predictive biomarker for cognitive decline in normal aging."
Reliable Data Needed
AUD creates a cascade of events that can culminate in cognitive decline or dementia, beginning with thiamine depletion.
The authors note that thiamine deficiency is present in up to 80% of AUD patients. The high-caloric but low-nutrient diet often associated with AUD both increases the demand for thiamine and reduces its gastrointestinal absorption.
Moreover, compromised liver function, common among patients with AUD, impedes the activation of thiamine into its biologically active form (thiamine pyrophosphate).
Animal research shows that thiamine deficiency can lead to a breakdown of the BBB, with ensuing vulnerability of the brain to iron accumulation.
The authors note that in medical conditions not associated with systemic iron overload, such as hereditary hemochromatosis, and that are not accompanied by thiamine depletion, central nervous system symptoms are rare, suggesting that systemic iron overload, in and of itself, does not lead to BOI, presumably because the thiamine at normal levels protects the brain by maintaining a functional BBB.
They recommend several ways to explore their hypothesis, including the collection of "reliable data" to pinpoint the true prevalence of BIO in AUD and its potential connection to cognitive decline, as well as translational studies of the potential underlying physiologic pathways involved in BIO, with particular focus on the role of thiamine.
One plausible approach might be to evaluate the use of chelators to reduce brain iron levels or provide thiamine substitution, the authors suggest.
A 'Good Start'
Commenting on the article for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer's Association, said, "These types of theoretical frameworks really allow or enable the sharing of ideas and other hypotheses of what might be happening in the underlying biology of dementia and cognitive decline.
"This paper underscores the complexities of our brains and what may go on biologically to contribute to cognitive decline a person may be experiencing, and what factors may be going on through their lives to contribute to that," Snyder added.
Also commenting, Thomas Shea, PhD, of the Laboratory for Neuroscience, Department of Biological Sciences, University of Massachusetts, Lowell, Massachusetts, said the analysis "adds to a growing body of literature demonstrating that key deficiencies can contribute to age-related cognitive decline, including that which can accompany dementia."
Shea, who was not involved in the review, noted that although a randomized, placebo-controlled trial would be necessary for definitive conclusions, the current review is "a good start."
Snyder said that people with increased alcohol use, especially over the course of a lifetime, "may have a more unbalanced diet and may not get enough thiamine, which is an essential component of the diet, and that could in turn contribute to biological dysfunction and dysregulation of iron and iron accumulation in the brain."
Shea agreed. "Although it is premature to draw any serious conclusions...these data suggest that a clinician should monitor an individual's levels, and should they be deficient, it would be prudent to suggest supplementation to bring levels within a normal, healthy range," he said.
The research did not receive funding from any agency. The authors and Snyder have disclosed no relevant financial relationships. Shea holds a patent on a neutraceutical formulation to improve or maintain cognitive function in individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease. It is marketed by Sevo Neutraceuticals, but the formulation does not contain thiamine.