Causes, consequences and clinical implications of alcohol-related brain shrinkage

Previous studies have demonstrated that the brains of alcoholics are smaller, lighter and "shrunken" when compared to nonalcoholic brains.

Symposium speakers at the October 2004 Congress for the International Society for Biomedical Research on Alcoholism in Mannheim, Germany reviewed what is known about the causes, consequences and clinical implications of alcohol-related brain shrinkage. Proceedings are published in the June issue of Alcoholism: Clinical & Experimental Research.

"The outer layer of brain, also called the cerebral cortex or gray matter, controls most complex mental activities," explained Clive Harper, symposium organizer and professor of neuropathology at the University of Sydney and Royal Prince Alfred Hospital. "The cortex is filled with nerve cells, also called neurons, that connect by single long fibres to different cortical regions and other neurons deep inside the brain and spinal cord. These nerve fibres make up white matter, which comprises the 'hard wiring' of the brain. Most of the fibres are insulated by a material called 'myelin' that is similar to the plastic coating around electrical wires. Nerve cells also have shorter and more numerous fibres or processes called dendrites with many fine branching processes - similar to the root system of a tree - that allow them to 'talk' with neighbouring neurons, often as many as five to 10,000 at a time."

Alcohol appears to be particularly damaging to the "white matter" or "hard wiring" of the brain, and can also cause shrinkage or retraction of neuronal dendrites; however, the damage appears to be at least partially reversible with abstinence.

"The aim of this symposium was to bring together scientists from different disciplines to compare results from human and animal studies of the effects of alcohol on the brain," said Harper. "Our objective was to better understand the mechanisms underlying alcohol's damage, with the ultimate goal of identifying how to prevent and/or reverse these effects."

Key presentation highlights were:

A number of toxic, metabolic, and nutritional factors interact in a complex way to cause brain damage in those individuals who abuse or are dependent on alcohol.

"The exact ways in which alcohol damages the brain are uncertain," said Harper. "It might be that alcohol, or a metabolic byproduct of alcohol such as acetaldehyde, are toxic. Research on malnutrition, a common consequence of poor dietary habits in some alcoholics, indicates that thiamine deficiency can contribute to impaired cognition. Cirrhosis of the liver, also common in alcoholics, is known to cause clinical and structural changes in the brain. In addition, head injury and sleep apnoea are more common in alcoholics and can contribute to brain damage. All of these factors - particularly the alcohol, thiamine deficiency and cirrhosis - are linked and probably contribute in a complex way to cause brain damage."

Both permanent and transient changes may occur in the alcoholic brain.

"The most important permanent structural change is nerve cell loss," said Harper. "Some nerve cells cannot be replaced, those in the frontal cortex, cerebellum and several regions deep in the brain."

However, he added, some changes can be transient, such as the shrinkage of dendrites, those fibers that allow neurons to "talk" with neighbouring neurons. "In experimental animals," he said, "these have been shown to grow and spread again after periods of abstinence - weeks to months - and have been accompanied by improved brain function. Structural and functional changes seen in cirrhosis of the liver are also potentially reversible if treated. Furthermore, thiamine deficiency can be treated easily with oral or injected thiamine. Patients with acute deficiency respond very quickly but some permanent damage can occur if patients are not treated and particularly if they suffer repeated episodes of the deficiency."

Combining in vivo brain imaging and animal research allows for an unprecedented examination of underlying mechanisms of damage.

"Alcohol dependence follows a longitudinal course," explained Harper, "from initiation to development of dependence, maintenance, withdrawal, and more often than not, a return to drinking. Throughout this course, the brain undergoes significant biochemical and structural modifications, some for the better and some for the worse, depending on when an individual is studied. Because human alcoholics cannot be forced to drink or not, researchers have no control over when in their course an alcoholic can be studied in the laboratory. By contrast, animal models of alcohol dependence can be exquisitely controlled, in terms of alcohol-exposure amounts, time in development of exposure, withdrawal, nutrition, and the like. When we combine the two approaches, we then have a means of translating knowledge about the change in the condition of the brain from the clinic to the laboratory and back to the clinic."

Both gene and protein changes can occur in the brains of alcoholics.

"Even after death, tissues can reveal the secrets of diseases," said Harper. "For this research, brain tissues were obtained, with ethical consent, from autopsies on alcoholic subjects. Scientists used modern molecular techniques to study the control mechanisms (genes) and building blocks (proteins) of the main component of white matter - the myelin. They found that the expression of genes that control the manufacture of structural proteins of the myelin was reduced in the alcoholic cases. In addition, the content of these proteins in the white matter was reduced. These changes likely alter the structure and function of the myelin sheath and ultimately the conduction of nerve impulses."

It is important for people who abuse alcohol to realize that some of the damage can be reversed.

"Neuropsychological studies have shown that some brain functions improve with abstinence," said Harper. "Although working memory, postural stability, and visuospatial ability may continue to show impairment for weeks to months with sobriety, with prolonged sobriety these brain functions can show improvement."

Some alcoholics can achieve long-term abstinence in spite of persistent deficits in decision-making.

"There is accumulating evidence that the generalized inherited vulnerability to alcoholism and other addictions involves abnormalities of the brain systems that process rewards and punishments," said George Fein, president of and senior scientist at Neurobehavioral Research, Inc., and one of the symposium co-presenters. "People with an inherited vulnerability to addiction, including alcoholism, are much more affected by immediate than delayed rewards. A hallmark of addictive substances is that they provide an immediate reward in the intoxicating experience. When actively drinking, an individual's inhibition processes become impaired and can further contribute to poor decisions and excessive drinking. With prolonged bouts of drinking, dependence may ensue along with neural systems damage, commonly affecting frontal lobe based systems and their functions, which include decision making, inhibition, problem solving, and judgment. This is part of the dynamic course of alcoholism that likely contributes to its maintenance. In the symposium, [we presented] data showing that alcoholics can surmount these impairments in decision making and evaluation of rewards and punishments to achieve multi-year sobriety."

Harper praised the symposium's multi-disciplinary approach to examining alcohol-induced brain damage, calling it critical to solving the puzzle. "The pathologist and neuroradiologist can identify the region of the brain to study, and the molecular biologist can take samples from these regions and look at the genes controlling structure and function and even identify individual proteins that might play a role in cognitive deficits as well as recovery and repair of the brain. Together we can develop strategies for public education and new approaches to therapy in people who use and abuse alcohol. People who abuse alcohol," he added, "should be informed that some of the brain damage could be reversed."