January 2007
The development, maintenance, and repair of myelin is the single most important factor affecting cognition and behavior, according to a UCLA neurology professor who has collected extensive data on the nerve insulator. In an article to be published in an upcoming issue of Biological Psychiatry, George Bartzokis, MD, asserts that myelin may be the universal cause or contributor to a wide range of neuropsychological brain disorders, from autism to Alzheimer’s disease. Dr. Bartzokis, who directs the UCLA Memory Disorders and Alzheimer’s Disease Clinic in Los Angeles, suggests that using noninvasive imaging technology to view the miles of myelin in the brain as it grows and breaks down throughout a human life cycle may offer insights leading to the development of new treatments for brain disorders. Nicotine, which studies have suggested enhances the growth and maintenance of myelin, could be one such novel treatment.
In some of the first research to approach brain disorders from a myelin-centered point of view, Dr. Bartzokis studied the effects of cholinergic treatments, including acetylcholinesterase inhibitors (AChEIs) that are used to improve a neuron’s synaptic signaling in people with diseases such as Alzheimer’s. Some data suggest that such treatments may even modify or slow the progression of Alzheimer’s as well as other diseases.
Nicotine, Age, and Disease
Dr. Bartzokis hypothesizes that cholinergic stimulation at neuronal synapses affects the myelination process throughout brain development in the course of a human’s lifetime.He found in clinical trials that cholinergic treatment protects brain cells, while postmortem and imaging data have shown cholinergic receptor changes during brain development and degeneration. Trials have also revealed epidemiologic evidence that nicotine from tobacco may have a protective effect on degenerative diseases of old age and younger psychiatric populations. Cholinergic treatments have also shown efficacy in the aging process and age-related neurodegenerative diseases such as Alzheimer’s disease, as well as some neurodegenerative diseases like autism and ADHD.
According to Dr. Bartzokis, myelination development resembles an inverted “U” over the course of a lifetime, with increasing myelin development peaking in middle age and breaking down and declining in later years. Following the analogy of the Internet, Dr. Bartzokis says the “connectivity” provided by myelination increases speed by 10-fold and decreases refractory time by 34-fold. Thus, myelination increases the “bandwidth,” or processing capacity, of our brain’s Internet by 340-fold and is “indispensable for developing our uniquely elaborate higher cognitive functions.”
Different cortical regions myelinate at different ages, with later-myelinating oligodendrocytes growing increasingly more complex as we age. Irregular development during the most complex stages of the myelination process contributes to several of the neuropsychiatric disorders that tend to manifest in the early years. These disorders—eg, autism, ADHD, schizophrenia, mood disorders, addictions—are defined by overlapping cognitive and behavioral symptom clusters.
According to Dr. Bartzokis, healthy individuals with normal myelin development typically lose 45% of their myelinated fiber length when they reach the degeneration phase in adulthood. This change in the brain may cause progressive losses of memory and cognitive functions, as well as mild to severe behavioral changes.
The loss of myelin and its components such as sulfatide, myelin basic protein, and cholesterol begins early in the development of Alzheimer’s disease, well before diagnosis of dementia or mild cognitive impairment. The myelin breakdown process is further modified by risk factors such as the presence of APOE ε4 or environmental factors such as a head trauma.
Nicotine's Effect on Myelination and Repair
Recent research has unveiled some surprising findings on the influence of nicotine on myelination and the aging process. Direct nicotinic stimulation associated with smoking has been shown to increase nicotinic receptors in the late myelinating frontal and temporal intracortical regions. Unlike most agonists, nicotine causes an up-regulation of its receptors and has been shown to accelerate brain function recovery when white matter is damaged.
Nicotine dependence is common among people with psychiatric disorders. Some researchers have suggested the high prevalence of nicotine use among the psychiatric population represents an unconscious effort to “self-medicate.” Research on proteins has suggested that nicotine may marginally increase the expression of myelin proteins; other addictive drugs (eg, cocaine, alcohol) along with developmental diseases (eg, schizophrenia, bipolar disorder, depression) show a decrease of these proteins.
Other research has found an association between nicotinic stimulation and protective effects in schizophrenia and autism, where cortical myelination deficits have been documented. While nicotine has well-known negative effects on overall health, smoking during later years is also associated with a reduced likelihood of the development of degenerative conditions like Alzheimer’s and Parkinson’s diseases. Using the myelin-centered model, the apparent beneficial aspects of smoking on brain disorders can be attributed to nicotine’s stimulation of oligodendrocyte precursors. Dr. Bartzokis believes that nicotine, delivered through a patch, not through smoking cigarettes, should be studied for its efficacy in promoting the growth and maintenance of myelin, and that AChEIs “deserve much closer scrutiny” as a therapy for the prevention of both developmental and degenerative brain disorders.
—Kathlyn Stone
Suggested Reading
Bartzokis G. Acetylcholinesterase inhibitors may improve myelin integrity. Biol Psychiatry. 2006 Oct 26; [Epub ahead of print].
Bartzokis G, Lu PH, Mintz J. Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimers Dis. 2004;6(6 suppl):S53-S59.
Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2000;58:427-433.
Morens DM, Grandinetti A, Reed D, et al. Cigarette smoking and protection from Parkinson’s disease: false association or etiologic clue? Neurology. 1995;45:1041-1051.
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