Cognitive Enhancement: Protecting Health of Neurons Supports the Aging Brain

Kimberly Pryor


Dementia can be looked upon as a thief that threatens to steal one of our most precious resources—our memories. Dementia occurs when the brain’s nerve cells (neurons) are permanently damaged or destroyed. Dementia is a general term for a group of symptoms such as loss of memory, judgment, language, complex motor skills, and other intellectual functions.

Alzheimer’s is the most common form of dementia, accounting for up to 60 percent of all dementia cases and is the most common cause of dementia in persons over the age of 65. Other forms of dementia affect a substantial portion of the population and can have an equally dramatic effect on lifespan and quality of life. Multi-infarct dementia, responsible for the memory loss that occurs after a stroke, and other vascular dementias caused by blockage of blood supply to the brain, also can take a toll on both the person suffering from the condition and his or her loved ones.

The clinical symptoms and the rate of disease progression vary according to the type of disease responsible for the dementia and the location and number of damaged brain cells. Some dementias progress slowly over years, while others are characterized by the rapid loss of cognitive function. Symptoms in people suffering from dementia can include forgetfulness of recent events, repeating themselves in conversation, being less concerned with activities or other people and less able to understand new ideas, the inability to adapt to change, anxiousness about having to make decisions, irritability when unable to manage a task, the loss of objects and becoming lost. In addition, people suffering from dementia may exhibit a change in behavior or personality. In its initial stages, dementia can be confused with depression, stress, or even bereavement as many of the symptoms listed above also occur concomitantly with these conditions.

Alzheimer’s Disease
According to the Alzheimer’s Foundation website, the term Alzheimer's disease was first used in 1906 when Dr. Alois Alzheimer, a German physician, presented a case history of a 51-year-old woman before a medical meeting. The woman suffered from a brain disorder, which a brain autopsy showed to be characterized by plaques and tangles. This disorder was subsequently termed Alzheimer’s disease.

Alzheimer’s is a progressive, degenerative disease that attacks the brain’s neurons. These neurons manufacture the neurotransmitter acetylcholine and their destruction cuts the connection with other nerve cells, much like a cut telephone line or cable wire. Ultimately, the neurons die, triggering a loss of memory, thinking, language skills and behavioral changes. Short-term memory fails in Alzheimer’s disease when nerve cells in the hippocampus are destroyed. In later stages of the disease, language skills and judgment are affected after neurons are destroyed in the cerebral cortex.

Two abnormal features are found in the brains of Alzheimer’s disease patients. Beta-amyloid plaques, protein fragments and cellular material that stick to neurons, are one of the features that characterize the disease. The other abnormal feature is neurofibrillary tangles, insoluble twisted fibers composed primarily of the protein tau that build up inside nerve cells. It is still unclear, however, whether these two features can cause the disease or are a consequence of it.

Other Dementias
One of the most common forms of non-Alzheimer’s dementia is related to damage that occurs after a stroke. According to the National Stroke Association, nearly 5 million people in the United States today have survived a stroke. Many of these stroke survivors suffer from cerebrovascular related memory loss, including multi-infarct dementia.

A stroke occurs when a blood clot blocking an artery or a blood vessel breaks, interrupting blood flow to an area of the brain. When either of these things happens, brain cells begin to die and brain damage occurs. When brain cells die during a stroke, abilities controlled by that area of the brain are lost. These abilities include speech, movement and memory. How a stroke patient is affected depends on where the stroke occurs in the brain and how much the brain is damaged. Multi-infarct dementia, the second most common cause of dementia, occurs when blood clots block small blood vessels in the brain and destroy brain tissue. It usually occurs after a series of ministrokes (transient ischemic attacks). Probable risk factors are high blood pressure and advanced age. Multi-infarct dementia typically begins between the ages of 60 and 75 and is slightly more likely to affect men than women. Over time, as more small vessels are blocked, there is a gradual mental decline.

Sometimes it is difficult to distinguish multi-infarct dementia from Alzheimer’s, and it’s possible to have both multi-infarct dementia and Alzheimer’s simultaneously, making it hard to obtain an accurate diagnosis.

Nerve Growth Factor, Free Radicals and Dementia
Researchers have begun to study the role that nerve growth factor plays in dementia, especially Alzheimer’s disease. Nerve growth factor is important to the survival and maintenance of cholinergic neurons in the central neuronal system. In Alzheimer’s, learning and memory are impaired by the loss of neurons, so any substance that could increase nerve growth factor may have an impact on neuron survival.

Free radicals—and the oxidative damage they trigger—also are known to be involved in Alzheimer’s disease. Free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder. In vitro and animal studies suggest that various antioxidant compounds can attenuate beta-amyloid-induced oxidative stress that occurs in Alzheimer’s.1

Finding a way to increase nerve growth factor while at the same time inhibiting free radical damage could prevent or delay the loss of neurons that occurs in Alzheimer’s disease as well as have beneficial effects in other forms of dementia. Taking this approach could not only improve brain health in people with these diseases but also could help anyone interested in preserving a healthy brain.
Idebenone and Brain Health

Idebenone is a synthetic analogue of Coenzyme Q10 that has been shown to both act as a powerful antioxidant and to increase levels of nerve growth factor. Idebenone can operate even under low oxygen conditions and can protect the mitochondria from oxidative damage. As an antioxidant, it can protect against cerebral ischemia (strokes) as well as help guard against nerve damage in the central nervous system.

Idebenone’s ability to protect against neuronal damage may also have to do with its ability to stimulate nerve growth factor. Since nerve growth factor does not cross the blood-brain barrier and is easily metabolized by enzymes when administered peripherally, it can be used for medical treatment only when directly injected into the brain. Consequently, finding a substance that stimulates the endogenous production of nerve growth factor could be valuable in supporting brain health. Researchers have found that idebenone not only increases nerve growth factor synthesis in vitro but also when administered orally to rats with lesions on their forebrains (although this effect wasn’t noted in young intact rats). In addition to stimulating nerve growth factor in the animals, idebenone also ameliorated their behavioral deficits.2

Idebenone’s ability to stimulate nerve growth factor and act as a powerful antioxidant is likely the reason it has demonstrated some impressive results in studies investigating its effects in Alzheimer’s and multi-infarct dementia. In a randomized, double-blind, placebo controlled study, idebenone treatment was studied in 108 elderly patients with mild to moderate mental deterioration of vascular origin.3 The subjects were given 45 mg of idebenone per day b.i.d. for 120 days.

The results indicated that idebenone significantly improved the scores on a number of tests measuring memory, attention and cognitive function. Idebenone was well tolerated.

According to the researchers, "Idebenone proved to be therapeutically effective in the treatment of multi-infarct dementia."

Idebenone also appears to correct neurotransmitter defects in the brains of patients with multi-infarct dementia and helps promote serotonin turnover.4

In Alzheimer’s patients, idebenone appears to exert equally beneficial effects. In a 2-year, randomized, double-blind study, researchers investigated the effects of idebenone on 450 subjects with mild to moderate Alzheimer’s disease.5 One hundred fifty three patients were randomized to a placebo for 12 months followed by 90 mg idebenone t.i.d. for 12 months. Another group of 148 patients received idebenone 90 mg t.i.d. for 24 months while a third group of 149 subjects received 120 mg t.i.d. for 24 months.

The researchers then measured the subjects’ outcome on a variety of tests measuring cognitive function. The primary outcome of idebenone or placebo treatment was determined based on the subjects’ total score on the Alzheimer's Disease Assessment Scale at month 6.

During the placebo controlled period (the first year of treatment), subjects on idebenone showed statistically significant dose-dependent improvement in the Alzheimer’s Disease Assessment Scale as well as on the other tests measuring cognitive function. In the second year, idebenone-treated patients continued to experience further improvement compared to the results at the 12 months’ visit. Throughout the second year of treatment, the benefits appeared to be dose dependent, with the subjects taking the 120 mg t.i.d. showing more improvement than the subjects taking 90 mg t.i.d.

"This suggests that idebenone exerts its beneficial therapeutic effects on the course of the disease by slowing down its progression," the study authors wrote.

Another randomized, double-blind study compared the safety and efficacy of idebenone with a standard drug used in Alzheimer’s treatment.6 The study included 203 subjects between ages 40 and 90 suffering from mild to moderate Alzheimer’s disease. The researchers randomized 104 subjects to receive 360 mg per day of idebenone and 99 subjects to receive 160 mg per day of the Alzheimer’s drug for 60 weeks.

At the end of the treatment period, idebenone appeared to have a greater compliance rate with 28.8 percent of the patients randomized to idebenone and only 9.1 percent of the patients randomized to the drug still on the treatment. Idebenone’s effects were also greater than that of the drug. Fifty percent of the patients randomized to idebenone but only 39.4 percent of the patients randomized to the drug showed an improvement in an index that measured cognitive function, daily living activities, and global function.

According to the researchers, “We conclude that the benefit-risk ratio is favorable for idebenone, and furthermore, that this ratio is likely to be similar when comparing idebenone to other cholinesterase inhibitors.”

Idebenone’s ability to protect neurons and improve cognitive function may also be due to its anti-inflammatory actions. In cells comprising the nervous system tissue, idebenone significantly inhibited the enzymatic metabolism of arachidonic acid by cyclooxygenase and lipoxygenase. Arachidonic acid is metabolized to inflammatory substances within the body and idebenone’s ability to stop its metabolism into these inflammatory substances indicates it possesses strong anti-inflammatory activity in the central nervous system.7

Conclusion
Alzheimer’s and other dementias are a very real threat to the aging population. The older we become, the more likely we will suffer from one of these disorders, or, at the very least, age-related memory loss. Idebenone’s ability to protect neurons and enhance cognitive function suggests it is a powerful tool in maintaining brain health as we age.

References
1. Pratico D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. Am J Med. 2000 Nov;109(7):577-85.
2. Nitta A, Murakami Y, Furukawa Y, Kawatsura W, Hayashi K, Yamada K, Hasegawa T, Nabeshima T. Oral administration of idebenone induces nerve growth factor in the brain and improves learning and memory in basal forebrain-lesioned rats. Naunyn Schmiedebergs Arch Pharmacol. 1994 Apr;349(4):401-7.
3. Marigliano V, Abate G, Barbagallo-Sangiorgi G, Bartorelli L, Capurso A, Cucinotta D, Cuzzupoli M, Senin U, Tammaro AE, Fioravanti M. Randomized, double-blind, placebo controlled, multicentre study of idebenone in patients suffering from multi-infarct dementia. Arch Gerontol Geriatr. 1992 Nov-Dec;15(3):239-48.
4. Kawakami M, Itoh T. Effects of idebenone on monoamine metabolites in cerebrospinal fluid of patients with cerebrovascular dementia. Arch Gerontol Geriatr. 1989 May;8(3):343-53.
5. Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl. 1998;54:301-10.
6. Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry. 2002 Jan;35(1):12-8.
7. Civenni G, Bezzi P, Trotti D, et al. Inhibitory effect of the neuroprotective agent idebenone and arachidonic acid metabolism in astrocytes. Eur J Pharmacol. 1999;370:161-7.