Chinese Club Moss (Huperzine A) and Alzheimer's Disease

Huperzine A (pronounced HOOP-ur-zeen) is a moss extract that has been used in traditional Chinese medicine for centuries. It has properties similar to those of cholinesterase inhibitors, one class of FDA-approved Alzheimer medications. As a result, it is promoted as a treatment for Alzheimer's disease.

What is Huperzine?

Huperzine, an anticholinesterase alkaloid, is divided into two chemical species, huperzine A and huperzine B, which have similar effects but differing activity levels (huperzine A being about 10 times as strong as huperzine B). Huperzine A was first isolated from the Chinese herb Lycopodium serratum in 1980 at the Zhejiang Academy of Medical Sciences and the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences. Huperzine B was isolated five years later. The plant source, originally called Qian Ceng Ta, meaning thousand-layers pagoda (referring to the tall multi-leafed appearance of the plant), is also known in China as Jin Bu Huan, a term meaning "more valuable than gold," usually applied to plants that have potent analgesic actions.

Clinical Trials

A number of animal studies have documented that huperzine A is a long acting acetylcholinesterase inhibitor with greater potency than tacrine or donepezil, two cholinesterase inhibitors approved for the treatment of Alzheimer's disease (AD). Huperzine A also appears to decrease neuronal cell death in the brain. Well designed human trials with huperzine A have not been published in the Western medical literature. Four clinical trials have been published in China, where it has been approved for treating dementia for many years. One of these studies was an 8 week, double-blind, placebo controlled trial of 103 patients with AD. Among patients who took 200 mcg of huperzine A twice daily, 58% improved in memory, cognition, behavior and function, compared to 36% of patients who took placebo. A derivative of huperzine A, huprine X, is also currently of interest for the treatment of AD.

Recently, the Alzheimer's Disease Cooperative Study (ADCS) conducted the first large-scale U.S. clinical trial of huperzine A as a treatment for mild to moderate Alzheimer’s disease. And the results were not so encouraging so far. Participants taking huperzine A experienced no greater benefit than those taking a placebo.

Huperzine A has been evaluated at the Mayo Clinic in Jacksonville, Florida. According to Alan Kozikowski, a chemist who is heading the research there, Huperzine A is more effective and more specific than tacrine, another anticholinesterase drug. Interneuron Pharmaceuticals in Lexington, Mass. is testing Huperzine A in human clinical trials.

Side Effects and Safety

No serious side effects have been reported with huperzine A. As a result of greater selectivity for central acetylcholinesterase, huperzine A may cause fewer cholinergic side effects (e.g., nausea, vomiting, diarrhea, anorexia) than tacrine, donepezil or rivastigmine. Bradycardia was reported in one clinical trial. Individuals with heart conditions should not use huperzine A without guidance from a physician. Possible contraindications include sick sinus syndrome and bradycardia. As an acetylcholinesterase inhibitor, huperzine A can be expected to interact with cholinergic agonists, anticholinergic drugs, and the muscle relaxant, succinylcholine.

Huperzine A should be avoided by children, pregnant women and nursing mothers. Because of possible adverse effects in those with seizure disorders, cardiac arrhythmias and asthma, those with these disorders should avoid huperzine A. Those with irritable bowel disease, inflammatory bowel disease and malabsorption syndromes should avoid huperzine A.

Dosage

There are various forms of huperzine A available, including extracts of Huperzia serrata, natural (-)-huperzine A and synthetic racemic (±)-huperzine A. Natural (-)-huperzine A is approximately three times more potent than the synthetic racemic mixture. The doses of natural (-)-huperzine A used in clinical studies ranged from 60 micrograms to 200 micrograms daily. Huperzine A should only be used with a physician's recommendation and monitoring. Now, it is mostly supplied in Capsules — 50 mcg and in Tablets — 50 mcg.

Conclusion

Because currently available formulations of huperzine A are dietary supplements, they are unregulated and manufactured with no uniform standards. Taking these unregulated preparations could increase the risks of serious side effects, especially if used in combination with FDA-approved Alzheimer drugs. It also can be a broad range of substances of differing quality.

For now, most doctors don't recommend taking huperzine A because FDA-approved cholinesterase inhibitor medications are available that have been tested for safety and effectiveness. The Alzheimer's Association recommends that you not take huperzine A if you're already taking a prescribed cholinesterase inhibitor, such as donepezil (Aricept), rivastigmine (Exelon) or galantamine (Razadyne). Taking both could cause stronger side effects, such as nausea, vomiting, diarrhea, dizziness and muscle cramps. Consult with your doctor before starting any dietary supplement, including huperzine A.

Sources and Additional Information:

http://www.alz.org/alzheimers_disease_alternative_treatments.asp

http://www.healthyplace.com/alternative-mental-health/alzheimers/huperzine-a-for-treatment-of-alzheimers-disease/menu-id-55/

http://www.itmonline.org/arts/alzheimers.htm

http://www.mayoclinic.com/health/huperzine-a/AN02022

http://www.alzheimersreadingroom.com/2007/01/huperzine-factsheet-alzheimers.html

http://www.huperzine.net/story/huperzine-a-study-seeks-alternative-alzheimers-treatment

Small Head Circumference as Risk Factor for Alzheimer’s Disease

The size of the skull is fixed by age 7. Brain size approximates the head size until old age, when it begins to shrink. Some evidence has reported an association between small head size (and therefore less brain volume) and Alzheimer's disease. Nevertheless, other studies have found no association between a small head size and Alzheimer's disease.

Some experts suggest that the relationship observed in other research may simply be due to social and economic factors, such as malnutrition or low birth weight, which have been associated with both Alzheimer's disease and small head size. Small head size independent of other factors, they argue, does not pose a higher risk for either Alzheimer's disease or low intelligence.

University of South Florida Research

According to researchers of University of South Florida (2001), the size of a person's head may be indeed one risk factor for Alzheimer's disease. People with a gene predisposing them to Alzheimer's who also have small heads were 14 times as likely to develop the disease than people without that gene variant and with larger heads.

The researchers believe people with smaller brains may be less able to compensate for the brain cell damage that is a hallmark of Alzheimer's disease, so symptoms like memory loss occur earlier in these people. But still this idea is debatable.

To test the theory, Borenstein Graves and her colleagues followed 1,700 healthy Americans age 60 or older for an average of about four years. During that time, 50 people developed Alzheimer's disease. The researchers measured the circumference of people's heads around the eyebrows and across the widest part of the skull. According to a study, participants with the smallest head measurements were slightly more likely to develop Alzheimer's than the people with the larger heads.

People with a gene variant called alipoprotein E 4 or ApoE4, a known risk factor for the disease, were 4.8 times more likely to be diagnosed with Alzheimer's. Alzheimer's developed most often among people with the ApoE4 gene variant and a small head circumference.

According to her head circumference probably does not influence the pathology (the underlying biological damage) of Alzheimer's, but is a mitigating factor in the development of symptoms. While brain growth is controlled in part by genetics, it also may be influenced by nutrition, infection, family size, and birth order. This study is not enough to definitively link smaller head size with an increased risk of Alzheimer's.

"Head circumference probably doesn't influence the pathology (the underlying biological damage) of Alzheimer's, but is a mitigating factor in the development of symptoms," Graves said. While brain growth is controlled in part by genetics, it also may be influenced by nutrition, infection, family size, and birth order, she said.

This study is not enough to definitively link smaller head size with an increased risk of Alzheimer's, said Neill Graff-Radford, chair of the department of neurology at the Mayo Clinic in Jacksonville, Fla. For one thing, a relatively small number of people developed Alzheimer's. Also, the study also shows "smaller head size is linked with older age, female gender, and less education," Radford said.

Previous studies have suggested people who have more education tend to be resistant to Alzheimer's disease, while women are more susceptible than are men. Increasing age probably is the biggest risk factor for Alzheimer's, while poor nutrition among children might explain their smaller heads, Radford said. "While it is plausible that head size might be related to Alzheimer's disease," he said, "it's still far from proven." "The question of brain reserve remains an open question," said Bill Thies, vice president for medical and scientific research at the Chicago-based Alzheimer's Association. "While head circumference may, long term, give us a better idea who should get preventive medicine, we don't have any such medicine available right now."

Chonnam National University Hospital Research

Community residents aged 65 or over (n = 916) within a defined geographic area of South Korea were screened clinically for dementia and dementia subtypes. Data on anthropometric measures (head circumference and leg length), demographics (age, gender), apolipoprotein E, and early life environment (birth order, number of siblings, parental occupation, area of residence, education) were gathered. Reproductive history was also ascertained in women.

Both smaller head circumference and shorter leg length were associated with increased age, rural residence in childhood and lower education. After adjustment for these factors, they were both independently associated with Alzheimer's disease but only in women. Reasons for gender differences in associations require clarification but, for this population and age group, may include preferential treatment of male children in Korea.

Summary

The studies about the relationship between brain and head size and the development of dementia has a pretty long history, for its linkage to the “brain reserve theory” developed by Katzman. In this theory the onset of dementia is related to the brain (size) and cognitive reserve (education). The head circumference is well related to the brain volume, and both are smaller in women^, so head size may be a “natural” predisposing factor for dementia in the female gender. But caution is needed when taking such conclusions. At first the findings of the Korean researchers must be considered: height and head size are strongly related, but are also independent factors for dementia and both may reflect a poorer childhood condition. Also lower education, a well known risk factor for dementia, may be due to the social condition and other data suggest an important correlation between head size and education. In particular data coming from the “Nun study” examined deeply this association, and found that it was strong in those who were destined to develop AD, those who carried apoE4 genotype and those who fulfilled neuropathologic criteria for AD. These findings are partially consistent with other studies that demonstrate an increased risk effect of the ApoE4 genotype in presence of smaller head circumference, with a younger age of onset of the disease^. All these data may support the “brain reserve” theory: education for the cognitive reserve, apoE4 for the genetic reserve, head circumference for the brain/neurons reserve.

On the other hand we know that social condition can affect at least in part body size and education, and that female gender can sum up a smaller congenital size, a lower education and, at least in some developing countries, less nutrition in childhood, so to have a diminished brain reserve because of both biological and social conditions. These conditions might be a major contribution to the high presence of Alzheimer disease among women.

Sources and Additional Information:

http://www.healthandage.com/encyclopedia/Alzheimers-disease-1

http://www.bio-medicine.org/medicine-news/Head-Size-Risks-for-Alzheimers-4312-1/

http://www.upi.com/Science_News/2001/10/22/Gene-head-size-risks-for-Alzheimers/UPI-24181003792903/

http://www3.interscience.wiley.com/journal/114274682/abstract

http://www.gendermedicine.org/index.php?q=node/389