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Jennifer CrummMichael ZemelNTR 302-001March 05, 2009 Ginkgo Biloba and Its Effects on Alzheimer's Disease

Alzheimer's disease is the most common form of dementia among the elderlytoday'. 'While progress has been made in researching how Alzheimer's affects the brainand the different treatments available for Alzheimer's patients, there is still so much moreto discover. To fully understand tIle severity of this disease, knowing how it affects thebrain and the different treatments available can give the patients and their caregiv:ers an

advantage in the fight to retain the memory of those affected. Alzheimer's disease attacksthe brain areas that control the memory and thinking skills. There are many treatmentsavailable for Alzheimer's , both drug and non-drug methods. Each treatment haspromising results, but some methods are more effective than others. Unfortunately, withrising costs in medication, it has become increasingly m.ore difficult to obtainpharmaceutical treatments to prevent the progression of Alzheimer's. However, there area number of alternative treatments, for example, coenzyme Q10, onlega-3 fatty acids, orginkgo biloba, that are popularly used as "memory enhancers or treatments forAlzheimer's disease and related diseases" (1). For centuries, Ginkgo Biloba extract, orGBE, was used in traditional Chinese medicine and is now used in Europe "to alleviatecognitive symptoms associated with a number of neurological conditions" (1). GinkgoBiloba is risillg in popularity in the States, but many studies have been conducted tochallenge the effectiveness of GBE on dementia, such as Alzheimer's.

D e m e ~ t i a , which "literally means loss of mentation, or thinking" (2), is a group ofdisorders that impair cognitive functions to which Alzheimer's is the most common.

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~ ; \ l z h e i m e r ' s disease has a briefhistory. Discovered in 1906, it is also known as AD,named after German doctor Alois Alzheimer who noticed changes in the brain tissue of awoman who had died of an unusual mental illness (3). He found what are now consideredsignificant signs ofAD. Along with symptoms ofmemory loss, language problems, andunpredictable behavior, abnormal clumps, or amyloid plaques, and tangled bllndles offibers, or neurofibrillary tangles, were found in the elderly patient ofDr. Alzheimer (3).Alzheimer's disease is progressive and irreversible and advances in stages, "progressingfrom mild forgetfulness and cognitive impairment to widespread loss ofmental abilities"

(2). Alzheimer's "[causes] problems with memory, thinking, and behavior severe enoughto affect work, lifelong hobbies or social life" (1). As Alzheimer's progresses, thepatient's memory, ability to learn, reason, make judgments, communicate and carry Olltdaily activities becomes diminished. I I I addition, changes in personality and behavior, aswell as development of delusions or hallucinations, are common in AD patients (2). ADadvances at different rates for each patient. Recent estinlates figure "2.4 to 4.5 millionAmericans are living with Alzheimer's disease" (3) and "about 360,000 people are newlydiagnosed each year" (2). On average, AD patients die four to six years after diagnosis.As the disease progresses, the brain areas that control the memory and thinking skills areaffected first by the nerve cells shrinking and ultinlately dying. These cells includeneurotransmitters, a critical chemical messenger that relays brain signals from one nervecell to another (2; 3). The neurotransmitter Acetylcholine occurs in lesser amounts inpeople with Alzheimer's. And, as these nerve cells disappear, the brain itself shrinks andthe syllapses, or "wrinkles", of the brain vanish, leaving a smoother surface (2). "By thefinal stage ofAD, damage is widespread and brain tissue has shrunk significantly" (3).

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Ginkgo Biloba extract is the most popular alternative medication for Alzheimer's.The mechanisms by which Ginkgo biloba might help alleviate Alzheimer's symptomsfocus on it functions as a "neuroprotective agent" (4), an antioxidant, and the "possibleeffects on amyloid metabolism" (5)0 The extract found in Ginkgo biloba extracts insupplements sold worldwide is Ginkgo extract EGb 761. This extract contains two mainconstituents, which are unique to Gir1kgo biloba trees: flavonoids and terpene lactone(ginkgolides and bilobalide) (6). "The flavonoids and ginkgolides have protean biologicalactivity in preclinical research" (6). The flavol10ids appear to have antioxidant andneuroprotective effects, where as the ginkgolides have multiple functions. There are threeginkgolides of interest, A, B, and J. Ginkgolide B inhibits platelet-activating factors andGinkgolides A and J inhibits l1euron dysfunction and neural cell death by amyloids (6).Ginkgolides A and J decrease the pathological behavior of amyloids, "enhanceneurogenesis in animal models ofAlzheimer disease" (6), and prevent amyloids fromaccumulating (6). The actions of Ginkgolides A and J provide convincing evidence forGinkgo biloba extract as a potential treatment for Alzheimer's disease. "Some of thecomponents of G biloba extract are as active in preclinical models ofneurodegenerationand Alzheimer disease as new drug candidates being developed" (6). However, thebiochemical properties of Ginkgo biloba may not be enough to provide consistent resultsin clinical tests where GBE is the sole preventative medication for Alzheimer's. Manystudies have been done to evaluate the efficacy of Ginkgo biloba's in treatingAlzheimer's.

One specific study aimed to "assess the efficacy of the [GBE] in patients withdementia of the Alzheimer type in slowing down the disease's degenerative progression

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and the patient's cognitive impairment" (7). In this 24-week long randomized placebocontrolled double-blind study, patients between the ages 50 and 80 years suffering frommild to moderate dementia were given one of three treatments: Ginkgo biloba (160mgdaily dose), donepenzil (5mg daily dose), or a placebo (7). The degree of severity ofdementia was determined by "the Syndrom Kurz test (SKT), a psychometric test batteryfor the assessment ofmemory and attention" (7). The patients in this study had mild tomoderate dementia, determined by a score between 8 and 23 on the SKT, and wereexcluded from the study if they had "dementia of other etiology, severe organic diseases(tumors, severe infectious diseases, brain trauma, epilepsy, cerebrovascularmalfoffilations, alcohol or drug abuse), pseudodementia or a history of schizophrenic oraffective psychoses" (7). Since much debate surrounds the efficacy ofGinkgo bilobaextract as treatment for A l z h ~ i m e r ' s , this study directly compared GBE to a"cholinesterase inhibitor" (7) in an effort to provide more support for GBE. After thecompletion of the study, the patients were administered the SKT once more. Whencompared to the baseline results, the differences of SKT scores in the GBE and donepezilgroups showed that GBE "patients ' attention and memory performance after 6 months oftreatment as measured by the SKT had shown significant improvements, comparable withthe results obtained by patients treated with donepezil" (7). The results of this studyconfirmed that Ginkgo biloba has clinical efficacy comparable to that of donepezil in thetreatment ofAlzheimer's. However promising this study is, many others have beenconducted that refute these results.

Over the past two decades, a number of studies have been conducted to assess theefficacy ofGBE in treating Alzheimer's disease. One of the most convincing studies

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declining the claims that GBE is an effective.treatment is the Ginkgo Evaluation ofMemory, "a randomized, double-blind trial sponsored by the National Center forComplementary and Alternative Medicille (NCCAM) and the National Institute on Agingof the National Institutes ofHealth (NIH)" (8). From 2000 to 2008, 3,069 volunteers age75 years or older, 2,587 with normal cognitive function and 482 wi th mild cognitiveimpairment, were assessed every 6 months for "incident dementia" (8). Participants wereexcluded from the study if they "1) currently taking the anticoagulant warfarill; 2) takingcholinesterase inhibitors for cognitive problems or dementia (memantine had not been

approved for use in the United States when the study began); 3) unwilling to discontinuetaking over-the-counter G biloba for the duration of the study; 4) currently beingtreatedwith tricyclic antidepressants, antipsychotics, or other medications with sigIlificantpsychotropic or central cholinergic effects (the anticholinergic effects of selectiveserotonin reuptake inhibitors were not believed to be substantial enough to warrantexclusion); 5) daily use ofmore than 400-IU vitaminE or unwillingness to reduce intaketo this level; 6) history of bleeding disorders; 7) hospitalization for depression within thelast year or electroconvulsive therapy within last 10 years; 8) history ofParkinson diseaseor taking anti-Parkinson medications; 9) abnormal thyroid tests, serum creatinine levelgreater than 2.0 mg/dL (to convert to ~ m o l / L , multiply by 88.4), or liver function testsmore than 2 times the upper limit of normal at baseline; 10) baseline vitamin B12 levels210 pg/mL or lower (to COllvert to pmol/L, multiply by 0.7378); 11) hematocrit level lessthan 30%; 12) platelet COlInt lower than 100 xl03/JlL; 13) disease-related life expectancyof less than 5 years; or 14) known allergy to G biloba" (8). Twice daily, the volunteerswere administered either 120-mg of Ginkgo biloba extract or a placebo. Chosen

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completel)! at random, 1,545 participants received the GBE dosage and the remaining1 ~ 5 2 4 received the placebo. Throughollt the study, 532 participants were diagnosed withdementia: 246 in the placebo group and 277 in the Ginkgo biloba group (8). In the GEMStudy with "3069 older adults with normal cognitive function or mild deficits, G bilabashowed no benefit for reducing all-cause dementia or dementiaof the Alzheimer type"(8). Due to the large sample size from a population with increased risk of developingdementia, the randomization in distributing the GBE dosage and placebo, and thefrequent cognitive tests to measure for any developing signs of dementia administered byexpert committees uninformed of the participant's group assignment (8), the results fromthis study are viable and are strongly upheld by the medical field.

There is no identified cause ofAlzheimer's disease and, unfortunately, no cure ison the horizon. However, millions of dollars are financing research so that one day thisdevastating disease will no longer be a death sentence. There are many treatments forAlzheimer's disease, ranging from supplements to prescription drugs. The risingpopularity ofGil1kgO biloba, with its history as a promoter of cognitive function, led tostudies that challenged its efficacy as an Alzheimer 's treatment. In the debate betweencholinesterase inhibitors, such as donepezil, and Ginkgo biloba as treatments, evidencepoints to pharmaceutical treatments as the most effective way to prevent and delay thedeveloping symptoms ofAlzheimer's. G-inkgo biloba certainly is more affordable thanprescription drugs but it is lacking in evidence to promote i t as a treatment forAlzheimer's; and when it comes to prolonging the memory, personality, and life of thoseafflicted with the disease, it is often best to choose the treatment that has proven itselfeffective.

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References

1. Alzheimer's Association. 27 Feb 2009.2 Mar 2009. .2. "What is Alzheimer's Disease." Fisher Center for Alzheimer's Research

Foundation. 2 Mar 2009. .

3. "Alzheimer's Disease Fact Sheet." U.S. National Institutes of Health- NationInstitute on Aging. 24 Feb 2009. 2 Mar 2009..

4. Blumenthal, Mark, Victor S. Sierpina, and Bernd Wallschlaeger. "Ginkgo Biloba."American Family Physician. 1 Sept 2003. PubMed. 24 Jan 2009..

5. Furberg, Curt D. and Steven T. DeKonsky. "Turning over a new leaf: Ginkgobiloba in prevention of dementia." NEUROLOGY 2008; 70: 1730-1731.PubMed. 24 Jan 2009..

6. Schneider, Lon S. "Ginkgo biloba Extract and Preventing Alzheimer Disease."JAMA 2008; 300 (19): 2306-2308. PubMed. 24 Jan 2009. .

7. Bria, P., A Capuano, M. Mazza, and S. Mazza. "Ginkgo biloba and donepezil: acomparison in the treatment of Alzheimer's dementia in a randomizedplacebo-controlled double-blind study." European Journal of Neurology. 13.9

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(2006): 981-985. PubMed..

8. DeKonsky, Steven T., et aL "Ginkgo biloba for Prevention of Dementia." JAMA2008; 300(19): 2253-2262. PubMed. 24 Jan 2009. .