The study presents the results of the largest-scale clinical trial conducted with Ginkgo biloba, assessing more than 3000 adults aged 72 to 96 years. (The investigators have used the same population to investigate other aspects of Gingko treatment, with results published in several journals.) The current study focuses on the prevention of cognitive decline in older adults. The participants received a twice-daily dose of 120 mg of Ginkgo biloba or placebo. Over the 6-year follow-up period, the rate of decline of cognitive function, as assessed by standard cognitive and psychoneurological function exams, was calculated. Overall, there was no difference in the rate of cognitive decline between participants receiving Ginkgo biloba or placebo. These results did not change when modifying factors, such as age, sex, race, education, genetic variations, or baseline cognitive impairment, were considered.

This hardly seems like newsworthy information, given the plethora of studies that say the same thing. To date, there are no large-scale, definitive studies demonstrating that Ginkgo biloba has much of an effect on anything.  Most studies that do report benefits of Ginkgo biloba therapy are not comprehensive and obtained limited data regarding cognitive function. The results lend themselves to statistical misinterpretation and inappropriate extrapolation of the data.

Still, Ginkgo biloba sales are in the hundreds of millions of dollars worldwide every year. It is commonly used in European medicine to improve memory and treat neuronal disorders and improve brain metabolism. In the United States, it enjoys widespread use as a botanical dietary supplement. The current study should leave consumers asking, “Why?” Once again, Ginkgo biloba is verifiably ineffective for preventing a decline in cognitive function. Plus, as with many unregulated over-the-counter supplements, Ginkgo biloba places patients at increased risk for possible side effects and drug interactions.

Growing old gracefully and successfully is of paramount importance with an ever-older population. It is natural to strive for maintaining, and even enhancing, cognitive reserves. But, there is no evidence that proves Ginkgo biloba will help to achieve those goals. Clinicians and patients are better served by identifying and treating known conditions that may reduce brain capacity and cognitive function, including vascular risk factors, diabetes, and sleep disorders, and promote activities and lifestyles that build cognitive reserve.

… And we don’t want to have to tell you again!

References

Canis, M., Olzowy, B., Welz, C., Suckfüll, M., & Stelter, K. (2009). Simvastatin and Ginkgo biloba in the treatment of subacute tinnitus: a retrospective study of 94 patients American Journal of Otolaryngology DOI: 10.1016/j.amjoto.2009.09.004

Daffner KR. Promoting Successful Cognitive Aging: A Comprehensive Review. J Alzheimers Dis. Dec 14 2009.

Kaschel, R. (2009). Ginkgo biloba: specificity of neuropsychological improvement-a selective review in search of differential effects Human Psychopharmacology: Clinical and Experimental, 24 (5), 345-370 DOI: 10.1002/hup.1037

Leistner, E., & Drewke, C. (2010). Ginkgo biloba and Ginkgotoxin. Journal of Natural Products, 73 (1), 86-92 DOI: 10.1021/np9005019

Snitz, B., O’Meara, E., Carlson, M., Arnold, A., Ives, D., Rapp, S., Saxton, J., Lopez, O., Dunn, L., Sink, K., DeKosky, S., & , . (2009). Ginkgo biloba for Preventing Cognitive Decline in Older Adults: A Randomized Trial JAMA: The Journal of the American Medical Association, 302 (24), 2663-2670 DOI: 10.1001/jama.2009.1913

More than 25 million people worldwide suffer from dementia, with Alzheimer’s disease accounting for most of the cases. With an aging population, the number of dementia cases is expected to exceed 80 million by 2040. For this reason, uncovering the causes and potential treatments for dementia is critical and urgent. Many studies have linked lifestyle choices and improved cognitive function in older age, including advanced education, increased physical activity, and mentally stimulating occupations and hobbies. A strong social network is also linked to a decreased risk of dementia and cognitive decline. Correspondingly, living as a couple is associated with improved health and longevity.

Now, research shows that people who are living with a partner at mid-life are at a significantly decreased risk of dementia, specifically Alzheimer’s disease, in later life. The newest study published in the British Medical Journal examined a population in Finland over a 21-year period. Overall, individuals living with a partner at 50 years old were less likely than those who were widowed, divorced, or separated to show cognitive decline 2 decades later. People who were single at mid-life and follow-up were 3 times as likely to show signs of dementia compared to those who were married or living with a partner. An earlier study of a French population showed similar results, plus an increased risk for Alzheimer’s disease in individuals who had never been married.

Of course, relationships are not the only risk factor for dementia. Many factors, including age and genetics, influence cognitive function. However, studies linking psychosocial factors and dementia provide one more incentive to maintain an active, healthy social and intellectual life.

Since being part of a couple increases lifespan, “til death do you part” may be farther away than many couples realize. Luckily, being part of a couple protects mental health and preserves cognitive function, allowing couples to grow old gracefully together.

References

Hakansson, K., Rovio, S., Helkala, E., Vilska, A., Winblad, B., Soininen, H., Nissinen, A., Mohammed, A., & Kivipelto, M. (2009). Association between mid-life marital status and cognitive function in later life: population based cohort study BMJ, 339 (jul02 2) DOI: 10.1136/bmj.b2462

Helmer C, Damon D, Letenneur L, et al. Marital status and risk of Alzheimer’s disease: a French population-based cohort study. Neurology. Dec 10 1999;53(9):1953-1958.

Manzoli, L., Villari, P., M Pirone, G., & Boccia, A. (2007). Marital status and mortality in the elderly: A systematic review and meta-analysis Social Science & Medicine, 64 (1), 77-94 DOI: 10.1016/j.socscimed.2006.08.031

Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111-128.

Earlier studies from the Whitehall Study group and related evaluations reported that long working hours are associated with cardiovascular and immunologic disorders, reduced sleep quality and duration, unhealthy lifestyle choices, and overall adverse health outcomes. Data examining the association between work hours and cognitive function is scarce, but the current study attempted to evaluate the link, since risk factors in midlife are important predictors of dementia in late life. For the cross-sectional study of 248 automotive workers in Britain, participants completed numerous tests related to memory and vocabulary, as well as general health, psychological well being, and physical functioning. People who worked more than 55 hours per week had significantly lower scores on vocabulary and reasoning tests at baseline and follow-up 5 years later, compared with those who worked 35 to 40 hours per week. The results were not changed when confounding factors were considered, including age, sex, marital status, education, occupation, income, and health risk factors.

Similar studies have concluded that it may not just be the total number of hours worked, but the length of shifts, that predict poor cognitive function. For example, reasoning and alertness is decreased in employees working 9- and 12-hour shifts compared to employees working more traditional 8-hour shifts. However, comparisons of total work hours and length of shift on cognitive function have not been completed. Additionally, long working hours are associated with sleep disorders, including difficulty falling asleep and early morning awakenings. Sleep disorders also contribute to cognitive decline and are a risk factor for dementia.

The generalizability of the latest findings is limited due to a small sample size that was not representative of a large population. Also, a 5-year follow-up period may not be long enough to accurately detect cognitive decline after middle age. Further, no study has isolated the causal relationship between long working hours and cognitive function. Are long working hours associated with education attainment, level of physical activity, or amount of job stress, and could these be the association with deceased cognitive function? Still, identifying risk factors for cognitive decline that may be modifiable can lead to at-risk persons maintaining cognitive function and preventing dementia later in life.

References

Elovainio, M., Ferrie, J., Singh-Manoux, A., Gimeno, D., De Vogli, R., Shipley, M., Vahtera, J., Brunner, E., Marmot, M., & Kivimaki, M. (2009). Cumulative exposure to high-strain and active jobs as predictors of cognitive function: the Whitehall II study Occupational and Environmental Medicine, 66 (1), 32-37 DOI: 10.1136/oem.2008.039305

Elovainio, M., Kivimaki, M., Ferrie, J., Gimeno, D., De Vogli, R., Virtanen, M., Vahtera, J., Brunner, E., Marmot, M., & Singh-Manoux, A. (2009). Physical and cognitive function in midlife: reciprocal effects? A 5-year follow-up of the Whitehall II study Journal of Epidemiology & Community Health, 63 (6), 468-473 DOI: 10.1136/jech.2008.081505

Virtanen M, Ferrie JE, Gimeno D, et al. Long working hours and sleep disturbances: the Whitehall II prospective cohort study. Sleep. Jun 1 2009;32(6):737-745.

Virtanen, M., Singh-Manoux, A., Ferrie, J., Gimeno, D., Marmot, M., Elovainio, M., Jokela, M., Vahtera, J., & Kivimaki, M. (2008). Long Working Hours and Cognitive Function: The Whitehall II Study American Journal of Epidemiology, 169 (5), 596-605 DOI: 10.1093/aje/kwn382

Wilson, R., Hebert, L., Scherr, P., Barnes, L., Mendes de Leon, C., & Evans, D. (2009). Educational attainment and cognitive decline in old age Neurology, 72 (5), 460-465 DOI: 10.1212/01.wnl.0000341782.71418.6c

Yaffe, K., Fiocco, A., Lindquist, K., Vittinghoff, E., Simonsick, E., Newman, A., Satterfield, S., Rosano, C., Rubin, S., Ayonayon, H., Harris, T., & , . (2009). Predictors of maintaining cognitive function in older adults: The Health ABC Study Neurology, 72 (23), 2029-2035 DOI: 10.1212/WNL.0b013e3181a92c36

The authors claim that NSAIDs do not prevent the onset of dementia, but may simply delay it, leading to an increased appearance of dementia in older patients. The study participants included more than 3000 adults aged 65 years or older. Approximately 25% of the subjects were over 80 years old. At baseline, all participants showed normal cognitive function. Their cognitive function was evaluated every two years for 12 years using the Cognitive Abilities Screening Instrument. The researchers also collected data on each subject’s NSAID use, and divided the drug exposure into light or no use, moderate use, or heavy use categories.

During the study period, 476 patients developed dementia. (Of these, 356 patients were diagnosed with AD.) Heavy NSAID use was associated with a 66% increased risk for dementia, compared to the light or no NSAID use group. While this seems contradictory to many popular opinions, the authors claim that it may, in fact, reinforce other theories of dementia prevention with NSAID use. Most other studies have used younger populations to assess NSAID use and dementia onset, but the current study had a much older population. Therefore, the authors conclude that heavy NSAID use may not prevent –- but delay — dementia onset. And, in traditionally late-in-life disease onset such as dementia and AD, delay could masquerade as prevention. Other studies with younger populations may have inaccurately observed a delayed onset of dementia as complete prevention.

The exact mechanism of how NSAIDs influence dementia are not well understood, but may be due to the anti-inflammatory properties of the drugs. NSAIDs reduce inflammatory markers in the brain, and may also reduce the deposits of amyloid proteins in the brain. (These protein deposits are believed to play a role in the pathogenesis of dementia.)

Dementia is a prevalent health concern among elderly people around the world. AD is the leading cause of dementia, accounting for 50 to 70% of cases worldwide. Its precise cause is not known, but is likely a combination of diverse genetic and environmental factors. Unfortunately, treatment options for dementia remain unpredictable. The bottom line of all of these studies is that no one knows the real relationship between NSAIDs, aging, and dementia. If practitioners want to change their prescribing habits of NSAIDs in the elderly, well-designed clinical trials are needed to investigate true clinical indications for preventing or treating dementia. NSAID use in the elderly is highly prevalent for a host of conditions, and continued examination of the neuroprotective effects of NSAIDs will lead to a better understanding of the risks and benefits of NSAID use.

References

BREITNER, J. (2003). NSAIDs and Alzheimer’s disease: how far to generalise from trials? The Lancet Neurology, 2 (9), 527-527 DOI: 10.1016/S1474-4422(03)00498-8

Breitner, J., Haneuse, S., Walker, R., Dublin, S., Crane, P., Gray, S., & Larson, E. (2009). Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort Neurology, 72 (22), 1899-1905 DOI: 10.1212/WNL.0b013e3181a18691

Cacabelos, R. (2008). Pharmacogenomics and therapeutic prospects in dementia European Archives of Psychiatry and Clinical Neuroscience, 258 (S1), 28-47 DOI: 10.1007/s00406-007-1006-x

Hayden, K., Zandi, P., Khachaturian, A., Szekely, C., Fotuhi, M., Norton, M., Tschanz, J., Pieper, C., Corcoran, C., Lyketsos, C., Breitner, J., Welsh-Bohmer, K., & , . (2007). Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study Neurology, 69 (3), 275-282 DOI: 10.1212/01.wnl.0000265223.25679.2a

. (2008). Cognitive Function Over Time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): Results of a Randomized, Controlled Trial of Naproxen and Celecoxib Archives of Neurology, 65 (7), 896-905 DOI: 10.1001/archneur.2008.65.7.nct70006

Szekely, C., Breitner, J., Fitzpatrick, A., Rea, T., Psaty, B., Kuller, L., & Zandi, P. (2008). NSAID use and dementia risk in the Cardiovascular Health Study*: Role of APOE and NSAID type Neurology, 70 (1), 17-24 DOI: 10.1212/01.wnl.0000284596.95156.48

Vlad, S., Miller, D., Kowall, N., & Felson, D. (2008). Protective effects of NSAIDs on the development of Alzheimer disease Neurology, 70 (19), 1672-1677 DOI: 10.1212/01.wnl.0000311269.57716.63

The study, published in a recent issue of Archives of Neurology, reports findings of a 4-year prospective study of nearly 5000 postmenopausal women in 25 countries. The study initially examined women with osteoporosis, but an ancillary study examined cognitive function in the study subjects. The women were screened for the components of the metabolic syndrome at baseline, and 10% of the women were diagnosed with the condition. Nearly all women were diagnosed with at least one component of the syndrome. All of the women were also screened for cognitive impairment at baseline, based on a combination of clinical diagnosis and standard neuropsychiatric evaluations, then yearly for 4 years. At baseline, no women showed signs of cognitive dysfunction.

Of the original 497 women diagnosed with metabolic syndrome, 7.2% developed cognitive impairment over the course of the study. Only 4.1% of women without metabolic syndrome developed cognitive impairment. Overall, there was a 23% increased risk of developing cognitive impairment per increase in component of metabolic syndrome. Of the components of metabolic syndrome, high fasting glucose levels or diabetes were associated with the most significant risk of cognitive impairment.

The mechanism by which metabolic syndrome increases cognitive dysfunction has not been clearly defined, and was not examined in this current study, but several previous studies have suggested that insulin resistance may increase the accumulation of beta-amyloid plaques that contribute to dementia. Further, obesity has been associated with brain atrophy and the degradation of neurons. Interestingly, type 1 diabetes — not usually associated with obesity or the metabolic syndrome — has also been associated with decreased cognitive function, indicating that chronic hyperglycermia and hyperinsulinemia might be to blame for decreased executive functions, cognitive impairment, and dementia. Type 1 diabetes has been shown to decrease mental speed and flexibility, while type 2 diabetes is additionally associated with changes in learning and memory.

Age may play a role in metabolic syndrome and its associated risk factors. Namely, the oldest groups of people studied seem not to experience cognitive decline at the same rate as younger subjects with metabolic syndrome. In a study of 599 people aged 85 and older with metabolic syndrome, cognitive decline actually slowed from 85 to 90 years old, compared to an accelerated decline in people with metabolic syndrome up to age 75. Some researchers argue that metabolic syndrome is less significant in the oldest of the old.

Numerous risk factors collectively influence cognitive function over a lifetime. Some occur early in life, such as education, or are unalterable, such as family history or genetic predisposition. Other risk factors, however, appear to controllable and modifiable, such as the components of the metabolic syndrome. Most of these components can be treated and managed with lifestyle modifications, and the earlier people address the risk factors and alter their behaviors, the earlier they can reduce the risk of developing any number of serious medical complications. While many studies agree that the components of metabolic syndrome are associated with decreased cognitive function, more studies need to be conducted to explain the mechanism behind this association. But, for now, people worldwide should take this information to heart (and mind) and curtail the growing prevalence of obesity, high cholesterol, high blood pressure, and diabetes. As if anyone needed one more reason.

References

BIESSELS, G., STAEKENBORG, S., BRUNNER, E., BRAYNE, C., & SCHELTENS, P. (2006). Risk of dementia in diabetes mellitus: a systematic review The Lancet Neurology, 5 (1), 64-74 DOI: 10.1016/S1474-4422(05)70284-2

van den Berg, E., Biessels, G., de Craen, A., Gussekloo, J., & Westendorp, R. (2007). The metabolic syndrome is associated with decelerated cognitive decline in the oldest old Neurology, 69 (10), 979-985 DOI: 10.1212/01.wnl.0000271381.30143.75

Xiong, G., Plassman, B., Helms, M., & Steffens, D. (2006). Vascular risk factors and cognitive decline among elderly male twins Neurology, 67 (9), 1586-1591 DOI: 10.1212/01.wnl.0000242730.44003.1d

Yaffe, K., Weston, A., Blackwell, T., & Krueger, K. (2009). The Metabolic Syndrome and Development of Cognitive Impairment Among Older Women Archives of Neurology, 66 (3), 324-328 DOI: 10.1001/archneurol.2008.566

The study was a large-scale clinical trial on the effectiveness of Ginkgo in reducing the incidence of dementia and Alzheimer’s disease. Six medical centers participated with 3069 volunteers 75 years or older. Of the total number of volunteers, 2587 had no cognitive disorders and 482 had mild cognitive impairment. The volunteers were tracked for a median of 6 years and used either a placebo or 120 mg ginkgo extract twice daily.

The dementia rate was 2.9 per 100 person-years in the placebo group and 3.3 in the Ginkgo group. The researchers concluded that 120 mg of Ginkgo biloba twice daily was not effective in reducing the rate of dementia or Alzheimer’s disease in either those with impaired or normal cognition. The press has interpreted this to mean that Ginkgo biloba is not generally effective.

Do you believe this conclusion?

“Well, yes, of course,” say a lot of health practitioners. “I won’t recommend it anymore in my practice!”

If you’re in that group of people who say they won’t consider using ginkgo, you may want to think again.

Scientific Oxymoron Unveiled

There’s a huge fallacy that exists in the minds of most people regarding research studies. That fallacy is that you can prove that something is NOT effective.

This is a scientific oxymoron. Science is the systematic observation, measurement and classification of observable phenomenon. The absence of a relationship cannot be observed, classified or measured. Thus, scientific studies can only prove what exists, not what does not exist.

You can’t show or prove safety in a research study. You can’t show or prove something does not have an effect. It’s impossible to qualify and quantify a relationship with something that does not exist. In this case, the absence of an effect of Ginkgo biloba on Alzheimer’s disease.

Pharmaceutical companies use scientific tests to prove that drugs are safe when very often it’s later found that many of them are not. Science has limitations. The ginkgo study is a good example; there are just too many variables that were not measured.

Jumping to Conclusions is Too Easy

There are too many research studies where scientists make blanket statements and generalizations and jump to conclusions without considering all of the data. These blanket statements are all too often the result of poor study design, inappropriate research study methods, lack of planning and possibly even financial backing to prove something for a company.

The ginkgo study superficially demonstrates a lack of effect of ginkgo on cognition; however, as stated above and for the following reasons, this conclusion is flawed:

• While numerous studies have found that ginkgo improves cognition, the two main causes of Alzheimer’s disease are clearly oxidation and glycation; yet in this study, researchers did not address either.
• Diet is the major cause of glycation and oxidation. Excess consumption of sugar and polyunsaturated fats maximize the production of advanced glycation endproducts in the body, which drastically increase the potential for Alzheimer’s disease and neurodegeneration. Any study relating to the initiation or progression of Alzheimer’s disease would have to monitor the two most important contributors to its development, glycation and oxidation.
• The wrong herb was used. A professional herbalist should have been consulted for this study. An herbalist is not a pharmacist and a pharmacist is not an herbalist. Herbalists seldom use a single herb to remediate a health situation or attempt to produce a change in the body.
• Hundreds of studies on ginkgo are listed, over 2000 total, on PubMed alone. These studies accurately measure both its quantitative and qualitative neuroprotective effects. A large body of evidence has been accumulated on the actions of ginkgo on the brain through population studies, animal studies, human studies with blood indices and tissue studies. It’s well known that Ginkgo increases circulation to specific tissues, including the brain. The median study time was 6 years. Alzheimer’s and dementia take decades to develop. A study with Ginkgo biloba alone would require several decades.
• The synergistic effect of a group of herbs taken together can be expected to produce a greater effect than the benefit of each herb taken by itself. Successful treatment will not come from any one substance.
• The bottom line is that no responsible herbalist would send someone home with Ginkgo biloba and tell them that Ginkgo was all that was needed to prevent neurodegeneration.
• Any good researcher would have looked at the available scientific evidence and found that alpha-lipoic acid, resveratrol, numerous polyphenols, carnosine, and benfotiamine have profound effects on the processes of oxidation and glycation and designed the study based on that evidence.

The JAMA study was poorly designed. It was not conducted for an adequate length of time. The conclusions of the study falsely suggest that herbal treatment of dementia and Alzheimer’s does not work.

One of President Elect Obama’s new goals is to do a line item review of what is being funded by the government. Why not start with faulty, inconclusive medical research that proves nothing?

More on preventing and treating Alzheimer’s disease successfully next time…

Reference

S. T. DeKosky, J. D. Williamson, A. L. Fitzpatrick, R. A. Kronmal, D. G. Ives, J. A. Saxton, O. L. Lopez, G. Burke, M. C. Carlson, L. P. Fried, L. H. Kuller, J. A. Robbins, R. P. Tracy, N. F. Woolard, L. Dunn, B. E. Snitz, R. L. Nahin, C. D. Furberg (2008). Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial JAMA: The Journal of the American Medical Association, 300 (19), 2253-2262 DOI: 10.1001/jama.2008.683

Ginkgo has long been touted for its antioxidant effects and its ability to preserve memory. JAMA reports the largest-scale clinical trial conducted with Ginkgo testing its effectiveness in reducing the incidence of dementia and Alzheimer’s disease. This study was conducted between 2000 and 2008 across 6 medical centers and included more than 3000 adults over 75 years of age. More than 2500 of the patients had normal cognition at the study’s onset, while 482 had mildly impaired cognition.

The participants were randomized to receive 120 mg twice daily of Ginkgo biloba or placebo. (The normal recommended supplement dose of Ginkgo biloba is 120 to 240 mg daily.) The follow-up averaged 6.1 years, and an astounding 94% of participants completed follow-up. Ultimately, 523 of the participants developed dementia over the course of the study — 277 in the treatment group, and 246 in the placebo group. Researchers concluded that 92% of these cases were in the early stage of Alzheimer’s disease. The rates of development of dementia were not significantly different between the groups: 3.3 cases per 100 person-years in the treatment group and 2.9 cases per 100 person-years in the placebo group. The rates of dementia did not differ between the participants with normal cognition at baseline, and those with cognitive impairment.

This study is unexpected, not just for the results, but for the size and scale of the study population and follow-up. Most efficacy studies of Ginkgo to date have included much smaller samples of patients, and, due to the age of the participants, long follow-up periods are difficult to complete. Also, most studies of Ginkgo in dementia have studied patients who already had dementia. This is the first study to examine Ginkgo as primary prevention of dementia.

The incidence of dementia increases dramatically with age, and people aged 85 years or older are at significant risk for dementia based on age alone. It is no wonder that patients and the medical community are searching furiously for ways to prevent this devastating disease. Currently, no drugs are approved for the prevention of dementia, and even the drugs available for the treatment of the disease have limited effectiveness and are not appropriate for all cases. Thus, people turned to alternative medicine and herbal supplements, like Ginkgo biloba, in an effort to thwart the effects of dementia. Globally, sales of Ginkgo biloba exceed $249 million each year. This latest study, however, makes it impossible for any practitioner to recommend the use of Ginkgo to prevent the onset of dementia or Alzheimer’s disease.

References

S. T. DeKosky, C. D. Furberg (2007). Turning over a new leaf: Ginkgo biloba in prevention of dementia? Neurology, 70 (Iss 19, Part 2), 1730-1731 DOI: 10.1212/01.wnl.0000311449.76944.6b

S. T. DeKosky, J. D. Williamson, A. L. Fitzpatrick, R. A. Kronmal, D. G. Ives, J. A. Saxton, O. L. Lopez, G. Burke, M. C. Carlson, L. P. Fried, L. H. Kuller, J. A. Robbins, R. P. Tracy, N. F. Woolard, L. Dunn, B. E. Snitz, R. L. Nahin, C. D. Furberg (2008). Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial JAMA: The Journal of the American Medical Association, 300 (19), 2253-2262 DOI: 10.1001/jama.2008.683

H. H. Dodge, T. Zitzelberger, B. S. Oken, D. Howieson, J. Kaye (2007). A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline Neurology, 70 (Iss 19, Part 2), 1809-1817 DOI: 10.1212/01.wnl.0000303814.13509.db

Hope is on the horizon, however, with the FDA’s approval of the first drug to treat HD in August of 2008. The drug, Xenazine (tetrabenazine) was developed in the 1950’s to treat psychosis, but had limited success. Now, it is available in the United States, as well as Europe, Canada, and Australia, to treat one of the hallmark symptoms of HD — chorea.

HD is inherited — each child of a parent with HD has a 50% chance of developing the disease – and is caused by an abnormal repeat of CAG basepairs on the short arm of chromosome 4. Symptoms of HD usually appear in people aged 30 to 50 years, and include chorea, or involuntary, jerky movements, dystonia, and dementia. The disease is characterized by a build up of malformed proteins in brain cells, primarily in the basal ganglia and the cerebral cortex. Usually, cells destroy waste products, such as malformed proteins, through a process called autophagy, or “self-eating”, but this process is incomplete in HD. This gradual build-up of protein, and the lack of autophagy, leads to the death of millions of neurons, which leads to cognitive difficulties, personality changes, and psychiatric symptoms.

Since there is no cure for HD, treatments are focused on symptom management and supportive care. Many adults with HD take neuroleptics or antipsychotic medications, such as haloperidol, or muscle relaxants to reduce chorea, but these drugs can severely impair alertness and learning ability. Newer antipsychotic drugs are associated with fewer side effects, but none — other than tetrabenazine — are approved for use in HD. Antidepressants are sometimes useful in adults with HD, and reduce sleep disturbances, but may aggravate seizures and trembling. Several high blood pressure and migraine medications are under investigation to stimulate autophagy, but have not yet been tested in humans.

Xenazine works in the brain to reduce the amount of dopamine available in the brain. Dopamine normally functions to communicate between brain cells, but in HD, dopamine is overactive and leads to the abnormal, involuntary movements called chorea. In clinical trials, patients with HD experienced at least a 25% improvement in chorea, leading to a dramatic improvement in quality of life. Patients with HD are often not able to complete daily activities, including eating at restaurants or attending church, and patients taking Xenazine were able to reclaim part of their daily life lost to HD.

Xanazine does present significant side effects, but many patients, and their physicians, feel that the benefits of improved symptoms outweigh the risks. The most common side effects seen in clinical trials were insomnia, depression, drowsiness, restlessness, and nausea. Most importantly, depression and thoughts of suicide were associated with Xenazine. Many HD patients are already at increased risk for suicidal behavior and close monitoring by family members and caregivers is critical.

Xenazine does not stop the disease process involved in HD, or delay its progression. But, its approval as an orphan drug is symbolic, as HD is increasingly becoming the focus of drug research and development.

Most HD patients die within 15 to 20 years after symptom onset, usually not from the disease itself, but from medical complications resulting from immobility. While this new drug cannot stop, or even delay, HD progression, it may offer patients and families suffering from HD improved quality of life.

References

Huntington Study Group (2006). Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial Neurology, 66 (3), 366-372 DOI: 10.1212/01.wnl.0000198586.85250.13

Aubeeluck A, Brewer H (2008). Huntington’s disease. Part 2: treatment and management issues in juvenile HD. Br J Nurs, 17 (4), 260-263 PMID: 18414272

Andrea Williams, Sovan Sarkar, Paul Cuddon, Evangelia K Ttofi, Shinji Saiki, Farah H Siddiqi, Luca Jahreiss, Angeleen Fleming, Dean Pask, Paul Goldsmith, Cahir J O’Kane, Rodrigo Andres Floto, David C Rubinsztein (2008). Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway Nature Chemical Biology, 4 (5), 295-305 DOI: 10.1038/nchembio.79

Heitz F, La Rosa S, Gonzalez-Couto E, Gaviraghi G, Terstappen GC (2008). Drug discovery and development for Huntington’s disease – an orphan indication with high medical need. IDrugs, 11 (9), 653-660 PMID: 18763216

Was it the genes? Well, it is true that longevity is genetically related, meaning if your parents lived a long time, then you probably will also. Van Andel’s mother died at the age of 100 and all her siblings lived past 70. Is it the diet? She joked that her daily diet of pickled herrings helped, but maybe it was more? Van Andel did not succumb to Alzheimer’s disease, but stomach cancer, and doctors said she could have lived much longer if it were not for the cancer. Perhaps van Andel’s and her family’s longevity can be attributed to not having Alzheimer’s, where the majority of people die from its complications. Scientists are we now coming to the realization that old age, or a very old age in this case, does not necessarily equilibrate to living with senility or dying from “natural causes”. Post mortem studies of van Andel touches on the theory that there must be a specific disease or culmination of diseases that cause death, and not necessarily just being old.

For those of you who do not have the “good genes” and won’t be rushing to add pickled herring to your diets, what can we do to prolong life? Researchers say that people whose occupation or hobbies requires them to exercise their brains have a lower risk of dementia and Alzheimer’s disease. Both conditions decrease the quality of life and increase the likelihood of death. Over the past two decades, we have discovered that our lust for fast food has sent us to the hospital or shortened our lives prematurely. Maybe if we exercised our brains and implemented healthy eating habits into our diets, we can cheat the grim reaper himself?

Let’s put that theory to test:

Do you have elderly family members who have sharp minds? What do they eat and do they regularly exercise? What were/ are their occupations? What are their hobbies? Do you think they are exercising their brains more than the average person?

Reference

DENDUNNEN, W., BROUWER, W., BIJLARD, E., KAMPHUIS, J., VANLINSCHOTEN, K., EGGENSMEIJER, E., HOLSTEGE, G. (2008). No disease in the brain of a 115-year-old woman. Neurobiology of Aging, 29(8), 1127-1132. DOI: 10.1016/j.neurobiolaging.2008.04.010

Because each of these disorders is treated differently, with some responding well to specific therapy, it is imperative to determine the true underlying cause of a patient’s symptoms.

Near-infrared optical spectroscopy may provide some help in clarifying this problem. This type of light is nonionizing and travels safely through the brain tissue with no adverse effects. The light is scattered by the physical components of the brain, and the brains of Alzheimer’s patients scatters this light differently, allowing for a noninvasive and simple diagnosis.

Currently, the diagnostic finding in Alzheimer’s disease is the presence of amyloid plaques and neurofibrillary tangles, which are only visible under the microscope. The amyloid plaques accumulate as the disease progresses, and this plaque accumulation affects the way near-infrared light scatters when it hits the brain. Optical spectroscopy detects the pattern of light scatter in living patients without the need for biopsy or invasive procedure.

Researchers used this technique recently to accurately predict the presence or absence of Alzheimer’s associated amyloid plaques in brain tissue. The technique is currently being studied in living patients to determine its viability as a diagnostic and prognostic tool.

In addition to allowing for accurate differentiation from other causes of dementia, near-infrared optical spectroscopy may also be used to detect the disease at an earlier state, before symptoms are apparent, and allow for early initiation of therapy. It could also prove useful as a measurement of response to treatment and as a method of following Alzheimer’s patients over time.

Reference

Hanlon, E.B., Perelman, L.T., Vitkin, E.I., Greco, F.A., McKee, A.C., Kowall, N.W. (2008). Scattering differentiates Alzheimer disease in vitro. Optics Letters, 33(6), 624. DOI: 10.1364/OL.33.000624

The surgeon was attempting to implant a deep brain stimulator into the hypothalamus of an obese man, in order to curb his appetite by stimulating brain cells that suppress hunger. With the patient conscious, in order to respond to the neurosurgeon’s probing, stimulation instead lead to a vivid recollection from over 30 years prior. The patient described a detailed memory of walking in the park with friends, including facial and clothing characteristics. Later, the patient was found to have significant improvements in learning when the electrodes were turned on.

Deep brain stimulation (DBS) is most commonly used to treat Parkinson’s disease, with over 40,000 patients in the US currently receiving this therapy. DBS involving the implantation of tiny electrodes into specific points in the brain that are attached to an external “battery pack.” Stimulation of the subthalamic nuclei in patients with Parkinson’s causes immediate and significant improvements in tremor. Theoretically, DBS could be used for a variety of medical conditions that can be linked to over- or under-activity at a specific location within the brain.

This unintentionally discovery is already being explored. Six Alzheimer’s patients have been implanted with DBS in order to see if they can recreate the findings.

By locating a specific area that responds to stimulation by increasing memory recollection and learning ability, it may be possible to treat dementia and other memory disorders with DBS. Perhaps by stimulating a specific location within the brain substance, patients will be able to recall memories that were previously lost, or will be able to learn tasks that they had forgotten.

Localization of a memory center within the brain will also allow researchers to study this region more closely and potentially develop molecular therapies that stimulate these cells chemically.

Reference

Jeremy Laurance. Scientists discover way to reverse loss of memory. The Independent. 2008.

Funded by the National Institute on Aging as well as a number of private foundations, the Nun Study is an endeavor of the Sanders-Brown Center on Aging at the University of Kentucky Chandler Medical Center intended to further research on Alzheimer’s disease and other diseases and disorders associated with the aging process. Many, if not most, studies of aging have historically focused on middle-aged, white males, and the Nun Study provides an opportunity to study women exclusively. Limitations in studies on Alzheimer’s patients often include the inability of subjects to recall information about earlier life choices and arrangements. The Nun Study is uniquely able to compensate for this probability with the contents of the convent archives, which provide records about birthplace, family history, as well as autobiographies written in mid-lives. Additionally, the sisters provide a number of built-in control factors: they live very similar lifestyles, including not smoking, drinking very little if at all, and all have similar housing, marital and reproductive statuses, occupations (approximately 85% of the sisters are or were teachers), and have similar access to health care.

The participating nuns are Roman Catholic sisters from the School Sisters of Notre Dame drawn from seven religious provinces across the United States. The 678 participants have all pledged to donate their brains to the study upon their deaths, as post-humus examination of the brain allows the researchers to accurately determine whether Alzheimer’s disease was indicated pathologically. This information is coupled with clinical indicators, such as memory loss, impairment in language, and/or impairment in social functioning to support a positive diagnosis of Alzheimer’s disease. The subjects were all between the ages of 75 and 102 when the study began. Each year, the participants are assessed in terms of cognitive and physical function, and submit to medical exams and blood tests which look at genetic and nutritive factors in aging.

The study identifying a link between oral health and dementia is only the most recent finding to be published out of the Nun Study. Other investigations have provided important information about Alzheimer’s disease and aging. One study provided a definitive neuropathological method to distinguish Alzheimer’s patients from control patients. Another utilized autobiographies gleaned from the convent archives which were written by the subjects at the age of 22. This study showed that a lower measure of linguistic ability demonstrated at this early age was correlated with higher degrees of impairment, cerebral atrophy, and clinical diagnosis of Alzheimer’s disease.

Reference

Stein, P., Desrosiers, M., Donegan, S., Yepes, J., and Kryscio, R. (2007). Tooth loss, dementia and neuropathology in the Nun Study. Journal of the American Dental Association , 138, 1314-1322.

Link to the Nun Study Web site.

Fish oil, exercise, and sugar-free soda may be the ticket to making it into old age with your memory and cognition in tact. University of California at Los Angeles researchers demonstrated that fish oil supplementation increased production of the protein LR11 in cultured human and rat neural cells and in live rats. LR11 activity is associated with decreased levels of beta-amyloid plaques, the histological hallmark of Alzheimer’s disease, and is found at lower levels in Alzheimer’s patients.

Fish oil consumption is part of the much-touted Mediterranean diet and is linked in numerous clinical studies to health and longevity. This new study gives molecular evidence of its promising effects on Alzheimer’s prevention and treatment.

An Italian study of 749 elderly men and women found moderate physical exercise to be linked with a decreased risk of vascular dementia. Patients who were the most physically active reduced their risk by 24 percent. What’s important about this study is that the activity that was followed was mild to moderate — including things like yard work, house cleaning, gardening and walking. So its not necessary to be a tri-athlete; benefits are seen with simple activities that many of use could easily work into our daily routine.

Perhaps the most interesting finding is that a diet with high levels of sugar water resulted in decreased learning and memory abilities and increased deposition of amyloid plaques in mice, demonstrated by researchers at the University of Alabama. Whether the harmful brain effects were due directly to the high sugar intake or to the effects of a high sugar diet (weight gain, elevated cholesterol, and insulin resistance) is unknown. Nonetheless, this one of the first trials to link a specific nutrient — one that is consumed in abundance in the American diet — with the signs of Alzheimer’s disease.

So what does all this mean? Diet and exercise have profound effects on our entire body, both in the immediate and long term sense. Following a healthy diet including omega-3 rich foods (found in fish oil), exercising and skipping the sugary sodas make me feel better and look better now. And if my chances of developing dementia can be decreased, even a little, by eating salmon, keeping my house clean and skipping the cola, you better believe I’m going to do it.

References

Qiu-Lan M, Teter B et al. Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer’s Disease (AD): Relevance to AD Prevention. J. Neurosci., Dec 2007; 27: 14299 – 14307.

G. Ravaglia, P. Forti et al. Physical activity and dementia risk in the elderly. Findings from a prospective Italian study. Neurology, first published on December 19, 2007 as doi:10.1212/01.wnl.0000296276.50595.86.

Dongfeng Cao, Hailin Lu et al. Intake of Sucrose-sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease. J. Biol. Chem., Dec 2007; 282: 36275 – 36282.

As we age, we all will have abnormal protein deposits in our brains that contribute to Alzheimer’s disease. But most people can reach a very old age without yet developing Alzheimer’s, a form of dementia. People who suffer silent strokes need less of these abnormal protein deposits to throw them into full-blown Alzheimer’s disease. It is not believed that the protein deposits contribute to the silent strokes, but instead the silent strokes are believed to be causes by hardening of the arteries from poor lifestyle choices like cigarette smoking and untreated high blood pressure. This study is not claiming to fully understand the connection between silent strokes and Alzheimer’s, but only reports that patients who suffer small silent strokes see a rapid acceleration of Alzheimer’s symptoms. There is no way to get rid of the gene for Alzheimer’s, but if you have it and live a healthy lifestyle, the chance of having a stroke is significantly diminished.

Keeping our brains and bodies healthy by making better lifestyle choices is the best advice any doctor could give. By following a proper nutritional plan and getting plenty of exercise, anyone can start now to improve the chances of a longer life without dementia, no matter what lifestyle choices they have made in the past. If anyone has to face Alzheimer’s disease later in life, it is best to live a healthier life now to decrease the chance of strokes that speed up this already difficult disease. Alzheimer’s patients can normally expect a slower progression of symptoms and a better quality of life if they can avoid having strokes. There is no vaccine or other prevention for Alzheimer’s now so take care of your body.

I must point out though, that it seems like scientists are always looking for something to blame most diseases on rather than our poor lifestyle choices. Some blame the genes for Alzheimer’s, others say it is exposure to certain chemicals, and now this new study say small strokes may be responsible. Let’s just be responsible for ourselves and make wise lifestyle decisions!

Reference

Song IU, Kim JS, Kim YI, Eah KY, Lee KS. Clinical significance of silent cerebral infarctions in patients with Alzheimer disease. Cogn Behav Neurol. 2007 Jun;20(2):93-8.

The saying “use it or lose it” is especially true when it comes to the human brain. We need daily stimuli, like puzzles to keep our brains exercised. Artistic activities that challenge you like drawing and painting can give your brain the stimulation and exercise needed for long term healthy function. These concepts are all utilized in most of the new brain games, and therefore the games are not all hype, but are proposed to help fight off Alzheimer’s and dementia. Though some scientists think that these games are premature and that the science doesn’t yet conclusively prove their benefit.

So maybe puzzles and artistic challenges alone enough to keep your brain young. An active brain is not necessarily a healthy one. There are several other things you can do to ensure you really keep your brain healthy. As you work to keep your body healthy through exercise and nutrition you are also feeding your brain. Research has shown that exercise develops new blood vessels in the brain that carry more oxygen-rich blood to the areas of the brain responsible for thinking. Maintaining a healthy lifestyle gives you the benefit of avoiding some of the other medical problems and habits that increase the chances of dementia in old age.

When planning your nutrition, remember your brain needs B vitamins. Leafy green vegetables and whole grains give you the folic acid, B12 and B6 necessary for the healthy function of your brain. Keeping your blood pressure healthy and your cholesterol low impacts your brain and is a natural byproduct of a healthy nutritional plan and exercise regimen. Avoiding the use of tobacco and abuse of alcohol lowers the chance that you will experience dementia, while moderate alcohol use can actually improve the health of the brain. There have been many scientific studies that offer preliminary proof that low doses of alcohol have been linked to a reduction in the risk of dementia.

The best options to reduce the chances of suffering dementia in old age are living a healthy well-rounded lifestyle, rather than just relying on a game to do it all. Combining the power of nutrition, exercise and mental stimulation, whether from a game or from other activities, give our bodies and brains the opportunity to function at their full capacity well into our twilight years.

Reference

Exercising to keep aging at bay. Nature Neuroscience. 2007 Mar;10(3):263.