Clinical Trials (Aging)

According to data provided by the National Institutes of Health (NIH), more than 3,000 clinical trials have been launched since the late 1990s to test potential therapies for age-related diseases such as Alzheimer’s disease (AD), cardiovascular disease (CVD), osteoporosis, and Parkinson’s disease. These trials typically enroll anywhere from 50 to 5,000 subjects and can last for just a few months to more than 50 years. The estimated cost of all of these trials is more than $20 billion, much of which comes from pharmaceutical companies. All of the trials discussed in this topic were preceded by years of basic research involving mice or primates, which establishes the basic protocol for subsequent human trials. Alzheimer’s disease, CVD, and osteoporosis are easily the subjects of the greatest number of trials, some of which have led to effective therapies. This topic also describes clinical trials involving Parkinson’s disease and the role of hormones, nutrition, and lifestyle in modulating the onset of age-related diseases.

Alzheimer’s disease

Clinical trials involving AD have focused on therapies that might rejuvenate the damaged neurons and eliminate the beta-amyloid plaques that are associated with this disease. Three such therapies that have been tested are antioxidants, amyloid immunotherapy, and gene therapy.

Antioxidants

According to the free radical theory of the aging process, antioxi-dants should help reduce some of the symptoms associated with cellular senescence. In addition, research on longevity genes has shown that some of these genes code for proteins that minimize oxidative damage to cells and tissues. Several lines of evidence going back to the 1990s suggest that antioxidants, such as vitamin C and E, protect the brain from Alzheimer’s disease and may even reverse some of the clinical symptoms in those patients already affected. Presumably, antioxidants block the formation of beta-amyloid and neurofibril-lary tangles or they aid in the removal of these substances.


Peter Zandi and his associates have studied the effects of vitamin C and E, alone and in combination, on elderly subjects (age 65 or older) in Cache County, Utah. All participants in the study were given a standardized battery of tests to assess the prevalence of AD within the group. Of the original 4,740 subjects, 1,513 either died or withdrew before the trial was completed, leaving a total of 3,227 subjects. Participants consumed at least 400 IU of vitamin E and/or 500 milligrams (mg) of Vitamin C every two weeks. The results showed that vitamins C and E, when taken together, reduced the prevalence and incidence of AD. Neither vitamin, when taken alone, had any effect.

In 2006 the American National Institute of Aging (NIA), a part of NIH, launched a multicenter clinical trial to confirm and extend these results. This study, titled "Evaluation of the Safety, Tolerability and Impact on Biomarkers of Anti-Oxidant Treatment of Mild to Moderate Alzheimer’s Disease" is a phase I clinical trial that enrolled 75 subjects, all of whom suffer from AD. The principal investigator is Douglas Galasko at the University of California, San Diego. All of the subjects were randomly sorted into three groups. One group received vitamin C, vitamin E, and an antioxidant, the second group received antioxidant only, and the third group was given a placebo. The treatment period is expected to last for five years. The effects of the two antioxidant treatments will be evaluated by determining the amount of beta-amyloid in the blood and cerebrospinal fluid (CSF) at the beginning and end of the period. A treatment that increases the removal of beta-amyloid from the brain is expected to decrease the level of this protein in general circulation and in the CSF.

Vitamin B has also been tested on patients suffering from AD. Scientists believe that this vitamin could slow the progression of AD by inhibiting the formation of homocystein, an amino acid that is elevated in people suffering from this disease. Dr. Paul Aisen and his team at the University of California, San Diego, studied the effects of vitamin B in 409 people with mild to moderate AD. These subjects were divided into two groups; one received the vitamin, and the other was given a placebo. Cognitive decline was then monitored over an 18-month period. The results showed that while the vitamin treatment did lower the levels of homocystein, it had no effect on reducing the incidence of cognitive decline and thus no effect on lowering the risk for AD. Moreover, the group receiving the vitamin was more prone to depression than were those receiving the placebo. These results were published in the October 15, 2008, issue of JAMA (the Journal of the American Medical Association).

Amyloid Immunotherapy

An alternative to removing beta-amyloid from the brain with antioxidants is to immunize the body against beta-amyloid. This approach was originated by scientists at Elan, a pharmaceutical company located in Dublin, Ireland, that develops treatments for neurological disorders. Preclinical research in the late 1990s demonstrated the effectiveness of this type of therapy. It was hypothesized that injection of a synthetic amyloid, AN-1792, into the bloodstream would lead to the formation of antibodies directed against AN-1792 as well as the native beta-amyloid, and that these antibodies would enhance clearance of beta-amyloid from the brain. Injection of AN-1792 appeared to stimulate clearance of the protein from the brains of experimental animals.

Elan initiated a phase I study of AN-1792 in 2000. This trial was designed to assess safety, tolerability, and immunogenicity (the amount of antibody produced by each subject) in response to injections of various doses of AN-1792. The trial also helped to identify doses and regimens that could be used in later studies. In 2001 Elan initiated a phase II trial to determine the clinical effectiveness of this therapy, but terminated it when four of the subjects developed encephalitis, one of whom died as a consequence. Despite these problems, the phase II trial provided evidence to support the beta-amyloid immunotherapy approach. After 12 months of treatment, several subjects responded with improved memory, attention, and concentration. Levels of the Tau protein in the cerebrospinal fluid decreased in the treated group, suggesting improved turnover and clearance. To overcome the problems associated with AN-1792, researchers at Elan adopted a different strategy by producing a monoclonal antibody called bapineuzumab (AAB-001) to beta-amyloid. This antibody was used in a subsequent phase I trial involving 30 subjects who were given a range of doses (0.5 mg per kg to 5.0 mg per kg). The trial was conducted for one year, and although one of the patients receiving the highest dose developed a fever, none developed serious clinical symptoms. A multicenter phase II trial was launched by NIA and Elan in April 2005 with 240 subjects enrolled. This trial is expected to run until 2010. The subjects, all between 50 to 85 years of age and diagnosed as probable AD cases, were randomly divided into two groups: one receiving the antibody and the other a placebo. The trial is double-blind, meaning that neither the subjects nor the personnel delivering the treatment know who is receiving the antibody or the placebo. Each patient’s participation is scheduled to last for approximately two years.

Gene Therapy

Mark Tuszynski and his team at the University of California in San Diego have used gene therapy in a phase I clinical trial to treat AD. Preclinical research has shown that neural growth factor (NGF), could slow the progression of AD symptoms when injected into the brains of mice. Tuszynski’s team began by isolating skin cells from each of the eight subjects enrolled in the trial, all of whom were diagnosed as suffering from AD. The skin cells were transfected with a viral vector containing the NGF gene and grown in tissue culture to confirm expression of the NGF gene. Cells testing positive for NGF were injected into the brains of the subjects from whom they were isolated. The first two patients received the injections under local anesthetic. One of these patients moved during the procedure and subsequently died from a brain hemorrhage. The remaining subjects were injected under a general anesthetic; all recovered fully from the operation. A follow-up in 2006 has shown that the extra NGF, being produced by the transgene, slowed the normal progression of the disease in six of the subjects. Memory tests indicated that cognitive decline was reduced by almost 50 percent. In addition, brain scans indicated increased activity levels over those obtained prior to the treatment. If these results are confirmed in other trials, it will be the first time a therapy actually prevented cell death in patients suffering from AD.

Ginkgo Biloba

Ginko biloba is a deciduous tree of ancient lineage that once grew in many parts of the world. Today it grows wild primarily in the Zhejiang province of eastern China. Ginkos are very hardy, and one specimen growing in China is said to be nearly 3,000 years old. The Chinese have long used an extract of the leaves as an herbal medicine to boost blood circulation and memory functions. It is also one of the top 10 natural pharmaceuticals used by Americans.

A ginkgo biloba extract has been tested by scientists at NIH for its ability to enhance memory in elderly subjects. Initial studies showed some promise, but a randomized controlled clinical trial concluded in 2008 that this herbal medicine is ineffective as a treatment for Alzheimer’s disease. Moreover, the treatment failed to reduce the incidence of cardiovascular disease, stroke, and overall mortality. This trial enrolled more than 3,000 subjects who were followed for nearly seven years.

Cardiovascular disease

CVD trials are observational and experimental. Observational trials study the lifestyle, diet, and natural progression of CVD in a selected population. The experimental trials have examined several possible therapies to treat atherosclerosis and damage to the heart muscle itself, which often occurs after a heart attack. The trials discussed in this section examined a large number of potential therapies for CVD, including an attempt to repair damaged heart muscle with gene therapy.

The Framingham Heart Study

In 1948 the American National Heart, Lung, and Blood Institute, a division of NIH, launched the Framingham heart study, the largest and most comprehensive CVD trial to date. At that time very little was known about CVD, but epidemiologists had noted that the disease, which began to appear in the early 1900s, had reached epidemic proportions by the 1940s. The objective of this observational study was to identify the common characteristics that contribute to CVD by following its development over a long period of time in a large group of subjects who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke.

The researchers recruited more than 5,000 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, for extensive physical examinations and lifestyle interviews that would be analyzed for their relevance to CVD. Since 1948 the subjects have returned to the study every two years for a detailed medical history, physical examination, and laboratory tests. In 1971 the study enrolled a second generation of subjects, consisting of the original participants’ adult children and their spouses. The study was expanded to include a third generation when the grandchildren of the original cohort were enrolled and currently involves more than 4,000 participants.

Analysis of the data produced by the Framingham trial has identified several risk factors (a term that was coined by the trial researchers): high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity. In addition, the trial collected a great deal of information on the effects of related factors, such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Although the Framingham cohort is primarily white, the importance of the risk factors identified in this group have been shown in other studies to apply to all racial and ethnic groups. The many and varied results obtained by the Fram-ingham study have been the subject of more than 1,200 articles in science and medical journals. Over the past 10 years the identification of CVD risk factors has become the focus of many experimental trials that have led to the development of effective therapies and preventive strategies.

The women’s Health Initiative (WHI)

The Women’s Health Initiative (WHI), sponsored by NIH, was a long-term study of health issues involving postmenopausal women. This initiative consisted of an experimental clinical trial and an observational study (OS) with a combined enrollment of more than 160,000 women at 40 clinics in the United States. The clinical trial, with an enrollment of more than 68,000 women, was divided into three components: dietary modification (DM), calcium and vitamin D supplementation (Cal-VDS), and hormone therapy (HT).

The HT trial tested the effects of hormones, specifically equine (horse) estrogen and progestin (a synthetic progesterone), on the age-related progression of breast cancer, colon cancer, and heart disease. The Cal-VDS trial (discussed in a later section) examined the role of calcium and vitamin D supplements on the development of osteoporosis and colon cancer, and the DM trial determined the effect of a low-fat, high fruit and vegetables diet on CVD and colon cancer. The OS tracked the medical history and health habits of women who were not receiving a WHI intervention.

The results of this initiative were surprising and disappointing. The HT trial was terminated prematurely when the results began to show that the treatment was doing more harm than good: It actually increased the incidence of CVD rather than reducing it. A similar result was obtained with a second group of women treated with equine estrogen only. The results of the DM trial, like the HT trial, failed to show any benefit. Contrary to prevailing wisdom, reducing total fat intake and increasing one’s consumption of fruits and vegetables did not reduce the risk of developing CVD.

As thorough as these studies were, they have been criticized on several points:

1. Using equine (horse) estrogen instead of 17ffl-estradiol (human estrogen) in the HT trial. These two forms of estrogen are not identical, and critics have pointed to a small clinical trial, concluded in 2001, that showed a reduction in the incidence of atherosclerosis among postmenopausal women receiving 17ffl-estradiol instead of the placebo.

2. Failure to ensure a reasonable level of physical activity in all subjects, whether they received the placebo or the HT. Interactions between physical activity and hormonal environment are known to be important in maintaining a healthy cardiovascular system. Variations in this study parameter could have negated any beneficial effects of the treatment.

3. Focusing on total fat rather than the type of fat in the DM trial. Medical researchers have known for decades that saturated fats from meat and dairy products can be harmful, whereas unsaturated fats, such as those found in olive oil, can be beneficial. All of the subjects had to reduce total fat intake, but the results are flawed if some of the women received their entire daily fat quota from dairy products instead of olive oil or whole grains. Critics point to a small clinical trial, conducted by Ramon Estruch of the University of Barcelona, Spain, which showed that a high-fat Mediterranean diet (i.e., fat from olive oil, fruits, and nuts) was better for the cardiovascular system than a typical North American low-fat diet (all fat obtained from meat and dairy products). Thus the type of fat is the critical factor, not total fat. The results of this study were published in the Annals of Internal Medicine on July 4, 2006.

Hormone replacement therapy (HRT)

Several prominent hormones, such as estrogen, testosterone, thyroid hormone, and growth hormone (GH) decrease dramatically as people reach their sixth decade. One example is the drop in estrogen levels when a woman goes through menopause. Men experience a similar, though more gradual, decline in testosterone levels when they reach a comparable age (referred to as andropause). The effect of this decline on human physiology is profound.A disturbance in this ratio weakens our bones, our immune system, and places us at an elevated risk of developing cancer, arthritis, osteoporosis and other diseases.

Estrogen and testosterone supplementation, which has been a routine medical procedure, is known to reverse the onset of osteoporosis and can alleviate the symptoms of osteoarthritis. The great concern associated with the use of these steroids is their suspected role in cancer induction. The results of the Women’s Health Initiative, described above, showed an increased risk in the group receiving HRT for heart attacks, breast cancer, and stroke. But the effect was relatively small. For example, the study suggested that of 10,000 women getting hormone therapy for a year, eight more will develop invasive breast cancer and seven more will have heart attacks than a similar group not taking hormones. The benefits would be six fewer cases of colorectal cancer and five fewer hip fractures. A follow-up study in 2009 confirmed the increased risk of breast cancer in women receiving estrogen supplements. The American researchers concluded that a 50 percent drop in the number of women taking HRT means 1,000 fewer cases of breast cancer each year. Nevertheless, many physicians believe HRT is still an appropriate therapy in many cases.

Human growth hormone (HGH) is another hormone that has been used in an effort to reverse the symptoms of age. The first clinical trial to test the effects of growth hormone supplements on the elderly was conducted in the early 1990s by Dr. Daniel Rud-man and his colleagues at the Medical College of Wisconsin. The trial ran for 21 months and enrolled 45 men, all of whom were 65 years of age or older. Half of the group received daily injections of synthetic hGH, and the other half received no treatment. At the end of the trial period, the experimental group showed an increase in bone density, lean muscle mass, and skin thickness, and a reduction in the amount of subcutaneous fat tissue.

Since the Rudman trial, several companies have begun selling hGH as an anti-aging miracle drug. But this hormone is much more dangerous to use than are the sex steroids. Growth hormone, as its name implies, promotes growth in children and adolescents, but in a fully mature individual, GH takes care of many other physiological chores, including the daily mobilization of energy reserves and amino acids. The adult chores require much less hGH than would be present in a child or an adolescent. Replacement therapies often produce dangerously high concentrations of hGH in the blood, which can lead to a condition known as acromegaly. This disease, first described in the 1930s, is the result of excessive GH production in an adult, leading to severe disfigurement of the face, hands, and feet, as well as overgrowth of soft tissue, leading to thickening of the skin and visceral organs.

In recent years acromegaly has occurred in laboratory-bred transgenic salmon, containing an extra GH gene. Initially, these fish simply grow faster than their cohorts, but as they approach sexual maturity, they suffer extreme deformities of the head and spine, making it difficult for them to feed and swim (these fish are produced for research purposes only). Because of its dangerous side effects, companies that attempt to sell hGH as a medicinal drug face the imposition of very stiff fines from the FDA.

Researchers at Washington University School of Medicine, St. Louis, Missouri, have shown an increase in bone density with a reduction in fat content in 74-year-old men and women being treated with dehydroepiandrosterone (DHEA). The effect was similar in magnitude to that observed in the Rudman trial.The trial ran for six months, and the experimental group, consisting of 10 women and eight men, received oral DHEA replacement at 50 mg per day.

Scientists in the United Kingdom (UK) have shown that the cognitive function of elderly men (55 to 75 years old) can be improved by inhibiting the synthesis of cortisol. Test subjects received carbenoxolone three times daily for four weeks. Carbenoxolone is a drug that inhibits the synthesis of cortisol from circulating inert cortisone. Subjects receiving carbenoxolone showed a marked improvement in verbal skills and memory function.

Researchers at the University of Washington have studied the effect of GH on mental acuity. This trial enrolled 89 adults, all of whom were over 65 years of age. Unlike the Rudman trial, the experimental group in this trial received regular injections of growth hormone-releasing hormone (GHRH) rather than GH itself. The results not only confirmed the earlier GH trial, but also suggested that the age-related decline in the amount of GH is due to an age-related change in the hypothalamus, where GHRH is synthesized.

Nutrition and lifestyle

A variety of studies dating back to the 1980s have shown that a proper diet, regular exercise, moderate alcohol consumption, and abstinence from smoking can reduce the incidence of age-related diseases and conditions, such as CVD, cancer, and AD.

A comprehensive trial titled "Healthy Ageing: a Longitudinal study in Europe (HALE)" examined the benefits of a Mediterranean diet on the prevention of coronary heart disease, cardiovascular disease, and cancer. The study, which ran from 1998 to 2004, enrolled more than 1,000 men and women, aged 70 to 90 years, in 11 European countries. The decision to focus on a Mediterranean diet was based on preliminary studies showing that such a diet was associated with extreme longevity and a healthy elderly population. Jeanne Calment, the longest-lived human to date, is a famous example of this relationship.

The Mediterranean diet, as practiced in southern Italy, southern France, Greece, Portugal, and Spain, is characterized by a high consumption of fruit and vegetables, bread and other cereals, olive oil, fish, and regular but moderate quantities of red wine. This diet was first described in 1945 by Ancel Keys, an American physician who noted that while North Americans and Mediterraneans consume an equivalent amount of fat, Mediterraneans experience lower rates of CVD, cancer, and other age-related diseases. Subsequent analysis of the Mediterranean diet has shown that the fat, obtained primarily from olive oil, is unsaturated and contains a high concentration of powerful antioxidants, which, as explained in topic 4, protect organs and cells from the damaging effects of free radicals. In addition, unlike the animal fat that is typical of a North American diet, olive oil lowers cholesterol levels in the blood and is resistant to oxidation; two features that could be directly responsible for the lower incidence of CVD in European populations.

In the HALE study, subjects adhering to a Mediterranean diet had a 50 percent lower rate of cancer and CVD, thus confirming the benefits of a healthy diet in general, and the Mediterranean diet in particular. Whether the Mediterranean diet can increase the mean human life span, the way caloric restriction increases the mean rodent life span, is yet to be determined. A starvation diet appears to be the only sure way to increase the mean life span of a mammal. It has been shown to work in mice, rats, and Rhesus monkeys. In these cases, caloric restriction is associated with a reduction in the amount of low-density lipoprotein (LDL), a lower body weight, and a more youthful appearance. On the other hand, these animals, by necessity, are less active and much more boring than the control group.

Caloric restriction is important from a theoretical point of view, but it is never likely to form a practical therapy. North Americans in general find it difficult maintaining even modest shifts in eating habits. The typical CR diet, which reduces caloric intake to one-third of normal levels, is not likely to attract a large following. Nevertheless, CR experiments highlight the importance of diet on the rate of aging, and this could at least encourage healthier, low caloric eating habits.

Several clinical trials have studied the benefits of physical activity in the elderly. One of the earliest of these trials was conducted in 1994 on 100 frail nursing home patients with an age range of 72 to 98 years. This trial was funded by the National Institute of Aging and conducted in Boston, Massachusetts. Half of the subjects, chosen at random, engaged in daily weight lifting exercise (resistance training) on a cable-pulley machine three days per week, 45 minutes per session, for 10 weeks. The control group engaged in three activities of their choice offered by the recreational-therapy service of the facility. No resistance training was allowed, but aerobic or flexibility exercises were permitted. Typical activities were walking, calisthenics while the subject was seated, board games, crafts, concerts, and group discussions. At the end of the trial, the experimental group showed a dramatic improvement in muscle strength (113 percent versus 3 percent in the control group). Gait velocity improved by 12 percent in the exercisers, but declined by 1 percent in the control group. Stair-climbing power improved by 28 percent in the exercisers, but only by 4 percent in the nonexercisers. On a qualitative level, the researchers noted an increase in the level of spontaneous physical activity among the experimental group, but not among the controls. The results also indicated that muscles in the elderly, even in the very elderly, could respond to weight-bearing exercise.

Since the Massachusetts trial, many recent studies have shown that exercise not only improves the overall physical well-being of the elderly, but it reduces the incidence of CVD, cancer, diabetes, and AD. Studies around the world have consistently shown that people who reach a healthy advanced age (85 or older) invariably have had a life-long habit of engaging in physical activity and generally adhere to a Mediterranean diet or something similar to it.

Osteoporosis

Many trials have been conducted to test a variety of treatments for osteoporosis. The most successful treatments to have come out of these trials include the bisphosphonates, parathyroid hormone, and estrogen.

Bisphosphonates

Risedronate (Actonel), alendronate (Fosamax) and ibandronate (Boniva) have been approved by the FDA for the treatment of osteoporosis. Only the first two are available in oral formulations and thus figure prominently in the clinical trials discussed below. Actonel and Fosamax are usually administered with calcium and vitamin D supplements.

Five placebo-controlled clinical trials have shown that Actonel and Fosamax substantially reduce the risk of vertebral fractures. In one trial, known as the hip intervention program (HIP), Actonel reduced hip and other nonvertebral fractures in 70- to 79-year-old women, who already had severe osteoporosis, by more than 60 percent. Similar results were obtained with Fosamax in a separate trial. A large multi-center trial known as the Vertebral Efficacy with Risedronate Therapy (VERT) study showed that Actonel is just as effective at preventing vertebral fractures (a reduction of 65 percent). A companion study known as the Fracture Intervention Trial (FIT) showed that Fosa-max reduced the incidence of bone fractures by 47 percent in elderly women who had already suffered vertebral fractures. The VERT trial, HIP, and FIT were three-year trials designed to test the effectiveness of Actonel and Fosamax on postmenopausal osteoporosis, which is the most severe form of this disease. It is important to note that these drugs not only increase bone mineral density (BMD), but also reduce the risk of secondary fractures, which are often the most debilitating.

Parathyroid Hormone

Several recent trials have shown that daily injections of a recombi-nant human parathyroid hormone called Forteo reduced the risk of vertebral fractures by 65 to 69 percent, and the risk of nonvertebral fractures by 40 percent. The long-term effects of this treatment are unknown; as a consequence, this drug is approved for a maximum of two years of use, and only for patients with severe osteoporosis who are at high risk of developing fractures.

Estrogen

The Women’s Health Initiative (WHI), described above in relation to CVD, also studied the effects of hormone therapy on osteoporosis. The analysis concluded that hormone therapy reduced the risk of vertebral and hip fractures by one-third as compared with a placebo. Subsequent concerns regarding long-term estrogen therapy, coupled with the success of the bisphosphonates, led to the recommendation that estrogen not be used to treat or prevent osteoporosis.

Parkinson’s disease

Most research concerning Parkinson’s disease is still at the preclini-cal stage. The primary treatment for this disorder is a drug known as levodopa, a precursor to dopamine. This drug alleviates some of the symptoms of PD, but only for a limited time. In 2006 the FDA approved a new drug call Azilect for the treatment of this disease. The effectiveness of this new drug was established in three 18- to 26-week, randomized, placebo-controlled trials. In one of these trials Azilect was given as initial monotherapy and in the other two as adjunctive therapy to levodopa. The studies, which included more than 1,500 patients, showed that Azilect slowed the progression of PD while also demonstrating good tolerability.

Azilect, produced by Teva Neuroscience, a pharmaceutical company based in Israel, exerts its effect by inhibiting an enzyme called monoamine oxidase (MAO), which in turn is responsible for destroying dopamine. Inhibition of MAO leads to a buildup of dopamine, which helps alleviate many of the symptoms associated with PD. Azilect is prescribed as a daily monotherapy, and as an addition to levodopa in more advanced cases.

Many scientists believe that vitamin deficiencies could exacerbate the progression of PD. Researchers at the Emory University School of Medicine in Atlanta, Georgia, tested this assumption in a trial consisting of 100 Parkinson’s patients, 97 Alzheimer’s patients, and 99 healthy people matched for age and other factors. The results showed that the subjects suffering from PD had the lowest concentration of vitamin D (31.9 nanograms per milliliter of blood), compared with 34.8 nanograms among Alzheimer’s patients and 37 nanograms among the healthy controls. Thus it may be possible that chronically low levels of vitamin D may increase the risk of develop -ing PD. This study was published in the October 2008 issue of the Archives of Neurology. Future studies will determine whether the maintenance of normal Vitamin D levels will improve the symptoms associated with Parkinson’s disease.

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