FETAL TRANSPLANTS BENEFIT SOME PATIENTS WITH PARKINSON’S DISEASE

Fetal cell transplantation can benefit some patients with severe Parkinson’s disease, according to the first prospective study comparing a transplantation group with a control group. Among the 20 patients who received the transplant, 17 demonstrated evidence that the transplanted cells survived and developed into dopaminergic neurons. The time course and magnitude of clinical changes, however, were more variable. “Transplantation had some benefits in patients 60 years old and younger, but not in older patients,” the researchers noted in the March 8 New England Journal of Medicine.

Forty patients (age range, 34 to 75) with severe Parkinson’s disease (mean duration, 14 years) were randomized to receive a transplant of cultured embryonic tissue into the putamen bilaterally or undergo sham surgery in which holes were drilled in the skull, but the dura was not penetrated. There were no serious perioperative complications except for an asymptomatic hemorrhage noted in one patient. After the first year, 14 of the 20 sham-treated patients opted to receive the implants.

At one year, patients younger than 60 years in the transplant group reported improvement on a subjective global rating scale. The United Parkinson’s Disease Rating Scale (UPDRS) conducted before the first morning dose of levodopa revealed greater improvement among younger patients in the transplant group than those in the sham-surgery group. There were small decreases in rigidity and bradykinesia, but no change in tremor or gait. The Schwab and England scores, which rate activities of daily living, improved significantly among the patients who underwent transplantation. There was no improvement over sham surgery when the patients were tested soon after receiving a dose of medication, the researchers pointed out.

Positron emission tomographic scans detected fiber outgrowth from the transplanted cells in 17 of the 20 patients in the treatment group, regardless of age. Autopsy results in two patients confirmed the growth of transplants in the putamen. Neuromelanin granules, a marker for mature dopamine neurons, were evident in the neurons three years after transplantation. “The fact that parkinsonism did not improve in the older patients during the first year after transplantation, despite the growth and development of dopamine neurons, may reflect a lower degree of plasticity of the brain or more diffuse brain disease in the older group,” the researchers said.

Despite improvements, dystonia and dyskinesia recurred in the second year after surgery in five patients who received transplants, even after substantial reductions in dosage or discontinuation of levodopa. A continued fiber outgrowth from the transplant may have led to a relative excess of dopamine, the researchers suggested. The amount and distribution of transplanted tissue are important factors for further study.

One of the important lessons from this study is that long-term evaluation is necessary, said Gerald D. Fischbach, MD, and Guy M. McKhann, MD, in an accompanying editorial. Mere survival of the transplant is not enough. In order to consider cell transplantation therapy for Parkinson’s disease—whether they are pluripotent stem cells, more restricted precursors, or differentiated neurons—further research is needed to understand their molecular function over time, they said.

Despite improvements, dystonia and dyskinesia recurred in the second year after surgery in five patients who received transplants, even after substantial reductions in dosage or discontinuation of levodopa. A continued fiber outgrowth from the transplant may have led to a relative excess of dopamine, the researchers suggested. The amount and distribution of transplanted tissue are important factors for further study.

The use of sham surgery in this study allowed the researchers to interpret their results more fully, noted Karen Antman, MD, Steven Lagakos, PhD, and Jeffrey Drazen, MD, in a separate editorial. Regrettably, cost constraints and small sample sizes with inadequate statistical power can lower the standards of evaluating novel therapies, such as neuronal transplantation for Parkinson’s disease. Patients often demand access to the new treatment before it can be rigorously evaluated. However, Dr. Antman and colleagues acknowledged, “it is hard to deny a last chance to someone who has no therapeutic options.”

Suggested Reading
1. Antman K, Lagakos S, Drazen J. Designing and funding clinical trials of novel therapies. N Engl J Med. 2001;344:762-763.
2. Fischbach GD, McKhann GM. Cell therapy for Parkinson’s disease. N Engl J Med. 2001;344:763-765.
3. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710-719.

CAN AN ACTIVE LIFESTYLE PROTECT AGAINST ALZHEIMER’S DISEASE?

People with Alzheimer’s disease participated less frequently in physical and intellectual activities between the ages of 20 and 60 than did healthy individuals of similar age, education, and income level, according to a case-control study published in the March 13 Proceedings of the National Academy of Sciences.

Researchers surveyed caretakers of 193 patients with Alzheimer’s disease as well as 358 of the patients’ healthy friends, neighbors, or organizational acquaintances about how frequently they participated in 26 different recreational activities categorized as intellectual, physical, or passive pursuits. The patients had probable (79%) or possible (21%) Alzheimer’s disease and symptom onset within five years of initial evaluation.

Healthy individuals had been more active in a wider variety of pursuits in all three categories during midlife than the patients with Alzheimer’s disease, even after age, sex, income, and education effects had been eliminated, the researchers found. Individuals with a relatively inactive lifestyle had about a 250% increased risk of developing Alzheimer’s disease.

Beneficial effects of physical activity that may be related to reduced risk of Alzheimer’s disease include lower body weight and improved blood pressure and cardiovascular health, the researchers suggested. Activity and environmental complexity have also been associated with enhanced cognitive functioning, and the “use it or lose it” principle might help explain the neuropathology of disease, the researchers said. An inactive lifestyle, therefore, may be a risk factor for the development of Alzheimer’s disease.

Alternatively, infrequent participation in activities may also reflect the very early effects of Alzheimer’s disease. For the average patient, reduction in intellectual pursuits from early to middle adulthood increases the probability of disease. “This relationship between disease and intellectual activity may be interpreted as evidence of the progressive effects of the disease on participation or may also represent a protective effect of intellectual activities,” the researchers said.

Suggested Reading
Friedland RP, Fritsch T, Smyth KA, et al. Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA. 2001;98:3440-3445.

LOW-FAT DIET LINKED TO INCREASED STROKE RISK IN SOME WOMEN

A diet very low in animal fat and protein may not be the best choice for the primary prevention of stroke and cardiovascular disease, according to a study published in the February 13 Circulation.

“Low intake of saturated fat and animal protein was associated with an increased risk of intraparenchymal hemorrhage, which may help to explain the high rate of this stroke subtype in Asian countries,” reported Hiroyasu Iso, MD, and colleagues. They noted that previously published studies have shown that Japan has a twofold higher stroke mortality rate than the United States does, and that the incidence of hemorrhagic stroke is three times higher among Japanese living in Japan than among Japanese living in the United States. In the current study, mean saturated fat consumption (17 g/d) in the lowest decile and median animal protein consumption (43 g/d) in the lowest quintile in the United States were similar to the mean intake in Japan, according to the authors.

Participants included 85,764 women in the Nurses’ Health Study who were between ages 34 and 59 and who were free of diagnosed cardiovascular disease and cancer at enrollment. In 1980, the cohort reported dietary habit as well as known risk factors for cardiovascular disease (ie, body mass index; exercise; alcohol and tobacco use; aspirin, vitamin E, and multivitamin use; hormone use in postmenopausal women; high cholesterol levels; hypertension; and diabetes). By 1994, 74 intraparenchymal hemorrhages were identified among the 690 incident strokes.

In an accompanying editorial, Margo A. Denke, MD, reviewed the study population, method of dietary assessment, reported end events, and significance of findings. “Observational studies have distinct limits, particularly when evaluating risks imparted by minor factors,” she observed. “The Iso et al article pushes the envelope.”

Although she lauded the exceptional follow-up of the Nurses’ Health Study cohort, Dr. Denke described the cohort as “highly selective,” as it is relatively healthy, educated, and predominantly white. This population is also at risk for unusual dietary habits (ie, anorexia nervosa) and is not free of unhealthy lifestyle habits (ie, alcohol and substance abuse), all of which are associated with intercerebral hemorrhage, she said. The study also did not control for advancing age.

The certainty with which the women could be classified according to nutrient intake is critical for the authors’ conclusions to be accepted, wrote Dr. Denke. However, the 61-item food frequency questionnaire is a less precise measure of food intake than more traditional assessments. Although Iso et al validated their choice of this method of dietary assessment by citing a previously published article, only 33% of individuals in that article were classified in the same quintile of food intake by both a food-frequency questionnaire and by dietary records. “In a data set such as the current one, where the major finding relies on the certainty of classification of lowest intake, this magnitude of error in misclassification could make or destroy a significant association,” wrote Dr. Denke.

The events in this study were only possible to see with such a large cohort. Although the incidence of stroke was 0.8% and the incidence of intraparenchymal hemorrhage (n = 74) was 0.09%, this calculated incidence did not control for the use of thrombolytic agents, which, she noted, “would overwhelm the small risk anticipated from dietary intake.”

“My suspicion is that the truth regarding the association between dietary factors and intraparenchymal hemorrhage is entangled in a web of ethnic differences in intracerebral hemorrhage risk, historical differences in pre-World War II protein adequacy of diets, differences in mineral intake associated with dairy and animal meat diets, and chance findings embedded in an imprecise tool used to measure dietary intake,” Dr. Denke concluded.

Suggested Reading
1. Denke MA. Dairy products and red meat: Midwesterners always knew they were good for something. Circulation. 2001;103:784-786.
2. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women. Circulation. 2001;103: 856-863.

BENEFITS OF VITAMIN E QUESTIONED

Vitamin E supplementation has been thought to ward off the oxidative stress associated with such diseases as atherosclerosis, cancer, and Alzheimer’s disease. However, results from a University of Pennsylvania study call into question these purported benefits.

To investigate the dose-response relationship of vitamin E with lipid peroxidation, Emma A. Meagher, MD, and colleagues performed a randomized, double-blind, placebo-controlled study from March 1999 to June 2000. The volunteers, 30 healthy men and women (age range, 18 to 60), were randomized to receive vitamin E at dosages of 200, 400, 800, 1200, or 2000 IU/d, or placebo, for eight weeks followed, by a washout period.

All volunteers were nonsmokers, weighed less than 120% of ideal body weight, and had normal levels of vitamin E, vitamin C, selenium, and cholesterol at screening. None had taken any vitamin supplementation or medications known to interfere with lipid metabolism within the previous month.

The researchers measured three indices of lipid peroxidation: urinary 4-hydroxynonenal (4-HNE) and isoprostanes iPF_2a-III and iPF_2a-IV. Measurements were compared in the six groups at baseline; after two, four, six, and eight weeks of dosing; and one, three, and eight weeks after supplementation was discontinued, according to a report in the March 7 JAMA.

During the trial, vitamin E levels increased in a dose-dependent manner, up to about fivefold. “We administered vitamin E over a broad dose range … all considerably in excess of the recommended daily allowance,” the research group wrote. However, regardless of when measurements were obtained, there was no significant impact of vitamin E on urinary 4-HNE levels or levels of iPF_2a-III or iPF_2a-IV, they noted.

The researchers believe that this study has implications for the evaluation of clinical trials of antioxidants. “We found no evidence of additional effects of supplementing these individuals with a range of dosages of vitamin E on their rate of lipid peroxidation in vivo,” Dr. FitzGerald and colleagues wrote. “Our findings question the potential benefit of the reportedly widespread consumption of vitamin E by healthy individuals.”

NR