CAN NONSTEROIDAL ANTI-INFLAMMATORY DRUGS REDUCE THE RISK OF PARKINSON’S DISEASE?

Research has suggested that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing Alzheimer’s disease, and now there is evidence that the drugs may delay or prevent the onset of Parkinson’s disease in humans as well.

As detailed in the August Archives of Neurology, researchers based their findings on two large cohorts of 44,057 men and 98,845 women who were initially free of Parkinson’s disease, stroke, or cancer. After a minimum of a 14-year follow-up, 415 incident cases of Parkinson’s disease were documented. The investigators found that participants who reported regular use of nonaspirin NSAIDs at the beginning of the study had a lower risk of developing Parkinson’s disease than did nonregular users during the follow-up. Also, when compared with nonusers, no significantly lower risk of Parkinson’s disease was observed among men and women who took two or more tablets of aspirin per day.

“In these large prospective studies, we found a 45% lower risk of Parkinson’s disease among regular users of nonaspirin NSAIDs compared with the nonusers,” reported Honglei Chen, MD, PhD, of the Harvard School of Public Health, and colleagues. “A similar decrease in risk was observed among participants who took two or more tablets of aspirin per day compared with nonusers, but not among those taking smaller amounts of aspirin. These results did not change appreciably after excluding the first two or four years of follow-up or after excluding participants with Parkinson’s disease and dementia.”

In addition, the researchers stated, “Our results are also consistent with the previous epidemiological support of a protective effect of NSAIDs on the risk of Alzheimer’s disease, for which similar biological hypotheses have been proposed. A protective role of NSAIDs in the central nervous system seems therefore likely and should be addressed in future investigations.”

In an accompanying editorial, Mya Schiess, MD, of the University of Texas-Houston Medical School, commented on the findings of Dr. Chen’s team. “Their data, however, do not allow specification of the duration and degree of exposure required to achieve maximum benefit for the population as a whole, information with important public health implications that will require further analysis. It is also likely that benefits of even greater magnitude might be demonstrable if this intervention were applied to the same population as it aged beyond 75 years, [an age group] in which some studies show prevalence rates for Parkinson’s disease exceeding 30%.”

Chen H, Zhang SM, Hernán MA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol. 2003;60:1059-1064.
Schiess M. Nonsteroidal anti-inflammatory drugs protect against Parkinson neurodegeneration. Arch Neurol. 2003;60:1043-1044.

SUN EXPOSURE IN CHILDHOOD MAY REDUCE RISK OF MULTIPLE SCLEROSIS

Greater sun exposure during childhood and early adolescence and more actinic damage are associated with a reduced risk of multiple sclerosis (MS), according to research published in the August 9 BMJ. Researchers at the University of Tasmania in Hobart, Australia, conducted a retrospective, self-report, population based, case-control study to examine the relationship between past sun exposure and MS in the denizens of a high latitude, where there are lower levels of ultraviolet radiation. (Tasmania, at 41-3°S latitude, also has a high prevalence of MS.)

There were 136 cases with MS defined both clinically and on MRI, and 272 randomly selected healthy controls matched for sex and age. Participants completed a standardized questionnaire on the “amount of time they would normally have spent in the sun during weekends and holidays in winter and summer,” said lead author Ingrid van der Mei, a doctoral student at the Menzies Centre for Population Health Research at the University of Tasmania. The questionnaire also addressed measures taken to protect against the sun, use of vitamin D supplements at ages 10 to 15, medical history (including infections and immunizations), and other factors suggested by prior work to be associated with MS. Silicone casts were then employed on the surface of the hand to measure actinic damage as an objective marker of cumulative lifetime sun exposure.

Overall, 68% of cases and controls were female. Average age for both groups was 43.5. After statistical analysis, the researchers found “a strong inverse association between sun exposure in childhood and adolescence and MS,” Ms. van der Mei reported. In particular, higher sun exposure between ages 6 and 15 (average two to three hours or more per day in summer during weekends and holidays) was associated with a one-third reduction in risk of MS. Higher exposure (greater than one hour) in winter between ages 6 and 10 was even more strongly associated with a reduction in risk of MS, Ms. van der Mie added.

Greater actinic damage was also associated with a reduced risk of MS, she noted. However, the effects of greater exposure were suspected to be highest before age 15, as the inclusion of later years into the cumulative lifetime effect diluted the effect. The investigators also observed that the odds of having light skin color (less than 2% melanin) was 1.59 times higher for patients with MS than for controls—though these results were of only borderline significance.

van der Mei IAF, Ponsonby A-L, Dwyer T, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ. 2003;327:316-321.

INFECTIONS LINKED TO MENTAL DECLINE IN ELDERLY

Infections resulting from herpes simplex virus types 1 and 2 and cytomegalovirus are “significantly associated with” cognitive impairment in home-dwelling elderly persons with cardiovascular diseases, according to a study in the September Stroke. Researchers in Finland found the association to be strong, graded, and independent of age, sex, education, and cardiovascular risk factors, including C-reactive protein. The finding was consistent both cross-sectionally and during a 12-month follow-up.

“Our results support earlier hypotheses that certain infections are associated with cognitive impairment and consequent dementia in old age,” reported Timo E. Strandberg, MD, PhD, from the University of Helsinki, and colleagues. “However, this may only apply to neurotropic viruses, such as herpes simplex virus and cytomegalovirus. In our elderly cohort, these viruses were probably contracted in childhood or young adulthood, but in modern society these are increasingly contracted later in life. If these results are verified in larger population-based studies, they may open new avenues to prevent dementia with antiviral drugs or possibly vaccinations.”

The researchers measured antibodies in 383 individuals (mean age, 80); 82% had a history of coronary heart disease, 37% had had a previous stroke, and 18% had type 2 diabetes mellitus. For both herpesviruses, seropositivity was significantly more common among individuals with cognitive decline. At baseline, 0 to 1, 2, and 3 positive titers toward viruses were found in 48, 229, and 106 individuals, respectively. Scores on the Mini-Mental State Examination (MMSE) decreased with increasing viral burden. At baseline, 58 individuals had cognitive impairment, which was found to be significantly associated with seropositivity for three viruses. The MMSE score decreased in 150 subjects in the 12-month follow-up. In addition, the prevalence of possible or definite dementia according to the Clinical Dementia Rating also increased with viral burden. The investigators found no significant association between bacterial burden and cognition.

“The strength of the association, the stepwise increase in the risk of cognitive impairment with increasing viral burden, the temporal association between baseline viral burden and cognitive decline during 12 months, and consistency of data in multiple analyses suggest a causal relationship between viral burden and cognitive impairment,” the researchers reported. “That the relation was independent of cardiovascular risk factors, C-reactive protein, and bacterial burden suggests that the pathogenic sequence may not be via atherosclerosis.”

Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003;34:2126-2131.

NONDOPAMINE DRUG REDUCES SYMPTOMS OF ADVANCED PARKINSON’S DISEASE

The adenosine A2A receptor antagonist istradefylline was well tolerated in patients with levodopa-treated Parkinson’s disease, according to Robert A. Hauser, MD, and colleagues. In addition, the severity of dyskinesia in these patients was unchanged, but “on” time with dyskinesia increased.

“Istradefylline was generally well tolerated and reduced ‘off’ time in this group of advanced Parkinson’s disease patients with both motor fluctuations and dyskinesias,” reported Dr. Hauser, of the University of South Florida, in the August 12 issue of Neurology. “ ‘Off’ time was reduced as assessed by home diaries, and there was a trend for reduced ‘off’ time as assessed by eight-hour in-office evaluations.” The investigators based their findings on a 12-week, double-blind, placebo-controlled study in which subjects with Parkinson’s disease were randomized to treatment with placebo, istradefylline up to 20 mg/day, or istradefylline up to 40 mg/day. Both doses of istradefylline were generally well tolerated, and nausea was the most common adverse event.

Also in the same issue of Neurology, W. Bara-Jimenez, MD, of the National Institutes of Health, and colleagues reported findings of their own in support of the hypothesis that A2A receptor mechanisms contribute to symptom production in Parkinson’s disease and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder. The researchers evaluated 15 patients with moderate to advanced Parkinson’s disease who were randomized to either the selective A2A antagonist istradefylline (KW-6002) or matching placebo.

“KW-6002 potentiated the antiparkinsonian action of a low dose of levodopa, without exacerbating dyskinesias,” Dr. Bara-Jimenez’s team reported. “Indeed, unlike standard treatments for this disorder, the addition of KW-6002 to levodopa actually produced less dyskinesias than levodopa alone given at equivalent antiparkinsonian doses.”

In an accompanying editorial, Andrew Feigin, MD, of the New York University School of Medicine, called the results of the first two human studies of istradefylline to be “encouraging.” He added, “Both trials are exploratory but serve a proof-of-principle.… In far-advanced Parkinson’s disease when intrinsic dopamine is gone, drugs such as istradefylline might be of benefit only when given with levodopa. In early Parkinson’s disease, however, when some intrinsic dopaminergic function remains, istradefylline might be effective as monotherapy.”

Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A2A receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61:293-296.
Feigin A. Nondopaminergic symptomatic therapies for Parkinson’s disease. Neurology. 2003;61:286-287.
Hauser RA, Hubble JP, Truong DD, Istradefylline US-001 Study Group. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;61:297-303.

KETOGENIC DIET AFFECTS LIPOPROTEIN LEVELS IN CHILDREN WITH EPILEPSY

A study to determine the effects of a high-fat ketogenic diet on plasma levels of the major apolipoprotein B (apoB)–containing lipoproteins and the major apolipoprotein A-1 (apoA-1)–containing lipoprotein in a population of pediatric patients with intractable seizures found that there were significant increases in the atherogenic, apoB–containing low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) and a decrease in the antiatherogenic, apoA-1–containing high-density lipoprotein (HDL). The results of the study were reported in the August 20 JAMA.

Investigators from Johns Hopkins University in Baltimore conducted a six-month prospective cohort study of 141 children with difficult-to treat seizures who were hospitalized for initiation of a high-fat ketogenic diet and followed up as outpatients. The mean age of the cohort was 5.2 for 70 boys and 6.1 for 71 girls. A subset of the cohort was also followed for 12 and 24 months.

The main outcome measures for the study were differences at baseline and follow-up for levels of total, VLDL, LDL, HDL, and non-HDL cholesterol; triglycerides; total apoB; and total apoA-1 after administration of a ketogenic diet of a high ratio of fat to carbohydrate and protein combined. After diet initiation, the caloric intake and ratio of fats to carbohydrate and protein were adjusted to maintain ideal body weight for height and maximal urinary ketosis for seizure control, the researchers reported.

At 6 months, the ketogenic diet significantly increased the mean plasma levels of total, LDL, VLDL, and non-HDL cholesterol; triglycerides; and total apoB. Mean HDL cholesterol decreased significantly, though apoA-1 increased. The researchers qualified these changes as “so extensive that only about one in six of the study population had either a cholesterol or triglyceride level in the acceptable range for a pediatric population,” adding that “the magnitude of the changes also considerably exceeds those that might be expected to occur with any laboratory drift overtime.” Additional significant but less marked changes persisted in the children observed at 12 and 24 months, the researchers noted.

Although the authors controlled for age, sex, weight, and ratio of fat to carbohydrate plus protein, the results of the study cannot be extrapolated to a general pediatric population because of the special nature of the cohort—though the researchers believe that it is highly unlikely that is the cause of such marked results.

NR

Kwiterovich PO Jr, Vining EPG, Pyzik BA, et al. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA. 2003;290:912-920.

Return to table of contents