The study found an inverse relationship between consumption of coffee or other sources of caffeine and the incidence of Lewy body pathology (LP), suggesting that the relationship may be biologically based.
It's been known for some time through prospective and case-control studies that coffee and caffeine are associated with a lower risk for PD, said lead investigator, G. Webster Ross, MD, Department of Veterans Affairs, Honolulu, Hawaii.
In a new study presented here at the American Academy of Neurology 64th Annual Meeting, Dr. Ross and colleagues report a relationship between coffee and caffeine consumption in life and the presence of LP on autopsy.
"The highest percentage of brains with Lewy pathology was in the group that had no coffee consumption during life, and there was a steady decline in the percent of range of Lewy body pathology as the amount of coffee went up, and this trend was significant," said Dr. Ross.
Protective Mechanism
A paper published in 2000 by Dr. Ross and colleagues that looked at the incidence of PD over 30 years of follow-up showed that the incidence of PD was highest among those who never drank coffee and lowest among those who consumed the most, with a similar trend for total caffeine intake.
The exact protective mechanism is unknown, but according to animal studies, caffeine blocks the adenosine A2A receptors that control movement, which are very sensitive to caffeine. Animal research has also shown a protective effect of genetic depletion of the A2A receptor in knockout models of the gene, said Dr. Ross.
For humans, the jury to date is still out. "Whether coffee or caffeine are neuroprotective in humans remains uncertain," said Dr. Ross. "There's still this sort of nagging idea that people with PD may for some reason avoid coffee and caffeine containing products."
For this study, researchers looked at the association between coffee consumption and LP at autopsy. The participants were enrolled in the Honolulu-Asia Aging Study (HAAS), a prospective analysis of more than 8000 Japanese American men who were living on the island of Oahu at the initiation of the study in 1965.
In 1991, researchers began to identify all cases of PD and dementia and to look for risk factors for these conditions. Since that time, study participants have been examined about every 2.5 to 3 years.
Throughout several decades of follow-up, investigators identified — initially through medical records and then through examinations and surveillance of the cohort — all cases of PD and dementia with Lewy bodies. Diagnoses were confirmed by a neurologist or trained geriatrician using diagnostic criteria.
Also since 1991, researchers have obtained autopsy findings for about 20% of participants who died. The group of 519 men with autopsies included in this study is fairly representative of the cohort as a whole in terms of cause of death, said Dr. Ross.
To identify LP (Lewy bodies and Lewy neurites), researchers used sensitive alpha-synuclein staining in multiple brain stem regions of the 519 participants and performed Braak PD staging. According to the Braak pattern, most PD cases start in the lower brainstem, olfactory bulb, and autonomic system and only later involve higher brain levels, such as the dopaminergic substantia nigra.
Of the 519 autopsied brains; 443 had no LP and 76 brains had LP.
Researchers had assessed coffee consumption during a baseline examination of 24-hour dietary recall from 1965 to 1968, when participants were aged 46 to 67 years (mean age, 54 years). They also assessed covariates of pack-years of smoking, physical activity, and constipation.
The average age at death was 85 years, and the average time from dietary assessment to death was 31.3 years .
Caffeine Quintiles
Investigators determined the percentage of brains with LP within common coffee consumption strata and across quintiles of caffeine (mg/d) intake. They found that the percentage of brains with LP decreased with increasing coffee consumption (P = .013 in test for trend).
Percentage of Brains With LP by Coffee Intake
| Intake Level (oz/d) | Brains With LP (%) |
| Nondrinkers | Reference |
| >0-8 | 14.8 |
| >8-16 | 17.2 |
| >16-24 | 11.4 |
| >24 | 4.7 |
There was a similar pattern for total caffeine intake: the highest percentage of participants with LP was in the lowest quintile of caffeine intake, and the lowest percentage was in the highest quintile of caffeine intake (P = .048 in test for trend).
Although the association with caffeine was weakened after adjustment for age, smoking, constipation, and physical activity (P = .112), the association with coffee intake persisted (P = .023).
After exclusion of PD cases, the age- and risk factor–adjusted results were similar. "The percent of brains with incident Lewy pathology continued to decline with increasing coffee intake," said Dr. Ross. "And the percent of brains with incident Lewy pathology in the top quintile was lower compared to the rest."
Time for a Trial?
Invited to comment on this research, Alberto Ascherio, MD, DrPH, professor of epidemiology and nutrition, Harvard School of Public Health, and professor of medicine, Harvard Medical School, Boston, Massachusetts, said the finding is important and comes from a well-established cohort.
"These results further strengthen the evidence from both epidemiological and experimental studies that caffeine has neuroprotective effects," he told Medscape Medical News. "They suggest that serious consideration should be given to randomized trials of caffeine in Parkinson disease."
The same point was raised during Dr. Ross's presentation by an audience member who pointed out that a single assessment of coffee or caffeine intake as used in this study probably underestimates the effect.
There may be other A2A antagonists that could be tested for other reasons that would provide an alternative, the commenter noted, "but I think the epidemiological data really points to caffeine, so why not do a trial of caffeine?"
Dr. Ross reports having received research funding from the Michael J. Fox Foundation. Dr. Ascherio has disclosed no relevant financial relationships.
American Academy of Neurology 64th Annual Meeting: Abstract #S42.005. Presented April 26, 2012.
Medscape Medical News © 2012 WebMD, LLC
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