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The aging process is associated with an accumulation of oxidative damage to mitochondrial DNA (mtDNA).1 2Mutations and deletions of mtDNA accumulate with aging in various tissues including germ lines.3 4 The resulting mitochondrial defects, if transmitted to offspring through the maternal line, could potentially play a part in the pathogenesis of several neurodegenerative illnesses including Parkinson's disease.5 In addition, advanced maternal age at the time of conception results in increased risk of genetic birth defects. This is in part due to chromosomal mutations and malfunctions within the ova which are in turn due to the increased age of the ovary and the ova. We examined the age of mothers at birth of patients with Parkinson's disease and controls to evaluate whether maternal age may be a risk factor in the development of Parkinson's disease.
Subjects were recruited from the Movement Disorders Clinic at the University of Virginia. We interviewed 629 consecutive patients with Parkinson's disease and 376 consecutive spousal controls regarding their mother's age at the time of the subject's birth (maternal age). The diagnosis of Parkinson's disease was based on internationally accepted criteria. At least two of the following three criteria had to be present: rest tremor, cogwheel rigidity, and bradykinesia. Asymmetry of these features at the time of diagnosis and at onset had to be present. Exclusion criteria included presence of atypical features, presence of a pre-existing possible cause, definite absence of response to levodopa, and a clearly non-progressive course over at least 3 years. Moreover, 69% of the patients with Parkinson's disease had been examined on multiple occasions thus increasing both our confidence in and accuracy of the diagnosis of Parkinson's disease.
The original data set of 1005 subjects was reduced to obtain groups of equal size as well as groups similar in sex proportion and age. Firstly, we excluded 79 cases in which maternal age was missing. This elimination of cases with missing data resulted in the groups being of similar age. From the new data set of 926 informants, we next randomly selected men and women from each subject group. The number of subjects to be selected was determined by the minimum group, the male control group (n=106), for which we were able to ascertain maternal age and also preserve the 1.5:1 male to female sex ratio found in the original sample. After this final exclusion of 572 cases, complete data from 177 patients with Parkinson's disease and 177 control subjects were used for the data analyses.
Data were analyzed using Student's t test for continuous variables and χ2 tests for categorical variables. Logistic regression was performed to determine whether maternal age was associated with risk of Parkinson's disease. All probability (p) values are two tailed.
The Parkinson's disease group and the control group each comprised 106 men (60%) and 71 women. The mean age (SD) of the patients was 67 (10) years compared with the control group mean age (SD) of 66 (10) (p=0.41). The age of onset of symptoms of Parkinson's disease among the patient group ranged from 32–82 years with a mean (SD) of 59 (11) years. Sixty three per cent of the patients received their diagnosis within 2 years of symptom onset (range<1 year to 10 years, with a mean (SD) of 1 year (1.8)).
The age of mothers at the time of the patients' birth ranged from 13 to 43 years with a mean (SD) of 27 (7) years. In the control group, maternal age ranged from 15–49 years with a mean (SD) of 27 (7) years. There was no difference between the groups for mean maternal age (p=0.63).
Maternal age was recoded into eight groups of 5 year increments. The percentage of patients and controls in each maternal age group is shown in figure 1. Not surprisingly, the greatest number of patients and controls were born to women age 20 to 35 years. Analysis by Χ2 showed no significant differences in the proportion of patients and controls across the maternal age categories (p=0.09).
Logistic regression examined the association between maternal age and Parkinson's disease. The odds ratio (0.99) for maternal age was not significant (p=0.63; 95% confidence interval (95% CI) 0.96–1.02) indicating that maternal age did not influence the risk of developing Parkinson's disease.
Our data show no differences between patients and controls for the age of mothers at the time of the subjects' birth. In fact, the distribution curve of mothers' age at the time of birth of patients with Parkinson's disease closely approximated the maternal birth curve of the control group. In addition, we found no differences in the proportion of patients and controls when maternal age was grouped in 5 year increments. Although a greater number of patients were born to women between ages 35 and 44, and only control group subjects were born to women over 44 years of age, these differences were not significant. Furthermore, the odds ratio did not approach significance, indicating that maternal age also did not affect the risk of developing Parkinson's disease.
The results of this study suggest that genetic mutations acquired by aging oocytes are not pivotal in the development of Parkinson's disease. If acquired mtDNA mutations of female gametes were a significant factor in the pathogenesis of Parkinson's disease, maternal age at birth would be higher for patients with Parkinson's disease than for age matched controls. These data show no difference in maternal age at birth between patients and controls. Thus, transmission to offspring of somatic mtDNA mutations that accumulate as the mothers age is unlikely to play a part in the cause of Parkinson's disease. However, the results of this study do not exclude a role for inherited abnormalities of mtDNA mutations in this disease. Homoplasmic polymorphisms or heteroplasmic sequence abnormalities could still account for a proportion of those with Parkinson's disease. Indeed, either of these possibilities, especially heteroplasmy, is consistent with the high degree of variability in the clinical expression of mtDNA mutations and the apparent sporadic occurrence of this disease.
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