Judith Dobson

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Predictors of weight loss in Parkinson's disease

The objective of this study was to examine the change of body weight (BW) among Parkinsons disease (PD) patients and controls over years and determine the predictors of weight loss among PD patients. Studies on weight loss in PD studies are cross‐sectional, have a short follow‐up, or lack in clinical detail. We examined the percentage of BW change over years among 49 PD patients and 78 controls. The controls were from another study on longitudinal evolution of BW and body composition in the elderly. We determined the BW, Hoehn and Yahr (HY) stage, and dyskinesia status of 49 consecutive nondemented PD patients with symptom duration of 6.1 ± 0.7 years (mean ± SEM) and ascertained their BW at the time of diagnosis and 2.4 ± 0.2 years before the diagnosis from medical records. We collected data again 7.2 ± 0.5 years after the first visit. The PD group lost 7.7% ± 1.5% of BW over the entire symptomatic period (13.1 ± 0.8 years), while the control group lost only 0.2% ± 0.7% of BW over 9.9 ± 0.1 years; weight loss was clinically significant (>5%) in 55.6% of PD patients vs. 20.5% of the controls (both P values < 0.001, adjusted for sex, baseline age, and observation period duration). PD patients lost weight in both the early and advanced phases. While worsening of parkinsonism was the most important factor, age at diagnosis, emergence of visual hallucinations, and possibly dementia were also associated with weight loss. We demonstrated significant weight loss in PD patients compared to controls over approximately 1 decade. Neurodegeneration involving both motor and nonmotor systems may be associated with weight loss in PD.

Stroke and its modification in Parkinson's disease.

Previous studies have not agreed on the incidence of ischemic stroke in persons with Parkinsons disease. There are epidemiologic and neurochemical facets of Parkinsons disease that might confer some benefit or protection against ischemic stroke. We used a case-control method to determine the lifetime history of ischemic stroke in 200 patients with Parkinsons disease and 200 controls of a similar age range. Analysis was also carried out for myocardial infarction as a marker of generalized atherosclerotic disease and for stroke risk factors. The cumulative incidence of ischemic stroke was significantly less in the patients with Parkinsons disease than in the controls, as was the cumulative incidence of myocardial infarction. Among risk factors, significantly fewer patients with Parkinsons disease used tobacco than controls. The decreased incidence of ischemic stroke in the patients with Parkinsons disease appears to be related to their less severe generalized atherosclerosis, possibly due to their lower incidence of tobacco use. In view of the known potential for dopamine to exacerbate experimental ischemic tissue damage, the possibility that the dopamine deficiency in the central nervous system of persons with Parkinsons disease confers an additional specific protective benefit against ischemic stroke cannot be excluded and requires further study.

Circadian fluctuations of contrast sensitivity in Parkinson's disease

Spontaneous circadian fluctuations of motor symptoms in Parkinsons disease (PD) often occur, with dysfunction typically less severe in the early morning than in the afternoon. In 23 PD patients with or without a history of circadian motor fluctuations, we studied contrast sensitivity (CS), a non-motor function, considered to be dependent on dopaminergic transmission to see if it exhibits similar circadian variability. We tested CS throughout the day at 2-hour intervals beginning at 8:30 am. To facilitate multiple testing sessions, we used a rapid, printed, forced choice test of CS not requiring a motor response. We tested CS in 43 eyes in the PD patients and 23 eyes in 12 controls at spatial frequencies of 1.5,3,6,12, and 18 cycles per degree (cpd). At 8:30 am, CS in PD did not differ from that of controls, but at all other testing times it was significantly worse at 3 or more spatial frequencies. In PD, CS was significantly worse at 2:30 pm than at 8:30 am at 3 and 6 cpd, but in controls it was unchanged throughout the day. Separate analysis of CS in PD patients, with and without a history of circadian change in motor symptoms, revealed no significant difference between the groups. These results suggest that in PD a non-motor dopaminergic function can exhibit circadian variability and that this pattern can exist in the absence of similar variability in motor symptoms. Circadian variability which parallels the most common pattern of motor variability in PD supports the notion that the CS abnormality in this condition is related to dopamine deficiency.

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinsons disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinsons disease in our large sample of familial PD patients.