Lillian J. Currie

Genome-wide scan for Parkinson's disease: The Gene PD Study

Article abstract— A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine β-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Epidemiologic study of 203 sibling pairs with Parkinson’s disease: The GenePD study

Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

Depression is associated with impairment of ADL, not motor function in Parkinson disease

Depression was diagnosed in 15% of 100 consecutive patients with Parkinson disease (PD). Depression was associated with lower cognition, history of depression, and a higher Unified Parkinson’s Disease Rating Scale score. The latter was due to differences in the activities of daily living (ADL) subscale (17 ± 7 vs 12 ± 6; p = 0.004) rather than the motor subscale (30 ± 13 vs 26 ± 13; p = 0.27). These results suggest that ADL impairment may in part be due to depression. Patients with PD with poor function should be closely evaluated for depression.

Effects of group interventions on cognition and depression in nursing home residents.

The effects of cognitive-behavioral group therapy, focused visual imagery group therapy, and education-discussion groups on cognition, depression, hopelessness, and dissatisfaction with life were studied among depressed nursing home residents. Seventy-six depressed subjects with mild to moderate cognitive decline participated in nurse-led 24-week protocols. Data were collected 4 weeks before the interventions, 8 and 20 weeks after treatment initiation, and 4 weeks after treatment termination. There were no significant changes in depression, hopelessness, or life satisfaction scores for any of the three conditions. Participants in the cognitive-behavioral and focused visual imagery groups showed a significant improvement beginning 8 weeks after treatment initiation on cognitive scores. These findings are encouraging indications that cognitive-behavioral and focused visual imagery group therapies may reduce cognitive impairment in depressed nursing home residents with mild to moderate cognitive decline.

UPDRS activity of daily living score as a marker of Parkinson's disease progression

The activities of daily living (ADL) subscore of the Unified Parkinsons Disease Rating Scale (UPDRS) captures the impact of Parkinsons disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross‐sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

A haplotype at the PARK3 locus influences onset age for Parkinson’s disease The GenePD study

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Gender ratio differences between Parkinson's disease patients and their affected relatives

Mitochondrial dysfunction in Parkinsons disease (PD) is suspected to arise from either acquired or inherited mutation of mitochondrial DNA (mtDNA). If inherited, epidemiologic analysis may reveal maternal transmission. We looked for maternal inheritance bias in our PD clinical database. About 13% of 600 PD probands reported an affected parent. Although 60% of the PD probands were male, only 42% of the affected parents were. The gender ratios for the proband and affected parent generations were dissimilar (p<0.005), indicating an underrepresentation of affected fathers or an overrepresentation of affected mothers. To address these possibilities we analyzed a non-PD control cohort. Four percent of the controls had a PD affected parent, and 75% of these affected parents were male. Apparent maternal inheritance bias in our PD cohort is therefore more likely due to overrepresentation of affected mothers, and is consistent with mitochondrial inheritance in some of our ascertained cases.

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinsons disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ‐1 genes in 292 cases of familial Parkinsons disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Early morning dystonia in Parkinson's disease

We interviewed 383 patients with PD regarding disease onset and medication history and evaluated them using the Unified Parkinsons Disease Rating Scale. Sixteen percent of the sample reported the occurrence of early morning dystonia (EMD). Patients with EMD had been taking levodopa for a longer time, were taking higher daily levodopa doses, demonstrated more disability in carrying out their activities of daily living, exhibited dystonia more often before initiation of levodopa treatment, and experienced more peak-dose and diphasic dyskinesias with levodopa therapy.

Risk profiles for nursing home placement of rural elderly: A cluster analysis of psychogeriatric indicators

In an effort to better understand the clinical and functional status of patients served by our Rural Elder Outreach Program, more effectively identify risk groups, and more efficiently target services, we performed a cluster analysis on 92 older adults served by our program. The first cluster included patients with very poor health, mild cognitive impairment, very high care demands, and migrating toward active risk for institutionalization. The second cluster included patients with poor physical but good mental health, intact cognition, high care demands, and at passive risk. The third cluster comprised patients with high functional, physical, and cognitive impairment, intensive care demands, moderate mental health problems, poor insight into their situation, and at active risk for institutionalization.