Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants.

OBJECTIVES: In a longitudinal follow-up study, we compared the clinical features and motor progression of patients with Parkinson disease (PD) who are carriers of the leucine-rich repeat kinase 2 (LRRK2) gene risk variants with patients who are noncarriers. METHODS: We prospectively evaluated a cohort of patients with PD for their clinical characteristics, disease severity, and LRRK2 genotype. Carriers of risk variants (G2385R, R1628P, S1647T) and noncarriers were classified separately. A longitudinal, linear mixed model analysis of motor score progression was performed to compare motor progression between the 2 groups. Motor score progression was defined as the difference between Unified Parkinson's Disease Rating Scale motor score at baseline and follow-up scores. RESULTS: A total of 184 patients (122 risk variant carriers and 62 noncarriers) were evaluated and followed up for up to 6.5 years. No differences in demographics and baseline disease characteristics were found. In the longitudinal, linear mixed model analysis, risk variant carriers experienced greater rate of motor progression than noncarriers after 4 years from the date of diagnosis (p ≤ 0.018). CONCLUSIONS: PD LRRK2 risk variant carriers showed greater motor progression after 4 years of disease duration compared with noncarrier patients, suggesting that these risk variants may facilitate neurodegeneration with increasing disease duration.

Prognostic factors for early mortality in Parkinson's disease.

INTRODUCTION: There are few large studies that have evaluated prognostic factors for mortality in Parkinson's disease (PD). This large study aimed to identify demographic and clinical features associated with early mortality in PD. METHODS: PD patients at the National Neuroscience Institute were identified from the Movement Disorders Database from which demographic information and prospectively collected baseline disease characteristics were obtained. All study patients were linked to the Singapore Registry of Birth and Death to obtain information on vital status through December 31, 2012. The prognostic variables analyzed include patient demographics, baseline disease characteristics, and type of PD medication used. Multivariate Cox regression analysis was carried out to identify factors associated with the risk of mortality in PD. RESULTS: Of the 1786 PD patients identified, 363 (20.3%) had died during the 11-year study period. Median survival time from diagnosis was 15.8 years (range 0.3-31). Factors associated with higher mortality (HR, 95% CI) were older age at diagnosis (1.06, 1.03-1.08), male gender (2.29, 1.57-3.35), Hoehn & Yahr (HY) stage ≥ 2.5 (1.54, 1.07-2.22), UPDRS motor score ≥ 30 (1.63, 1.13-2.35), higher bradykinesia subscores (1.05, 1.01-1.09) and cognitive impairment (2.30, 1.55-3.41). CONCLUSIONS: In the largest study to date evaluating baseline disease characteristics prognostic of mortality risk in PD, we found that male gender, older age at diagnosis, higher baseline HY stage, higher baseline UPDRS motor scores, higher bradykinesia subscores and baseline cognitive impairment were associated with early mortality in PD.

Progression of Parkinson's disease as evaluated by Hoehn and Yahr stage transition times.

This study was carried out to evaluate progression in Parkinson's disease (PD) by analyzing time taken to transit from one Hoehn and Yahr (H&Y) stage to the next stage and to investigate the variables that would be associated with H&Y transition times using a large PD database that contained prospectively collected information. Data were obtained from the movement disorder database of the National Neuroscience Institute in Singapore. Kaplan-Meier (KM) survival analysis was adopted to investigate the time taken to progress through various H&Y stages. Cox regression analysis was used to examine the association between the baseline variables at the entry point of each H&Y stage and the progression to the next stage. A total of 695 patients (mean age: 65.2, male: 57.3%) were studied. Using KM analysis, the median time taken to transit from H&Y stage 1 to 2, 2 to 2.5, 2.5 to 3 were 20, 62, and 25 months, respectively; whereas the median time taken to progress from stage 3 to 4 and 4 to 5 were 24 and 26 months, respectively. Cox regression analysis revealed that older age-at-diagnosis, longer PD duration, and higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at baseline were associated with a significantly faster progression through various H&Y stages. Gender and ethnicity were not associated with disease progression. In conclusion, H&Y transition time is a useful measure of disease progression in PD and may be utilized in clinical studies evaluating therapeutic interventions and prognostic factors in PD.

Cognitive decline in early Parkinson's disease.

Data on the prevalence and severity of cognitive impairment among patients with newly diagnosed idiopathic Parkinson's disease (PD) is limited. Using a prospectively collected clinical database, we studied the longitudinal trend of mini-mental state examination (MMSE) change and baseline factors predictive for MMSE decline. One hundred six patients with mean age of 61.2 years and mean baseline MMSE of 27.8 +/- 2.3 were studied. MMSE increased by 0.4 points/year among patients without cognitive decline (n = 73) and decreased by 2.39 points/year among patients with cognitive decline (n = 33). Univariate analysis demonstrated education, age of diagnosis, depression, and diabetes mellitus to be associated with cognitive decline. Motor scores and hallucination were not associated with cognitive decline. Multivariate analysis demonstrated higher level of education to be protective (HR = 0.91, 95% CI 0.82-0.99, P = 0.047) and depression having borderline significance in predicting cognitive decline (HR = 2.00, 95% CI 0.97-4.15, P = 0.061). We found that 31% of newly diagnosed idiopathic PD patients have measurable cognitive decline at an early stage of disease. Higher education is protective while depression may be predictive of cognitive decline.