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1.  A prospective study of statin use and risk of Parkinson disease 
Archives of Neurology  2012;69(3):380-384.
Statins have been found to have potent anti-inflammatory and immunomodulating effects, which led to the hypothesis that statins could be neuroprotective agents. However, the beneficial effects of statins could be offset by their unfavorable effects on lowering plasma coenzyme Q10 and urate. We therefore prospectively examined whether use of statins was associated with altered risk of PD.
Design, setting, and participants
A prospective study including 38,191 men and 90,874 women participating in two ongoing US cohorts, the Health Professional Follow-up and the Nurses’ Health Study. Information on regular cholesterol lowering drug use (2+ times/week) was collected in 1994 in both cohorts via questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were computed using Cox proportional hazards models adjusting for age, smoking, caffeine intake, duration of hypercholesterolemia, and other covariates.
Main outcome
Incident PD.
During 12 years of follow-up (1994-2006), we documented 644 incident PD cases (338 women and 306 men). The risk of PD was lower among current statin users (adjusted pooled RR=0.74; 95% CI: 0.54, 1.00; P=0.049), relative to non-users. A significant association was observed in participants who were aged <60 years at baseline (adjusted pooled RR=0.31, 95% CI: 0.11, 0.86; P=0.02), but not among those who were older (adjusted pooled RR=0.83, 95% CI: 0.60, 1.14; P=0.25) (p for interaction=0.03).
We found that regular use of statins was associated with a modest reduction in PD risk. The possibility that some statins may reduce PD risk deserves further consideration.
PMCID: PMC3398841  PMID: 22410446
2.  Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of five prospective cohorts 
Archives of Neurology  2011;68(2):207-213.
Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but epidemiological studies supporting this hypothesis have been small and mostly retrospective. We therefore prospectively examined the relation between smoking and ALS in five well-established large cohorts.
Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years.
Participants of the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, and the NIH-American Association of Retired Persons Diet and Health Study.
Main Outcome Measure
ALS deaths identified through the National Death Index. In NHS and HPFS confirmed non-fatal incident ALS was also included.
832 participants with ALS were documented among 562,804 men and 556,276 women. Smokers had a higher risk of ALS than never smokers: age- and sex-adjusted relative risks=1.44 (95%CI: 1.23–1.68;p<0.0001) for former smokers, and 1.42 (95%CI: 1.07–1.88;p=0.016) for current smokers. Although the risk of ALS was positively associated with pack-years smoked (p<0.0001), duration (9% increase for each 10-years of smoking; p=0.006) and cigarettes smoked per day (10% increase for 10 cigarettes per day; p<0.001), these associations did not persist when never smokers were excluded. However, among ever-smokers, risk of ALS increased as age at smoking initiation decreased (p=0.028).
Results of this large longitudinal study support the hypothesis that cigarette smoking increases the risk of ALS. The potential importance of age at smoking initiation and the lack of a dose-response deserve further investigation.
PMCID: PMC3319086  PMID: 21320987
3.  Urate predicts rate of clinical decline in Parkinson disease 
Archives of neurology  2009;66(12):1460-1468.
The risk of Parkinson disease (PD) and its rate of progression may decline with increasing blood urate, a major antioxidant.
To determine whether serum and cerebrospinal fluid (CSF) concentrations of urate predict clinical progression in patients with PD.
Design, Setting, and Participants
800 subjects with early PD enrolled in the DATATOP trial. Pre-treatment urate was measured in serum for 774 subjects and in CSF for 713.
Main Outcome Measures
Treatment-, age- and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the pre-specified primary endpoint.
The HR of progressing to endpoint decreased with increasing serum urate (HR for 1 standard deviation increase = 0.82; 95% CI = 0.73 to 0.93). In analyses stratified by α-tocopherol treatment (2,000 IU/day), a decrease in the HR for the primary endpoint was seen only among subjects not treated with α-tocopherol (HR = 0.75; 95% CI = 0.62 to 0.89, versus those treated HR = 0.90; 95% CI = 0.75 to 1.08). Results were similar for the rate of change in the United Parkinson Disease Rating Scale (UPDRS). CSF urate was also inversely related to both the primary endpoint (HR for highest versus lowest quintile = 0.65; 95% CI: 0.54 to 0.96) and to the rate of change in UPDRS. As with serum urate, these associations were present only among subjects not treated with α-tocopherol.
Higher serum and CSF urate at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate and PD and the rationale for considering CNS urate elevation as a potential strategy to slow PD progression.
PMCID: PMC2795011  PMID: 19822770
4.  Smoking and Disease Progression in Multiple Sclerosis 
Archives of neurology  2009;66(7):858-864.
Although cigarette smokers have an increased risk of developing multiple sclerosis (MS), the effect of smoking on MS progression remains uncertain.
To establish the relationship between cigarette smoking and MS progression using clinical and MRI outcomes
Cross-sectional survey and longitudinal follow-up for an average of 3.29 years, ending January 15, 2008.
Partners MS Center (Boston, MA), a referral center for MS patients
1465 patients with clinically definite MS (25.1% men) with mean baseline age of 42.0 years (range: 16–75) and disease duration of 9.4 years (range: 0–50.4) -- 780 (53.2%) patients were never smokers, 428 (29.2%) ex-smokers, and 257 (17.5%) were current smokers.
Main Outcome Measures
Smoking groups were compared in terms of baseline clinical and MRI characteristics as well as progression and sustained progression on the expanded disability status scale (EDSS) at 2 years and 5 years and the time until conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction (BPF) and T2 hyperintense lesion volume was compared.
Current smokers had significantly worse disease at baseline than never-smokers in terms of EDSS (adjusted p<0.0001), multiple sclerosis severity score (adjusted p<0.0001), and BPF (adjusted p=0.004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio=2.41; 95% CI: 1.09, 5.34). In longitudinal analyses, smokers converted from relapsing remitting MS to secondary progressive MS faster than never-smokers (HR for current smokers versus never smokers, =2.50, 95% CI: 1.42, 4.41) and had a faster rate of increase in the T2 lesion volume (p=0.017) and a faster rate of decrease in BPF (p=0.021).
Our data suggest that cigarette smoke has an adverse influence on MS progression and accelerates the conversion from a relapsing-remitting to a progressive course.
PMCID: PMC2754172  PMID: 19597087
Disease progression; MRI; Multiple sclerosis; Smoking
5.  1!Serum urate as a predictor of clinical and radiographic progression in Parkinson’s disease 
Archives of neurology  2008;65(6):716-723.
Prospective epidemiological studies consistently indicate that Parkinson’s disease (PD) risk declines with increasing serum urate.
To determine whether serum urate, a purine metabolite and potent antioxidant, predicts prognosis in PD.
Design, Setting, and Participants
Prospective study among 804 subjects with early PD enrolled in the PRECEPT study, a clinical trial of the neuroprotectant potential of CEP-1347, conducted between April 2002 and August 2005 (average follow-up time 21.4 months).
Main Outcome Measures
The primary study endpoint was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching endpoint according to quintiles of baseline serum urate, adjusting for gender, age and other potential covariates. Change in striatal uptake of [123I]β-CIT, a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects.
The adjusted HR of reaching endpoint declined with increasing baseline concentrations of urate; subjects in the top quintile reached the endpoint at only half the rate of subjects in the bottom quintile (HR=0.51; 95% CI: 0.37 to 0.72; p=0.0002). This association was markedly stronger in men (HR=0.39; 95% CI: 0.26 to 0.60; p<0.0001) than in women (HR=0.77; 95% CI: 0.39 to 1.50; p=0.4). The percent loss in striatal [123I]β-CIT uptake also improved with increasing serum urate concentrations (overall p for trend=0.002; men, p=0.0008; women, p= 0.4).
These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease modifying therapy in PD.
PMCID: PMC2574855  PMID: 18413464

Results 1-5 (5)