Lonneke M. L. de Lau

Epidemiology of Parkinson's disease

The causes of Parkinsons disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.

Genomewide Association Studies of Stroke

BACKGROUND The genes underlying the risk of stroke in the general population remain undetermined. METHODS We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Serum uric acid levels and the risk of Parkinson disease

In a prospective population‐based cohort study among 4,695 participants aged 55 years and older, with repeated in‐person examination and on average 9.4 years of follow‐up, we observed that higher serum levels of uric acid were associated with a significantly decreased risk of Parkinson disease (adjusted hazard ratio per standard deviation increase 0.71 [95% confidence interval 0.51–0.98]), with evidence for a dose–effect relationship (p value for trend over quartiles 0.040). Our findings support the hypothesis that oxidative stress contributes to the risk of Parkinson disease and suggest a potential protective effect of the natural antioxidant and free radical scavenger uric acid. Ann Neurol 2005;58:797–800

Nonsteroidal Anti-Inflammatory Drugs and the Risk of Parkinson Disease

Background: Several lines of evidence suggest a role of inflammatory processes in Parkinson disease, although it is still unclear whether inflammation is a cause or rather a consequence of neurodegeneration. Methods: In a prospective population-based cohort study among 6,512 participants aged ≧55 years, with repeated in-person examination, we evaluated the association between cumulative use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of Parkinson disease. Complete information on filled prescriptions was available from automated pharmacy records. Data were analyzed by means of Cox proportional hazards regression analysis, adjusted for age, sex, smoking habits and coffee consumption. Results: After an average 9.4 years of follow-up, 88 new cases of Parkinson disease were detected. No association was found between use of NSAIDs and the risk of Parkinson disease (adjusted hazard ratio for any NSAID use, 1.50; 95% confidence interval, 0.95–2.37). Conclusion: Our findings do not support the hypothesis that NSAIDs might decrease the risk of Parkinson disease.

Methylenetetrahydrofolate reductase C677T genotype and PD

In a prospective, population‐based cohort study among 5,920 participants aged 55 years or older, we observed that the TT variant of the methylenetetrahydrofolate reductase C677T polymorphism is associated with an increased risk for Parkinsons disease in smokers. Both smoking and the TT genotype are known to induce hyperhomocystinemia, and synergistic effects on homocysteine levels have been reported. Increased plasma levels of homocysteine through direct neurotoxic effects might accelerate the selective dopaminergic cell death underlying Parkinsons disease. Our findings support the hypothesis that homocysteine plays a role in the pathogenesis of Parkinsons disease. Ann Neurol 2005;57:927–930

Catechol‐O‐methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease

The A‐allele of the catechol‐O‐methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability.

Genetic variation in homocysteine metabolism, cognition, and white matter lesions.

Several studies have shown an association between homocysteine concentration and cognitive performance or cerebral white matter lesions. However, variations in genes encoding for enzymes and other proteins that play a role in homocysteine metabolism have hardly been evaluated in relation to these outcome measures. In the population-based Rotterdam Scan Study, we examined the association of seven polymorphisms of genes involved in homocysteine metabolism (MTHFR 677C>T, MTHFR 1298A>C, RFC 80G>A, TC 776C>G, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68) with plasma total homocysteine, cognitive performance, and cerebral white matter lesions among 1011 non-demented elderly participants. Of all the studied polymorphisms, only MTHFR 677C>T was associated with homocysteine concentration. No significant relationship was observed for any of the polymorphisms with cognitive performance or severity of cerebral white matter lesions.

Acute Disseminating Encephalomyelitis Following Legionnaires Disease

OBJECTIVE To describe 2 patients presenting with severe neurological deficits and extensive lesions on brain magnetic resonance imaging after having experienced Legionella pneumonia. DESIGN Case reports. SETTING University hospital. PATIENTS Two patients who developed severe neurological symptoms, including encephalopathic signs, following Legionella infection, with widespread lesions on magnetic resonance imaging compatible with demyelination. RESULTS After extensive ancillary investigations, a diagnosis of acute disseminating encephalomyelitis was considered most likely. Steroid therapy was initiated in 1 of the patients, followed by plasmapheresis. In both patients, clinical and radiological signs gradually recovered, with only slight residual deficits. CONCLUSION In patients presenting with neurological symptoms after an episode of pneumonia, Legionella infection and a subsequent immune-mediated process such as acute disseminating encephalomyelitis should be considered.

Acute CNS white matter lesions in patients with inflammatory bowel disease

Background: Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation. Methods: Two cases of patients diagnosed with inflammatory bowel disease developing neurological symptoms with corresponding lesions in the white matter of the central nervous system led us to search a neurological database with clinical and radiological data for similar cases. Results: We identified five patients who presented with acute neurological deficits preceding or following a diagnosis of inflammatory bowel disease with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infetcion, coagulation disorders, or vasculitis. Conclusions: These cases, together with previous reports, suggest that white matter lesions may be another extraintestinal manifestation of inflammatory bowel disease. (Inflamm Bowel Dis 2009)

Serum cholesterol, use of lipid‐lowering drugs, and risk of Parkinson disease

In a recent article in this journal, Huang et al. report their findings that lower serum concentrations of LDL-cholesterol were associated with a higher prevalence of Parkinson Disease (PD), whereas use of cholesterol-lowering drugs was significantly associated with a decreased occurrence of PD.1 These observations were made in a relatively small, retrospective case–control study among 124 PD cases and 112 controls. The authors write “these are clinically relevant observations that deserve to be confirmed in larger prospective studies and in other populations” and “it seems timely and critical to replicate our results in other populations”, but that the association between cholesterol levels and PD has been the subject of only one previous abstract (from 1991) thus far. We would like to draw attention to our recent publication from the Rotterdam Study, describing a significant association between higher levels of total serum cholesterol and a decreased risk of PD, with analyses in quintiles showing a clear linear relation.2 The Rotterdam Study is a large, prospective, population-based cohort study among participants aged 55 years or older with intensive case-finding methods involving in-person screening for PD. We prospectively studied the association between serum cholesterol levels and incident PD in 6,465 participants free from Parkinsonism and dementia at baseline. Total cholesterol and LDL-cholesterol were determined at baseline, that is before the clinical onset of PD. During follow-up (mean follow-up; 9.4 years) 87 incident cases of PD were detected. The inverse association between total serum cholesterol and incident PD (HR per 1.0 mmol increase in total cholesterol 0.77 (95% CI: 0.64–0.94) remained statistically significant after adjustment for age, sex, smoking, coffee consumption, BMI, vitamin E intake, and use of lipid-lowering drugs at baseline. The findings of Huang et al. are thus in line with the results from our prospective cohort study. Since they also found a significant inverse association between use of cholesterol-lowering drugs and occurrence of PD, we examined the association between statin use and PD in our cohort. Data on medication use, including statins, are available in the Rotterdam Study from seven fully automated pharmacies in the study area in which nearly all participants (99.7%) are registered. These pharmacies continuously provide details on all filled prescriptions, including the product name, generic name, number of tablets, date of delivery, prescribed number of tablets, and daily drug dosage. We evaluated the association between any use of statins during the study period and the risk of PD by means of Cox’ proportional hazards regression with statin use as a time-dependent variable and with adjustment for age, sex, and smoking habits. One thousand eight participants (15.6%) had at least one filled prescription of statins during the study period. We found no significant association between statin use and risk of incident PD (HR 0.33, 95% CI 0.08–1.35), but size and direction of the estimate are in line with the findings Huang et al. report from their case–control study. Huang et al. propose that their findings suggest either an etiologic role of LDL-cholesterol in PD pathogenesis or a neuroprotective effect of statins. We would like to add an alternative explanation. Serum cholesterol is the most important determinant of serum levels of coenzyme Q10, which is a powerful antioxidant and electron acceptor for mitochondrial complex I.3 Given the hypothesis that oxidative stress and mitochondrial complex I dysfunction play a central role in the pathogenesis of PD, coenzyme Q10 is considered a candidate drug for treatment of PD and has already been investigated in small trials.4,5 The observed association between serum cholesterol and PD might thus reflect a relation between levels of coenzyme Q10 and PD risk. In conclusion, the findings from Huang et al. are confirmed in the prospective Rotterdam Study, but further research is needed to unravel the association between cholesterol, coenzyme Q10, and PD pathogenesis.