Incidence, Risk and Prognosis of Parkinson Disease

Parkinson disease (PD) is the second most common neurodegenerative disorder, and is clinically characterized by resting tremor, rigidity, bradykinesia and postural imbalance. These typical motor symptoms result from a selective degeneration of dopamine-producing neurons in the substantia nigra in the brain stem. Despite intensive research in the last decades, the pathogenetic mechanisms responsible for this process are still not completely understood and therapies for PD are as yet only symptomatic. Current thinking is that in the majority of cases, PD is a multifactorial disease that results from interactions between several genetic and nongenetic risk factors. Since 1997, several gene mutations have been identified that cause familial forms of the disease with a clear Mendelian mode of inheritance, but monogenetically determined PD is thought to make up only 10% of all cases. Although there seem to be many different causes for PD, they converge on several common molecular mechanisms that ultimately lead to dopaminergic cell death. These include dysfunction of mitochondria, oxidative stress and impaired function of the ubiquitinproteasome system, which is responsible for the elimination of misfolded or damaged proteins. More insight in these pathogenetic pathways is needed to acquire a better understanding of the disease and to develop effective therapeutic interventions. The aim of this thesis was to assess the impact of PD in the general population in terms of frequency and prognosis, and to identify potential risk factors for the disease. The studies we conducted were all embedded in the Rotterdam Study, a large prospective population-based cohort study in 7,983 participants aged 55 years and older, with assessment of many potential risk factors at baseline and repeated in-person screening for PD. Chapter 1 is a brief introduction to the work presented in this thesis. In Chapter 2, I discuss currently available evidence on diagnosis, frequency, risk factors and prognosis of PD from an epidemiological point of view. Numerous epidemiological studies on PD have been carried out, but many of them were hampered by inferior study designs, low numbers of included subjects or inadequate case ascertainment or –definition. We therefore paid special attention to methodological issues and the influence of study design on the usefulness of epidemiological data and interpretation of findings. In Chapter 3.1, I describe the results of our study on the incidence of parkinsonism and PD. The incidence of both parkinsonism and PD consistently increased with age. Incidence rates in our study were higher than those reported by most previous studies, most likely due to our intensive case-finding methods. Over one third of the incident PD cases that we identified had not been diagnosed with PD before. The incidenceof PD seemed higher in men, possibly as a result of neuroprotective effects that have been found for estrogens. These findings suggest a substantial underdiagnosis of PD in the general population and emphasize the importance of direct examination of all participants in epidemiological studies on PD. In Chapter 3.2, I evaluate the relationship between subjective motor complaints at baseline in participants free of dementia and without clinically obvious parkinsonian signs, and the risk to develop PD during follow-up. Subjective complaints of tremors, stiffness, slowness, a feeling of imbalance or falling were reported by more than half of the participants at baseline, although no parkinsonian signs were observed on physical examination. We found that subjective complaints about stiffness, tremors or imbalance at baseline were associated with an increased risk to develop PD during follow-up. Our results suggest that early dopamine deficiency may induce subtle signs before onset of typical motor symptoms, and that a questionnaire on subjective complaints could add to the earlier recognition of PD. Chapter 4.1 addresses the relationship between dietary intake of various types of fat and the risk of PD. People with higher intake of unsaturated fatty acids at baseline had a significantly decreased risk of incident PD. Given the reported antioxidant properties of polyunsaturated fatty acids, this is in line with the hypothesis that oxidative stress plays a role in dopaminergic cell death in PD. On the other hand, recent evidence suggests that alterations in fat metabolism might be involved in PD pathogenesis. In Chapter 4.2, I describe the association between serum levels of total and HDL cholesterol and PD risk. Higher baseline levels of total cholesterol were associated with a significantly lower risk of PD in a dose-effect manner, although only in women. Possible explanations for this association include the link with fat metabolism or the correlation between cholesterol and the strong antioxidant and electron acceptor for mitochondrial complex I, coenzyme Q10. Evidence from animal studies suggests that high levels of homocysteine may contribute to neuronal cell death in PD, probably by increasing oxidative stress. In Chapter 5.1, I therefore explore the association between the TT variant of the methylenetetrahy drofolate reductase (MTHFR) C677T polymorphism, which is associated with mild hyperhomocysteinemia, and the risk of PD. The TT genotype was associated with an increased risk of PD, particularly in smokers, which fits reported synergistic effects of smoking and TT genotype on plasma homocysteine levels. In Chapter 5.2 we investigated the effect on PD risk of dietary intake of folate, vitamin B12 and vitamin B6, essential co-factors that are required to keep plasma homocysteine levels low. Higher dietary intake of vitamin B6, but not of folate or vitamin B12, was associated with a significantly decreased risk of PD. These findings may be explained by the antioxidant properties that have been reported for vitamin B6 (in addition to its homocysteine-lowering effects), or its role in dopamine synthesis. To further explore the role of oxidative stress in PD, we studied the relationship between serum levels of the antioxidant uric acid and the risk of PD. In Chapter 5.3 I report our finding that higher levels of uric acid were associated with a significantly lower risk of PD, with a clear dose-effect relationship. Chapter 6 describes the prognosis of PD patients in terms of risk of dementia and mortality. Patients with PD had a significantly increased risk of developing dementia and a reduced life expectancy compared to participants without PD. The risk of dementia was especially pronounced in participants carrying at least one APOE ε2 allele. Although modifying effects of APOE genotype on the prevalence of PD and the risk of dementia associated with PD have been described previously, a biological explanation is as yet lacking. Increased mortality risk was more prominent in PD patients with longer disease duration and was attenuated after adjustment for the occurrence of dementia, which suggests that the increased risk of dementia is partly responsible for the reduced survival in PD patients. In Chapter 7 an attempt is made to place our findings in a broader perspective. I discuss how our findings fit into current knowledge and models for PD pathogenesis, reflect on the relevance and potential implications of our observations and discuss directions for future research

Screening tests for aphasia in patients with stroke: a systematic review

Aphasia has a large impact on the quality of life and adds significantly to the costs of stroke care. Early recognition of aphasia in stroke patients is important for prognostication and well-timed treatment planning. We aimed to identify available screening tests for differentiating between aphasic and non-aphasic stroke patients, and to evaluate test accuracy, reliability, and feasibility. We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing aphasia in stroke patients. The reference lists of the selected articles were scan

Survival in Parkinson's disease. Relation with motor and non-motor features

Neurological Motor Disorder

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.Paroxysmal Cerebral Disorder

Catechol-O-methyltransferase Val158Met and the Risk of Dyskinesias in Parkinson's Disease

Neurological Motor Disorder

Subjective complaints precede Parkinson disease: The Rotterdam study

Background: Neuronal degeneration and dopamine loss in the preclinical phase of Parkinson disease may produce subtle complaints before clinically recognizable symptoms emerge. Objective: To examine whether subjective complaints of stiffness, slowness, tremors, or postural imbalance in persons without clinical signs of parkinsonism are related to an increased risk of future Parkinson disease. Design: Population-based cohort study. We recorded subjective complaints of stiffness, slowness of movement, tremors, falling, or a feeling of imbalance in a standardized interview of 6038 participants without dementia in whom no parkinsonian signs were found on physical examination at baseline, and we studied them prospectively for the occurrence of incident Parkinson disease. Setting: General population. Participants: A total of 6038 participants who were free of dementia and parkinsonian signs. Main Outcome Measures: Incident Parkinson disease. Participants were examined in person both at baseline (January 1990-June 1993) and at 2 follow-up visits (September 1993-December 1994 and April 1997-December 1999), and the cohort was continuously monitored through computerized linkage of the study database to general practitioners' medical records. We analyzed the data using Cox proportional hazards regression models. Results: Participants who reported stiffness, tremors, or imbalance at baseline had a significantly increased risk of developing Parkinson disease during follow-up (for stiffness, hazard ratio, 2.11; 95% confidence interval, 1.25-3.55; P=.005; for tremors, hazard ratio, 2.09; 95% confidence interval, 1.12-3.90;P=.002; and for imbalance, hazard ratio, 3.47; 95% confidence interval, 1.69-7.00; P=.001). Conclusions: Subjective complaints of stiffness, tremors, and imbalance are associated with an increased risk of future Parkinson disease and may reflect early effects of dopamine shortage, even when standard neurological testing cannot yet demonstrate any motor symptoms

Serum cholesterol levels and the risk of Parkinson's disease

Several recent findings suggest a role of lipid and cholesterol metabolism in the pathogenesis of Parkinson's disease. Therefore, the authors examined the association between serum levels of cholesterol and the risk of Parkinson's disease in the prospective, population-based Rotterdam Study among 6,465 subjects aged 55 or more years with repeated in-person examination and on average 9.4 years of follow-up (1990-2004). Higher serum levels of total cholesterol were associated with a significantly decreased risk of Parkinson's disease (age- and sex-adjusted hazard ratio per mmol/liter increase in cholesterol = 0.77, 95% confidence interval: 0.64, 0.94), with evidence for a dose-effect relation. The association was restricted to women and remained unchanged after adjustment for multiple potential confounders. These findings may indicate a role of lipids in the pathogenesis of Parkinson's disease. Alternatively, they could reflect the strong correlation-especially in women-between levels of serum cholesterol and the antioxidant coenzyme Q10. If confirmed, this would provide further support for an important role of oxidative stress in the pathogenesis of Parkinson's disease

Relation of Clinical Subtypes in Parkinson's Disease With Survival

Neurological Motor Disorder

γ/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke

Fibrinogen γ' (γ') is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of γ' fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of γ' in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 156 control persons. Total fibrinogen and γ' levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when >2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean γ' levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p<0.001), and patients also had a higher γ'/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The γ'/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of γ'/total fibrinogen ratio 1.27, 95% confidence interval 1.09-1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen γ' and suggests a trend towards an increased γ'/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen γ' relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke