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• W2912083484 abstract "textabstractParkinson disease (PD) is the second most common neurodegenerative disorder,and is clinically characterized by resting tremor, rigidity, bradykinesia and posturalimbalance. These typical motor symptoms result from a selective degeneration ofdopamine-producing neurons in the substantia nigra in the brain stem. Despiteintensive research in the last decades, the pathogenetic mechanisms responsiblefor this process are still not completely understood and therapies for PD are asyet only symptomatic. Current thinking is that in the majority of cases, PD is amultifactorial disease that results from interactions between several genetic and nongeneticrisk factors. Since 1997, several gene mutations have been identified thatcause familial forms of the disease with a clear Mendelian mode of inheritance, butmonogenetically determined PD is thought to make up only 10% of all cases. Althoughthere seem to be many different causes for PD, they converge on several commonmolecular mechanisms that ultimately lead to dopaminergic cell death. These includedysfunction of mitochondria, oxidative stress and impaired function of the ubiquitinproteasomesystem, which is responsible for the elimination of misfolded or damagedproteins. More insight in these pathogenetic pathways is needed to acquire a betterunderstanding of the disease and to develop effective therapeutic interventions.The aim of this thesis was to assess the impact of PD in the general populationin terms of frequency and prognosis, and to identify potential risk factors for thedisease. The studies we conducted were all embedded in the Rotterdam Study, alarge prospective population-based cohort study in 7,983 participants aged 55 yearsand older, with assessment of many potential risk factors at baseline and repeatedin-person screening for PD.Chapter 1 is a brief introduction to the work presented in this thesis. In Chapter2, I discuss currently available evidence on diagnosis, frequency, risk factors andprognosis of PD from an epidemiological point of view. Numerous epidemiologicalstudies on PD have been carried out, but many of them were hampered by inferiorstudy designs, low numbers of included subjects or inadequate case ascertainmentor –definition. We therefore paid special attention to methodological issues and theinfluence of study design on the usefulness of epidemiological data and interpretationof findings.In Chapter 3.1, I describe the results of our study on the incidence of parkinsonismand 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 incidentPD cases that we identified had not been diagnosed with PD before. The incidenceof PDseemed higher in men, possibly as a result of neuroprotective effects that havebeen found for estrogens. These findings suggest a substantial underdiagnosis of PDin the general population and emphasize the importance of direct examination of allparticipants in epidemiological studies on PD.In Chapter 3.2, I evaluate the relationship between subjective motor complaints atbaseline in participants free of dementia and without clinically obvious parkinsoniansigns, 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 halfof the participants at baseline, although no parkinsonian signs were observed onphysical examination. We found that subjective complaints about stiffness, tremors orimbalance at baseline were associated with an increased risk to develop PD duringfollow-up. Our results suggest that early dopamine deficiency may induce subtlesigns before onset of typical motor symptoms, and that a questionnaire on subjectivecomplaints could add to the earlier recognition of PD.Chapter 4.1 addresses the relationship between dietary intake of various types of fatand the risk of PD. People with higher intake of unsaturated fatty acids at baselinehad a significantly decreased risk of incident PD. Given the reported antioxidantproperties of polyunsaturated fatty acids, this is in line with the hypothesis thatoxidative 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 PDpathogenesis. In Chapter 4.2, I describe the association between serum levels of totaland HDL cholesterol and PD risk. Higher baseline levels of total cholesterol wereassociated with a significantly lower risk of PD in a dose-effect manner, althoughonly in women. Possible explanations for this association include the link with fatmetabolism or the correlation between cholesterol and the strong antioxidant andelectron acceptor for mitochondrial complex I, coenzyme Q10.Evidence from animal studies suggests that high levels of homocysteine may contributeto 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 methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which is associated with mildhyperhomocysteinemia, and the risk of PD. The TT genotype was associated with anincreased risk of PD, particularly in smokers, which fits reported synergistic effectsof smoking and TT genotype on plasma homocysteine levels. In Chapter 5.2 weinvestigated the effect on PD risk of dietary intake of folate, vitamin B12 and vitaminB6, 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 associatedwith a significantly decreased risk of PD. These findings may be explained by theantioxidant properties that have been reported for vitamin B6 (in addition to itshomocysteine-lowering effects), or its role in dopamine synthesis. To further explorethe role of oxidative stress in PD, we studied the relationship between serum levelsof the antioxidant uric acid and the risk of PD. In Chapter 5.3 I report our finding thathigher levels of uric acid were associated with a significantly lower risk of PD, witha clear dose-effect relationship.Chapter 6 describes the prognosis of PD patients in terms of risk of dementia andmortality. Patients with PD had a significantly increased risk of developing dementiaand a reduced life expectancy compared to participants without PD. The risk ofdementia was especially pronounced in participants carrying at least one APOE Iµ2allele. Although modifying effects of APOE genotype on the prevalence of PD andthe risk of dementia associated with PD have been described previously, a biologicalexplanation is as yet lacking. Increased mortality risk was more prominent in PDpatients with longer disease duration and was attenuated after adjustment for theoccurrence of dementia, which suggests that the increased risk of dementia is partlyresponsible for the reduced survival in PD patients.In Chapter 7 an attempt is made to place our findings in a broader perspective. Idiscuss how our findings fit into current knowledge and models for PD pathogenesis,reflect on the relevance and potential implications of our observations and discussdirections for future research." @default.
• W2912083484 created "2019-02-21" @default.
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• W2912083484 date "2006-02-01" @default.
• W2912083484 modified "2023-09-27" @default.
• W2912083484 title "Incidence, Risk and Prognosis of Parkinson Disease" @default.
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