Incidence, Risk and Prognosis of Parkinson Disease
Year: 2006
Type: dissertation
Study design: Observational Study
Abstract: Parkinson disease (PD) is the second most common neurodegenerative \\ndisorder,\\nand is clinically characterized by resting tremor, rigidity, \\nbradykinesia and postural\\nimbalance. These typical motor symptoms result from a selective \\ndegeneration of\\ndopamine-producing neurons in the substantia nigra in the brain stem. \\nDespite\\nintensive research in the last decades, the pathogenetic mechanisms \\nresponsible\\nfor this process are still not completely understood and therapies \\nfor PD are as\\nyet only symptomatic. Current thinking is that in the majority of \\ncases, PD is a\\nmultifactorial disease that results from interactions between several \\ngenetic and nongenetic\\nrisk factors. Since 1997, several gene mutations have been identified \\nthat\\ncause familial forms of the disease with a clear Mendelian mode of \\ninheritance, but\\nmonogenetically determined PD is thought to make up only 10% of all \\ncases. Although\\nthere seem to be many different causes for PD, they converge on \\nseveral common\\nmolecular mechanisms that ultimately lead to dopaminergic cell death. \\nThese include\\ndysfunction of mitochondria, oxidative stress and impaired function \\nof the ubiquitinproteasome\\nsystem, which is responsible for the elimination of misfolded or damaged\\nproteins. More insight in these pathogenetic pathways is needed to \\nacquire a better\\nunderstanding of the disease and to develop effective therapeutic \\ninterventions.\\nThe aim of this thesis was to assess the impact of PD in the general \\npopulation\\nin terms of frequency and prognosis, and to identify potential risk \\nfactors for the\\ndisease. The studies we conducted were all embedded in the Rotterdam \\nStudy, a\\nlarge prospective population-based cohort study in 7,983 participants \\naged 55 years\\nand older, with assessment of many potential risk factors at baseline \\nand repeated\\nin-person screening for PD.\\nChapter 1 is a brief introduction to the work presented in this \\nthesis. In Chapter\\n2, I discuss currently available evidence on diagnosis, frequency, \\nrisk factors and\\nprognosis of PD from an epidemiological point of view. Numerous \\nepidemiological\\nstudies on PD have been carried out, but many of them were hampered \\nby inferior\\nstudy designs, low numbers of included subjects or inadequate case \\nascertainment\\nor \\xc3\\xa2\\xe2\\x82\\xac\\xe2\\x80\\x9cdefinition. We therefore paid special attention to \\nmethodological issues and the\\ninfluence of study design on the usefulness of epidemiological data \\nand interpretation\\nof findings.\\nIn Chapter 3.1, I describe the results of our study on the incidence \\nof parkinsonism\\nand PD. The incidence of both parkinsonism and PD consistently \\nincreased with age.\\nIncidence rates in our study were higher than those reported by most \\nprevious studies,\\nmost likely due to our intensive case-finding methods. Over one third \\nof the incident\\nPD cases that we identified had not been diagnosed with PD before. \\nThe incidenceof PD\\nseemed higher in men, possibly as a result of neuroprotective effects \\nthat have\\nbeen found for estrogens. These findings suggest a substantial \\nunderdiagnosis of PD\\nin the general population and emphasize the importance of direct \\nexamination of all\\nparticipants in epidemiological studies on PD.\\nIn Chapter 3.2, I evaluate the relationship between subjective motor \\ncomplaints at\\nbaseline in participants free of dementia and without clinically \\nobvious parkinsonian\\nsigns, and the risk to develop PD during follow-up. Subjective \\ncomplaints of tremors,\\nstiffness, slowness, a feeling of imbalance or falling were reported \\nby more than half\\nof the participants at baseline, although no parkinsonian signs were \\nobserved on\\nphysical examination. We found that subjective complaints about \\nstiffness, tremors or\\nimbalance at baseline were associated with an increased risk to \\ndevelop PD during\\nfollow-up. Our results suggest that early dopamine deficiency may \\ninduce subtle\\nsigns before onset of typical motor symptoms, and that a \\nquestionnaire on subjective\\ncomplaints could add to the earlier recognition of PD.\\nChapter 4.1 addresses the relationship between dietary intake of \\nvarious types of fat\\nand the risk of PD. People with higher intake of unsaturated fatty \\nacids at baseline\\nhad a significantly decreased risk of incident PD. Given the reported \\nantioxidant\\nproperties of polyunsaturated fatty acids, this is in line with the \\nhypothesis that\\noxidative stress plays a role in dopaminergic cell death in PD. On \\nthe other hand,\\nrecent evidence suggests that alterations in fat metabolism might be \\ninvolved in PD\\npathogenesis. In Chapter 4.2, I describe the association between \\nserum levels of total\\nand HDL cholesterol and PD risk. Higher baseline levels of total \\ncholesterol were\\nassociated with a significantly lower risk of PD in a dose-effect \\nmanner, although\\nonly in women. Possible explanations for this association include the \\nlink with fat\\nmetabolism or the correlation between cholesterol and the strong \\nantioxidant and\\nelectron acceptor for mitochondrial complex I, coenzyme Q10.\\nEvidence from animal studies suggests that high levels of \\nhomocysteine may contribute\\nto neuronal cell death in PD, probably by increasing oxidative \\nstress. In Chapter 5.1,\\nI therefore explore the association between the TT variant of the \\nmethylenetetrahy\\ndrofolate reductase (MTHFR) C677T polymorphism, which is associated \\nwith mild\\nhyperhomocysteinemia, and the risk of PD. The TT genotype was \\nassociated with an\\nincreased risk of PD, particularly in smokers, which fits reported \\nsynergistic effects\\nof smoking and TT genotype on plasma homocysteine levels. In Chapter \\n5.2 we\\ninvestigated the effect on PD risk of dietary intake of folate, \\nvitamin B12 and vitamin\\nB6, essential co-factors that are required to keep plasma \\nhomocysteine levels low.\\nHigher dietary intake of vitamin B6, but not of folate or vitamin \\nB12, was associated\\nwith a significantly decreased risk of PD. These findings may be \\nexplained by the\\nantioxidant properties that have been reported for vitamin B6 (in \\naddition to its\\nhomocysteine-lowering effects), or its role in dopamine synthesis. To \\nfurther explore\\nthe role of oxidative stress in PD, we studied the relationship \\nbetween serum levels\\nof the antioxidant uric acid and the risk of PD. In Chapter 5.3 I \\nreport our finding that\\nhigher levels of uric acid were associated with a significantly lower \\nrisk of PD, with\\na clear dose-effect relationship.\\nChapter 6 describes the prognosis of PD patients in terms of risk of \\ndementia and\\nmortality. Patients with PD had a significantly increased risk of \\ndeveloping dementia\\nand a reduced life expectancy compared to participants without PD. \\nThe risk of\\ndementia was especially pronounced in participants carrying at least \\none APOE \\xc3\\x8e\\xc2\\xb52\\nallele. Although modifying effects of APOE genotype on the prevalence \\nof PD and\\nthe risk of dementia associated with PD have been described \\npreviously, a biological\\nexplanation is as yet lacking. Increased mortality risk was more \\nprominent in PD\\npatients with longer disease duration and was attenuated after \\nadjustment for the\\noccurrence of dementia, which suggests that the increased risk of \\ndementia is partly\\nresponsible for the reduced survival in PD patients.\\nIn Chapter 7 an attempt is made to place our findings in a broader \\nperspective. I\\ndiscuss how our findings fit into current knowledge and models for PD \\npathogenesis,\\nreflect on the relevance and potential implications of our \\nobservations and discuss\\ndirections for future research.
Author: Lau, Lonneke
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7029309365