14 research outputs found
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