49 research outputs found
Silent brain infarcts : frequency, risk factors, and prognosis
Silent- i.e. asymptomatic -brain infarcts are frequently seen on cerebral
magnetic resonance imaging (MRl) scans in patients admitted to the
hospital with their first stroke. With the increasing use and improvement
of imaging techniques, these silent lesions are more often found in people
without stroke-like symptoms.' In contrast to symptomatic brain infarcts, the
relevance of these so-called silent brain infarcts is not known. Because knowledge
of the consequences of silent infarcts is lacking, special treatment regimens have
not been developed yet for patients with these lesions. In selected patient groups
however, silent brain infarcts seem to increase the risk of stroke and death?
Furthermore, hospital-based studies found that they are more frequently present in
elderly patients with dementia and depression than in other patients.3
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4 Prospective
longitudinal research in which large groups of asymptomatic people undergo brain
imaging is needed to examine the clinical relevance of silent brain infarcts in the
general population.
In this thesis the following questions are investigated:
1. How frequent are silent brain infarcts in the general population?
2. What are the risk factors for silent brain infarcts?
3. What are the clinical consequences of silent brain infarcts?
To answer these questions, data was used from the Rotterdam Scan Study, a large
cohort study among elderly people from the general population who underwent
MRl scanning of the brain. The presence of (silent) brain infarcts was scored on
MRI, as were other brain abnormalities including white matter lesions and global
brain atrophy. Both are thought to have a vascular pathogenesis and frequently
coexist in ischaemic brains.5·6 In chapter 2, the prevalence and incidence of silent
brain infarcts is presented. Furthermore, this chapter describes studies on the risk
factors for silent brain infarcts, in which a comparison with the classical risk factors
for symptomatic infarcts is made. The investigation of the relationship with one of
the relative new risk factors, the potentially modifiable homocysteine, is also
reported here. For studies described in chapter 3, this cohort is followed over time
and monitored for mortality and major morbidity. This chapter describes the
relationship between silent brain infarcts and the risk of three frequent and disabling disorders in elderly people, namely stroke, dementia, and depression. In
chapter 4, I discuss and review all findings and make suggestions for further
researc
Silent brain infarcts and the risk of dementia and cognitive decline
BACKGROUND: Silent brain infarcts are frequently seen on magnetic
resonance imaging (MRI) in healthy elderly people and may be associated
with dementia and cognitive decline. METHODS: We studied the association
between silent brain infarcts and the risk of dementia and cognitive
decline in 1015 participants of the prospective, population-based
Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia
and stroke at base line. Participants underwent neuropsychological testing
and cerebral MRI at base line in 1995 to 1996 and again in 1999 to 2000
and were monitored for dementia throughout the study period. We performed
Cox proportional-hazards and multiple linear-regression analyses, adjusted
for age, sex, and level of education and for the presence or absence of
subcortical atrophy and white-matter lesions. RESULTS: During 3697
person-years of follow-up (mean per person, 3.6 years), dementia developed
in 30 of the 1015 participants. The presence of silent brain infarcts at
base line more than doubled the risk of dementia (hazard ratio, 2.26; 95
percent confidence interval, 1.09 to 4.70). The presence of silent brain
infarcts on the base-line MRI was associated with worse performance on
neuropsychological tests and a steeper decline in global cognitive
function. Silent thalamic infarcts were associated with a decline in
memory performance, and nonthalamic infarcts with a decline in psychomotor
speed. When participants with silent brain infarcts at base line were
subdivided into those with and those without additional infarcts at
follow-up, the decline in cognitive function was restricted to those with
additional silent infarcts. CONCLUSIONS: Elderly people with silent brain
infarcts have an increased risk of dementia and a steeper decline in
cognitive function than those without such lesions
Homocysteine and brain atrophy on MRI of non-demented elderly
Patients with Alzheimer's disease have higher plasma homocysteine levels
than controls, but it is uncertain whether higher plasma homocysteine
levels are involved in the early pathogenesis of the disease. Hippocampal,
amygdalar and global brain atrophy on brain MRI have been proposed as
early markers of Alzheimer's disease. In the Rotterdam Scan Study, a
population-based study of age-related brain changes in 1077 non-demented
people aged 60-90 years, we investigated the association between plasma
homocysteine levels and severity of hippocampal, amygdalar and global
brain atrophy on MRI. We used axial T(1)-weighted MRIs to visualize global
cortical brain atrophy (measured semi-quantitatively; range 0-15) and a 3D
HASTE (half-Fourier acquisition single-shot turbo spin echo) sequence in
511 participants to measure hippocampal and amygdalar volumes. We had
non-fasting plasma homocysteine levels in 1031 of the participants and in
505 of the participants with hippocampal and amygdalar volumes.
Individuals with higher plasma homocysteine levels had, on average, more
cortical atrophy [0.23 units (95% CI 0.07-0.38 units) per standard
deviation increase in plasma homocysteine levels] and more hippocampal
atrophy [difference in left hippocampal volume -0.05 ml (95% CI -0.09 to
-0.01) and in right hippocampal volume -0.03 ml (95% CI -0.07 to 0.01) per
standard deviation increase in plasma homocysteine levels]. No association
was observed between plasma homocysteine levels and amygdalar atrophy.
These results support the hypothesis that higher plasma homocysteine
levels are associated with more atrophy of the hippocampus and cortical
regions in elderly at risk of Alzheimer's disease
Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia
BACKGROUND: Consumers of light-to-moderate amounts of alcohol have a lower risk of dementia and, possibly, Alzheimer disease than do abstainers. Because vascular disease may contribute to symptoms of Alzheimer disease, reduction of cerebrovascular disease in consumers of light amounts of alcohol could account for that observation. However, a low concentration of alcohol may also have direct effects on the hippocampus, a brain structure highly affected by Alzheimer disease. OBJECTIVE: We investigated alcohol intake in relation to brain magnetic resonance imaging (MRI) findings of presumed vascular
Cohort study ON Neuroimaging, Etiology and Cognitive consequences of Transient neurological attacks (CONNECT): Study rationale and protocol
Background: Transient ischemic attacks (TIA) are characterized by acute onset focal neurological symptoms and complete recovery within 24hours. Attacks of nonfocal symptoms not fulfilling the criteria for TIA but lacking a clear alternative diagnosis are called transient neurological attacks (TNA). Although TIA symptoms are transient in nature, cognitive complaints may persist. In particular, attacks consisting of both focal and nonfocal symptoms (mixed TNA) have been found to be associated with an increased risk of dementia. We aim to study the prevalence, etiology and risk factors of cognitive impairment after TIA or TNA. Methods/Design: CONNECT is a prospective cohort study on cognitive function after TIA and TNA. In total, 150 patients aged ≤45years with a recent (<7days after onset) TIA or TNA and no history of stroke or dementia will be included. We will classify events as: TIA, nonfocal TNA, or mixed TNA. Known short lasting paroxysmal neurological disorders like migraine aura, seizures and Ménière disease are excluded from the diagnosis of TNA. Patients will complete a comprehensive neuropsychological assessment and undergo MRI <7days after the qualifying event and again after six months. The primary clinical outcomes will be cognitive function at baseline and six months after the primary event. Imaging outcomes include the prevalence and evolution of DWI lesions, white matter hyperintensities and lacunes, as well as resting state networks functionality and white matter microstructural integrity. Differences between types of event and DWI, as well as determinants of both clinical and imaging outcomes, will be assessed. Discussion: CONNECT can provide insight in the prevalence, etiology and risk factors of cognitive impairment after TIA and TNA and thereby potentially identify a new group of patients at increased risk of cognitive impairment
Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention
BackgroundTriple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic opportunities. Recently, splicing factors have gained attention as potential targets for cancer treatment. Here we systematically evaluated the role of RNA splicing factors in TNBC cell proliferation.MethodsIn this study, we performed an RNAi screen targeting 244 individual splicing factors to systematically evaluate their role in TNBC cell proliferation. For top candidates, mechanistic insight was gained using amongst others western blot, PCR, FACS, molecular imaging and cloning. Pulldown followed by mass spectrometry were used to determine protein-protein interactions and patient-derived RNA sequencing data was used relate splicing factor expression levels to proliferation markers.ResultsWe identified nine splicing factors, including SNRPD2, SNRPD3 and NHP2L1, of which depletion inhibited proliferation in two TNBC cell lines by deregulation of sister chromatid cohesion (SCC) via increased sororin intron 1 retention and down-regulation of SMC1, MAU2 and ESPL1. Protein-protein interaction analysis of SNRPD2, SNRPD3 and NHP2L1 identified that seven out of the nine identified splicing factors belong to the same spliceosome complex including novel component SUN2 that was also critical for efficient sororin splicing. Finally, sororin transcript levels are highly correlated to various proliferation markers in BC patients.ConclusionWe systematically determined splicing factors that control proliferation of breast cancer cells through a mechanism that involves effective sororin splicing and thereby appropriate sister chromatid cohesion. Moreover, we identified SUN2 as an important new spliceosome complex interacting protein that is critical in this process. We anticipate that deregulating sororin levels through targeting of the relevant splicing factors might be a potential strategy to treat TNBC.Cancer Signaling networks and Molecular Therapeutic
Observational Dutch Young Symptomatic StrokE studY (ODYSSEY): Study rationale and protocol of a multicentre prospective cohort study
Background: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce.Methods/design: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/TIA. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment.Discussion: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size
Risk, clinical course, and outcome of ischemic stroke in patients hospitalized with COVID-19: a multicenter cohort study
Background and Purpose: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. Methods: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. Results: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. Conclusions: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was approximate to 2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.Paroxysmal Cerebral Disorder
Risk factors and causes of ischemic stroke in 1322 young adults
Background:Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study).Methods:This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification.Results:The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%).Conclusions:Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.Neurological Motor Disorder