Inflammation, nutrition and risk of dementia : the Rotterdam Study

The aim of the research described in this thesis was to further investigate the relation between inflammatory factors, antioxidants and lipids, and dementia and to examine whether these associations could be explained by atherosclerosis. All studies in this thesis were based on the Rotterdam Study, an ongoing prospective population-based study among 7983 subjects of 55 years and over, who were living in Ommoord, a suburb in Rotterdam, the Netherlands. At baseline (1990-1993), 7525 participants of the Rotterdam Study underwent extensive screening for dementia, of whom 482 were diagnosed as having dementia. Of these, 353 (73%) suffered from Alzheimer's disease and 72 from vascular dementia (15%). The 7043 subjects who were dementia-free at baseline were followed up for 5. 7 yea:rs on average. During this period, 395 participants developed dementia, of whom 293 (7 4%) had Alzheimer's disease and 57 (14%) vascular dementia. In this general discussion, I will give an overview of the main findings in this thesis in the light of current knowledge regarding dementia pathogenesis. In addition, some methodological issues will be discussed as well as the clinical relevance of our findings. Finally, I will give some recommendations for future research

Organic Pollutants, Heavy Metals and Toxicity in Oil Spill impacted Salt Marsh Sediment Cores, Staten Island, New York City, USA

Sediment cores from Staten Island's salt marsh contain multiple historical oil spill events that impact ecological health. Microtox solid phase bioassay indicated moderate to high toxicity. Multiple spikes of TPH (6524 to 9586 mg/kg) and Σ16 PAH (15.5 to 18.9 mg/kg) were co-incident with known oil spills. A high TPH background of 400–700 mg/kg was attributed to diffuse sources. Depth-profiled metals Cu (1243 mg/kg), Zn (1814 mg/kg), Pb (1140 mg/kg), Ni (109 mg/kg), Hg (7 mg/kg), Cd 15 (mg/kg) exceeded sediment quality guidelines confirming adverse biological effects. Changes in Pb206/207 suggested three metal contaminant sources and diatom assemblages responded to two contamination events. Organic and metal contamination in Saw Mill Creek Marsh may harm sensitive biota, we recommend caution in the management of the 20–50 cm sediment interval because disturbance could lead to remobilisation of pre-existing legacy contamination into the waterway

Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database

Objectives To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up. Methods Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models. Results 826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms. Conclusion SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage

Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population

Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations.

Contains fulltext : 48368.pdf (publisher's version ) (Closed access)OBJECTIVE: To characterize and distinguish the types of sensorineural hearing impairment (SNHI) that occur in hereditary motor and sensory neuropathy Type 1a (HMSN-1a) and hereditary neuropathy with liability to pressure palsies (HNPP), which are caused by deletion or frameshift mutation. STUDY DESIGN: Prospective study. SETTING: Ambulatory patients in a university hospital. PATIENTS: Twelve patients with HMSN-1a due to a duplication of the PMP22 gene on chromosome 17p11.2, 16 patients with HNPP due to the common PMP22 deletion (HNPP del), and 11 HNPP patients with a frame shift mutation (heterozygous PMP22 G-insertion) (HNPP mut), all confirmed by molecular genetic analysis. INTERVENTIONS: Pure-tone audiograms and speech audiograms were obtained. MAIN OUTCOME MEASURES: Results of cross-sectional analysis comprising linear regression of hearing threshold on age. RESULTS: Pure-tone audiograms showed mild to moderate SNHI, predominant at the low and the high frequencies. SNHI showed significant progression by approximately 0.4 dB per year at 0.25 to 4 kHz and up to 1 to 2 dB per year at 4 to 8 kHz. Patients with HMSN-1a had substantial, presumably congenital, SNHI but did not show significant progression beyond presbyacusis. Patients with HNPP showed postnatal onset at age 11 years with progression of SNHI in excess of presbyacusis by 0.4 dB per year. All three types of neuropathy showed normal speech recognition. CONCLUSIONS: All three types of neuropathy showed SNHI with normal speech recognition. HMSN-1a showed stable SNHI without progression beyond presbyacusis. HNPP showed progression beyond presbyacusis with postnatal onset. The differences in SNHI may be explained by the differences in PMP22 expression. The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder

Plasma Levels of Antioxidants Are Not Associated with Alzheimer's Disease or Cognitive Decline.

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Exploring mechanisms of compaction in salt-marsh sediments using Common Era relative sea-level reconstructions

Salt-marsh sediments provide precise and near-continuous reconstructions of Common Era relative sea level (RSL). However, organic and low-density salt-marsh sediments are prone to compaction processes that cause post-depositional distortion of the stratigraphic column used to reconstruct RSL. We compared two RSL reconstructions from East River Marsh (Connecticut, USA) to assess the contribution of mechanical compression and biodegradation to compaction of salt-marsh sediments and their subsequent influence on RSL reconstructions. The first, existing reconstruction ('trench') was produced from a continuous sequence of basal salt-marsh sediment and is unaffected by compaction. The second, new reconstruction is from a compaction-susceptible core taken at the same location. We highlight that sediment compaction is the only feasible mechanism for explaining the observed differences in RSL reconstructed from the trench and core. Both reconstructions display long-term RSL rise of ~1 mm/yr , followed by a ~19th Century acceleration to ~3 mm/yr. A statistically-significant difference between the records at ~1100 to 1800 CE could not be explained by a compression-only geotechnical model. We suggest that the warmer and drier conditions of the Medieval Climate Anomaly (MCA) resulted in an increase in sediment compressibility during this time period. We adapted the geotechnical model by reducing the compressive strength of MCA sediments to simulate this softening of sediments. 'Decompaction' of the core reconstruction with this modified model accounted for the difference between the two RSL reconstructions. Our results demonstrate that compression-only geotechnical models may be inadequate for estimating compaction and post-depositional lowering of susceptible organic salt-marsh sediments in some settings. This has important implications for our understanding of the drivers of sea-level change. Further, our results suggest that future climate changes may make salt marshes more susceptible to the impacts of RSL rise by enhancing sediment compressibility. We stress, however, that the cause of the softening remains enigmatic. Until this is better constrained, it is premature to widely extrapolate our findings to existing core-based reconstructions of Holocene RSL

Inflammatory proteins in plasma and the risk of dementia: the rotterdam study.

Contains fulltext : 58088.pdf (publisher's version ) (Closed access)BACKGROUND: Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. OBJECTIVE: To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. DESIGN AND SETTING: A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. PARTICIPANTS: The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. MAIN OUTCOME MEASURES: The associations between plasma levels of alpha1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. RESULTS: High levels of alpha1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for alpha1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. CONCLUSION: Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia

Relative sea-level change in South Florida during the past ~5 ka

A paucity of detailed relative sea-level (RSL) reconstructions from low latitudes hinders efforts to understand the global, regional, and local processes that cause RSL change. We reconstruct RSL change during the past ~5 ka using cores of mangrove peat at two sites (Snipe Key and Swan Key) in the Florida Keys. Remote sensing and field surveys established the relationship between peat-forming mangroves and tidal elevation in South Florida. Core chronologies are developed from age-depth models applied to 72 radiocarbon dates (39 mangrove wood macrofossils and 33 fine-fraction bulk peat). RSL rose 3.7 m at Snipe Key and 5.0 m at Swan Key in the past 5 ka, with both sites recording the fastest century-scale rate of RSL rise since ~1900 CE (~2.1 mm/a). We demonstrate that it is feasible to produce near-continuous reconstructions of RSL from mangrove peat in regions with a microtidal regime and accommodation space created by millennial-scale RSL rise. Decomposition of RSL trends from a network of reconstructions across South Florida using a spatio-temporal model suggests that Snipe Key was representative of regional RSL trends, but Swan Key was influenced by an additional local-scale process acting over at least the past five millennia. Geotechnical analysis of modern and buried mangrove peat indicates that sediment compaction is not the local-scale process responsible for the exaggerated RSL rise at Swan Key. The substantial difference in RSL between two nearby sites highlights the critical need for within-region replication of RSL reconstructions to avoid misattribution of sea-level trends, which could also have implications for geophysical modeling studies using RSL data for model tuning and validation