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Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.
To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies.
We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard.
At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52–77%), specificity 88% (76–95%) and accuracy 76% (68–84%), with positive likelihood ratio 5.3.
It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically.
Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).
A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.
Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.
These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.
Peroxisome Proliferator-Activated Receptor α (PPARα) is a known regulator of lipid and energy metabolism. In animal experiments of PPARα activation, we have reported on altered plasma concentration of metabolites related to one-carbon metabolism and B-vitamin status. Several of these metabolites, e.g. homocysteine and dimethylglycine, have been associated with increased cardiovascular disease risk. Diet can influence one-carbon metabolism, and this may partly be mediated through altered PPARα activity as dietary fatty acids can activate PPARα. As diet is a modifiable life style factor, the aim of this investigation is to explore potential associations between dietary composition and plasma concentration of one-carbon metabolites and markers of B-vitamin status.
Materials and methods:
The study population consisted of 1977 patients with stable angina (geometric mean age 61 years, 80% male) from the Western Norway B-vitamin Intervention Trial (WENBIT), who completed a self-administered food frequency questionnaire at baseline. Data on outcome variables were obtained from the baseline blood samples (35% fasting). Outcome variables of interest were metabolites related to one-carbon metabolism and B-vitamin status. Cross-sectional associations between protein, carbohydrate and fat intake with the outcome metabolites were analysed with linear regression, adjusted for age, sex, fasting status, BMI and reported energy intake. Estimates are given as % change in the outcome variable per isoenergetic increment of 1 energy % (E%) in the exposure nutrient.
The average distribution [95% prediction interval] of energy intake (E%) in the population was 48.5 (37.1, 63.4) from carbohydrate, 31.4 (21.9, 44.9) from fat and 16.5 (12.2, 22.3) from protein.
The strongest associations were seen for increasing protein intake, while the associations with fat and carbohydrate intake were weaker. The most pronounced associations (% change [95% confidence interval]) with increasing protein intake were higher cobalamin (2.9 [2.1, 3.7]), PLP (2.7 [1.7, 3.7]) and riboflavin (2.3 [1.0, 3.6]), and lower tHcy (-1.4 [-1.9, -0.9]) and MMA (-1.3 [-1.9, -0.7]).
The current observations indicate that dietary macronutrient composition may influence plasma concentration of one-carbon metabolites and markers of B-vitamin status. The strongest associations are observed with increasing protein intake, but elucidating the importance of the nutrient substituted remains. Whether the observed associations are due to macronutrients per se, or reflect differences in food choices/nutrient intakes, or effects on physiological factors, i.e. inflammation or PPARα activation, is not known.
The recent observations of ferromagnetic order in several two-dimensional (2D) materials have generated an enormous interest in the physical mechanisms underlying 2D magnetism. In the present Prospective Article, we show that Density Functional Theory combined with either classical Monte Carlo simulations or renormalized spin-wave theory can predict Curie temperatures for ferromagnetic insulators that are in quantitative agreement with experiments. The case of materials with in-plane anisotropy is then discussed, and it is argued that finite size effects may lead to observable magnetic order in macroscopic samples even if long range magnetic order is forbidden by the Mermin–Wagner theorem.
Women suffering from first onset postpartum mental disorders (PPMD) have a highly elevated risk of suicide. The current study aimed to: (1) describe the risk of self-harm among women with PPMD and (2) investigate the extent to which self-harm is associated with later suicide.
We conducted a register-based cohort study linking national Danish registers. This identified women with any recorded first inpatient or outpatient contact to a psychiatric facility within 90 days after giving birth to their first child. The main outcome of interest was defined as the first hospital-registered episode of self-harm. Our cohort consisted of 1 202 292 women representing 24 053 543 person-years at risk.
Among 1554 women with severe first onset PPMD, 64 had a first-ever hospital record of self-harm. Women with PPMD had a hazard ratio (HR) for self-harm of 6.2 (95% CI 4.9–8.0), compared to mothers without mental disorders; but self-harm risk was lower in PPMD women compared to mothers with non-PPMD [HR: 10.1, (95% CI 9.6–10.5)] and childless women with mental disorders [HR: 9.3 (95% CI 8.9–9.7)]. Women with PPMD and records of self-harm had a significantly greater risk for later suicide compared with all other groups of women in the cohort.
Women with PPMD had a high risk of self-harm, although lower than risks observed in other psychiatric patients. However, PPMD women who had self-harmed constituted a vulnerable group at significantly increased risk of later suicide.
To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups – probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer’s disease (probable MCI-AD) – as well as associations with clinical features.
Memory clinics and dementia services.
Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20).
Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated.
There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026).
There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.
Chronic inflammation is associated with disease risk and mortality in the general population. Soluble urokinase plasminogen activator receptor (suPAR) is a stable marker of chronic inflammation, and a higher serum-concentration of suPAR is found in individuals with an unhealthy lifestyle such as smoking. This article investigates the association between suPAR and dietary quality measured with the dietary quality score (DQS). The DQS is an index of the overall quality of an individual’s dietary habits assessed through a self-administered FFQ. Furthermore, this article investigates the association of both suPAR and the DQS with CVD risk and mortality in the general Danish population. We analysed 5347 individuals aged 30–60 years from the Danish Inter99 study cohort. Multiple linear regression analyses showed a linear inverse association between the DQS and suPAR (P=0·0005). Cox regression analyses showed an 18 (95 % CI 9, 26) % increase in the risk of death from any cause with each 1 ng/ml increase in suPAR. We found no significant association between the DQS and the mortality (hazard ratio: 1·16, 95 % CI 0·79, 1·69). All analyses were adjusted for demographics and lifestyle factors. The association between the DQS and suPAR on the one hand and suPAR and mortality on the other supports the argument that low dietary quality may constitute a health risk through its influence on chronic inflammation. Future research should examine whether suPAR is modifiable through changes in dietary habits.
Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage.
We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal.
The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7).
Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.
The accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimer's disease MCI (MCI-AD).
Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy.
MCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD.
MCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.
To study the natural recovery from sports concussion, 12 concussed high school football athletes and 12 matched uninjured teammates were evaluated with symptom rating scales, tests of postural balance and cognition, and an event-related fMRI study during performance of a load-dependent working memory task at 13 h and 7 weeks following injury. Injured athletes showed the expected postconcussive symptoms and cognitive decline with decreased reaction time (RT) and increased RT variability on a working memory task during the acute period and an apparent full recovery 7 weeks later. Brain activation patterns showed decreased activation of right hemisphere attentional networks in injured athletes relative to controls during the acute period with a reversed pattern of activation (injured > controls) in the same networks at 7 weeks following injury. These changes coincided with a decrease in self-reported postconcussive symptoms and improved cognitive test performance in the injured athletes. Results from this exploratory study suggest that decreased activation of right hemisphere attentional networks mediate the cognitive changes and postconcussion symptoms observed during the acute period following concussion. Conversely, improvement in cognitive functioning and postconcussive symptoms during the subacute period may be mediated by compensatory increases in activation of this same attentional network. (JINS, 2013, 19, 1–10)
Life is but a continuous process of energy conversion and transformation. The accomplishments of civilization have largely been achieved through the increasingly efficient and extensive harnessing of various forms of energy to extend human capabilities and ingenuity. Energy is similarly indispensable for continued human development and economic growth. Providing adequate, affordable energy is a necessary (even if by itself insufficient) prerequisite for eradicating poverty, improving human welfare, and raising living standards worldwide. Without economic growth, it will also be difficult to address social and environmental challenges, especially those associated with poverty. Without continued institutional, social, and technological innovation, it will be impossible to address planetary challenges such as climate change. Energy extraction, conversion, and use always generate undesirable by-products and emissions – at a minimum in the form of dissipated heat. Energy cannot be created or destroyed – it can only be converted from one form to another, along a one-way street from higher to lower grades (qualities) of energy. Although it is common to discuss energy “consumption,” energy is actually transformed rather than consumed.
This Energy Primer 1 aims at a basic-level introduction to fundamental concepts and data that help to understand energy systems holistically and to provide a common conceptual and terminological framework before examining in greater detail the various aspects of energy systems from challenges and options to integrated solutions, as done in the different chapters of the Global Energy Assessment (GEA).
A common objective for a monitoring program is to characterize an environmental resource based on inference from the sites selected to be monitored to the entire target population. The scale of monitoring ranges from local studies, to regional monitoring, to nationwide monitoring programs. Rarely can these monitoring efforts monitor at all locations, or sites, within the study region. Consequently, a major consideration is how to select representative sites from which it is possible to make inferences to the entire study region.
In addition to the different spatial scales of interest across monitoring efforts, these studies may focus on different environmental resources. A state or province may be interested in all small lakes (e.g. < 10 ha) with the objective of classifying the lakes as meeting designated uses (i.e. having values of designated water quality attributes that do not exceed a specified threshold), partially meeting designated uses, or not meeting designated uses. In this case, the elements of the environmental resource are individual lakes and site selection is based on selecting a subset of lakes from the target population. Alternatively, a state may be interested in all perennial streams and rivers within the state to determine the total stream length that meets a nutrient criterion. In this case, the elements of the environmental resource are all possible locations on the stream and river network within the state and site selection is based on selecting sites on the stream network to be monitored. The stream network is the target population and is viewed as a continuous linear network. Finally, a state may be interested in monitoring a single large estuary within the state (e.g. Puget Sound in Washington State, USA) to determine the proportion of the estuarine area that has sediment contamination exceeding a criteria. In this case, the environmental resource, i.e. the target population, is an area and sites are selected from all possible locations within the estuarine surface area. Similar examples can be given for terrestrial environmental resources.
Typical objectives for environmental resource monitoring programs include estimating the current status of the resource, estimating change in status between two time periods, and estimating trends in status over time. For most monitoring programs, status is estimated using multiple indicators (monitoring variables) determined for each sample site that are derived from measurements of biological, chemical, and physical attributes obtained at the site. What is meant by estimating current status? First, the estimate applies to a specified portion of the region included in the monitoring program, typically the entire region. Second, a specific summary measure must be chosen. Common summary measures are estimates of the population mean, the percentage of the population that is less than a particular value (e.g. percentage of water bodies meeting a water quality standard or percentage of a dry forest region that has tree densities < x trees/ha), the population median, the percentage of the population occurring in categories, or the population standard deviation for an indicator.
An additional summary measure is an estimate of the population cumulative distribution for the indicator. The population cumulative distribution is simply the percentage of the population that is less than or equal to each possible value of an indicator. The population cumulative distribution provides complete information about the indicator distribution (Box 14.1). It has the advantage that it can be used for both categorical and continuous data. It is common in statistics to call the cumulative distribution the cumulative distribution function (CDF) and we will adopt that convention in this chapter. Measurements for indicators obtained from a probability survey can be used to estimate these summary measures of status. For complex survey designs that employ stratification or unequal probability of selection, estimation of current status for any of these summary measures must use weights that are derived from the stratification or unequal probability of selection used in the design.
Nanomechanical testing of silicon is primarily motivated toward characterizing scale effects on the mechanical behavior. “Defect-free” nanoscale silicon additionally offers a road to large deformation permitting the investigation of transport characteristics and surface instabilities of a significantly perturbed atomic arrangement. The need for developing simple and generic characterization tools to deform free-standing silicon beams down to the nanometer scale, sufficiently equipped to investigate both the mechanical properties and the carrier transport under large strains, has been met in this research through the design of a versatile lab-on-chip. The original on-chip characterization technique has been applied to monocrystalline Si beams produced from Silicon-on-Insulator wafers. The Young’s modulus was observed to decrease from 160 GPa down to 108 GPa when varying the thickness from 200 down to 50 nm. The fracture strain increases when decreasing the volume of the test specimen to reach 5% in the smallest samples. Additionally, atomic force microscope-based characterizations reveal that the surface roughness decreases by a factor of 5 when deforming by 2% the Si specimen. Proof of concept transport measurements were also performed under deformation up till 3.5% on 40-nm-thick lightly p-doped silicon beams.
Congenital heart defect patients may experience neurodevelopmental impairment. We investigated their educational attainments from basic schooling to higher education.
Patients and methods
Using administrative databases, we identified all Danish patients with a cardiac defect diagnosis born from 1 January, 1977 to 1 January, 1991 and alive at age 13 years. As a comparison cohort, we randomly sampled 10 persons per patient. We obtained information on educational attainment from Denmark's Database for Labour Market Research. The study population was followed until achievement of educational levels, death, emigration, or 1 January, 2006. We estimated the hazard ratio of attaining given educational levels, conditional on completing preceding levels, using discrete-time Cox regression and adjusting for socio-economic factors. Analyses were repeated for a sub-cohort of patients and controls born at term and without extracardiac defects or chromosomal anomalies.
We identified 2986 patients. Their probability of completing compulsory basic schooling was approximately 10% lower than that of control individuals (adjusted hazard ratio = 0.79, ranged from 0.75 to 0.82 0.79; 95% confidence interval: 0.75–0.82). Their subsequent probability of completing secondary school was lower than that of the controls, both for all patients (adjusted hazard ratio = 0.74; 95% confidence interval: 0.69–0.80) and for the sub-cohort (adjusted hazard ratio = 0.80; 95% confidence interval: 0.73–0.86). The probability of attaining a higher degree, conditional on completion of youth education, was affected both for all patients (adjusted hazard ratio = 0.88; 95% confidence interval: 0.76–1.01) and for the sub-cohort (adjusted hazard ratio = 0.92; 95% confidence interval: 0.79–1.07).
The probability of educational attainment was reduced among long-term congenital heart defect survivors.
Within a project on Stone Age sites of NE Germany, 26 burials from the Ostorf cemetery and some further Neolithic sites have been analyzed by more than 40 accelerator mass spectrometry (AMS) dates. We here present the results of stable isotope and radiocarbon measurements together with reference 14C dates on grave goods from terrestrial animals such as tooth pendants found in 10 of the graves. Age differences between human individuals and their associated grave goods are used to calculate 14C reservoir effects. The resulting substantial reservoir effects have revealed misleadingly high 14C ages of their remains, which originally indicated a surprisingly early occurrence of graves and long-term use of this Neolithic burial site. We demonstrate that in order to 14C date the human bones from Ostorf cemetery, it is of utmost importance to distinguish between terrestrial- and freshwater-influenced diet. The latter may result in significantly higher than marine reservoir ages with apparent 14C ages up to ∼800 yr too old. The carbon and nitrogen isotopic composition may provide a basis for or an indicator of necessary corrections of dates on humans where no datable grave goods of terrestrial origin such as tooth pendants or tusks are available. Based on the associated age control animals, there is no evidence that the dated earliest burials occurred any earlier than 3300 BC, in contrast to the original first impression of the grave site (∼3800 BC).