Vaccination prevented short-term memory loss, but deteriorated long-term spatial memory in Alzheimer's disease mice, independent of amyloid-β pathology

Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer's disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed.Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD.Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests.Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter.Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation.</p

Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases

Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases

De-identifying a public use microdata file from the Canadian national discharge abstract database

<p>Abstract</p> <p>Background</p> <p>The Canadian Institute for Health Information (CIHI) collects hospital discharge abstract data (DAD) from Canadian provinces and territories. There are many demands for the disclosure of this data for research and analysis to inform policy making. To expedite the disclosure of data for some of these purposes, the construction of a DAD public use microdata file (PUMF) was considered. Such purposes include: confirming some published results, providing broader feedback to CIHI to improve data quality, training students and fellows, providing an easily accessible data set for researchers to prepare for analyses on the full DAD data set, and serve as a large health data set for computer scientists and statisticians to evaluate analysis and data mining techniques. The objective of this study was to measure the probability of re-identification for records in a PUMF, and to de-identify a national DAD PUMF consisting of 10% of records.</p> <p>Methods</p> <p>Plausible attacks on a PUMF were evaluated. Based on these attacks, the 2008-2009 national DAD was de-identified. A new algorithm was developed to minimize the amount of suppression while maximizing the precision of the data. The acceptable threshold for the probability of correct re-identification of a record was set at between 0.04 and 0.05. Information loss was measured in terms of the extent of suppression and entropy.</p> <p>Results</p> <p>Two different PUMF files were produced, one with geographic information, and one with no geographic information but more clinical information. At a threshold of 0.05, the maximum proportion of records with the diagnosis code suppressed was 20%, but these suppressions represented only 8-9% of all values in the DAD. Our suppression algorithm has less information loss than a more traditional approach to suppression. Smaller regions, patients with longer stays, and age groups that are infrequently admitted to hospitals tend to be the ones with the highest rates of suppression.</p> <p>Conclusions</p> <p>The strategies we used to maximize data utility and minimize information loss can result in a PUMF that would be useful for the specific purposes noted earlier. However, to create a more detailed file with less information loss suitable for more complex health services research, the risk would need to be mitigated by requiring the data recipient to commit to a data sharing agreement.</p

Statistical disclosure control methods for census frequency tables

This paper provides a review of common statistical disclosure control (SDC) methods implemented at Statistical Agencies for standard tabular outputs containing whole population counts from a Census (either enumerated or based on a register). These methods include record swapping on the microdata prior to its tabulation and rounding of entries in the tables after they are produced. The approach for assessing SDC methods is based on a disclosure risk–data utility framework and the need to find the balance between managing disclosure risk while maximizing the amount of information that can be released to users and ensuring high quality outputs. To carry out the analysis, quantitative measures of disclosure risk and data utility are defined and methods compared. Conclusions from the analysis show that record swapping as a sole SDC method leaves high probabilities of disclosure risk. Targeted record swapping lowers the disclosure risk, but there is more distortion to distributions. Small cell adjustments (rounding) give protection to Census tables by eliminating small cells but only one set of variables and geographies can be disseminated in order to avoid disclosure by differencing nested tables. Full random rounding offers more protection against disclosure by differencing, but margins are typically rounded separately from the internal cells and tables are not additive. Rounding procedures protect against the perception of disclosure risk compared to record swapping since no small cells appear in the tables. Combining rounding with record swapping raises the level of protection but increases the loss of utility to Census tabular outputs. For some statistical analysis, the combination of record swapping and rounding balances to some degree opposing effects that the methods have on the utility of the tables

Data swapping for protecting census tables

The pre-tabular statistical disclosure control (SDC) method of data swapping is the preferred method for protecting Census tabular data in some National Statistical Institutes, including the United States and Great Britain. A pre-tabular SDC method has the advantage that it only needs to be carried out once on the microdata and all tables released (under the conditions of the output strategies, eg. fixed categories of variables, minimum cell size and population thresholds) are considered protected. In this paper, we propose a method for targeted data swapping. The method involves a probability proportional to size selection strategy of high risk households for data swapping. The selected households are then paired with other households having the same control variables. In addition, the distance between paired households is determined by the level of risk with respect to the geographical hierarchies. The strategy is compared to a random data swapping strategy in terms of the disclosure risk and data utility

Neutrophil gelatinase-associated lipocalin and microglial activity are associated with distinct postoperative behavioral changes in rats

Neutrophil gelatinase-associated lipocalin (NGAL) has recently gained interest as a marker for neuroinflammation and associated behavioral dysfunction. We aimed to explore the link between NGAL and behavior in a rat model of postoperative cognitive dysfunction (POCD). Material collected in two previous studies on POCD was analyzed and associated with outcomes for exploratory behavior and spatial learning. Plasma and hippocampal NGAL and microglial activity were analyzed. Pearson's correlations and backward linear regression were performed to study the associations between behavioral parameters, NGAL concentrations, and microglial activity. Plasma and hippocampal NGAL were increased following surgery. Plasma NGAL was associated with impaired spatial learning only, microglial activity was associated with exploratory behavior only, while hippocampal NGAL was associated with both behavioral aspects. Spatial learning was best predicted by a model containing plasma NGAL concentrations and hippocampal microglial activity. NGAL may serve as a sensitive marker in connecting the peripheral inflammatory state to POCD, while postoperative changes in exploratory behavior are better reflected by hippocampal neuroinflammation. These findings warrant further exploration in the role of NGAL in development of postoperative behavioral deficits.</p

Neutrophil gelatinase-associated lipocalin and microglial activity are associated with distinct postoperative behavioral changes in rats

Neutrophil gelatinase-associated lipocalin (NGAL) has recently gained interest as a marker for neuroinflammation and associated behavioral dysfunction. We aimed to explore the link between NGAL and behavior in a rat model of postoperative cognitive dysfunction (POCD). Material collected in two previous studies on POCD was analyzed and associated with outcomes for exploratory behavior and spatial learning. Plasma and hippocampal NGAL and microglial activity were analyzed. Pearson's correlations and backward linear regression were performed to study the associations between behavioral parameters, NGAL concentrations, and microglial activity. Plasma and hippocampal NGAL were increased following surgery. Plasma NGAL was associated with impaired spatial learning only, microglial activity was associated with exploratory behavior only, while hippocampal NGAL was associated with both behavioral aspects. Spatial learning was best predicted by a model containing plasma NGAL concentrations and hippocampal microglial activity. NGAL may serve as a sensitive marker in connecting the peripheral inflammatory state to POCD, while postoperative changes in exploratory behavior are better reflected by hippocampal neuroinflammation. These findings warrant further exploration in the role of NGAL in development of postoperative behavioral deficits

Effects of selective TNFR1 inhibition or TNFR2 stimulation, compared to non-selective TNF inhibition, on (neuro)inflammation and behavior after myocardial infarction in male mice

BACKGROUND: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI. METHODS: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation. RESULTS: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior. CONCLUSION: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed