Revising the definition of Alzheimer's disease: a new lexicon

Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.     

Age Differences in Outdated Information Processing During News Reports Reading

In two experiments, the authors explored whether there are any age differences associated with the ability to process outdated information during news reports comprehension. Younger and older participants (mean age: 70 years old) read passages in which a cause was first said to be responsible for the occurrence of a news event. New elements emerged from the investigation in progress and revealed that the original cause was incorrect. Inference response times indicated that older adults more than younger ones took advantage of an alternative cause mentioned in the text to put the outdated information in the background, whereas younger readers probably kept both causes activated. The research tested the concepts involved with age differences in updating situation model.     

Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome

Objectives

To evaluate the outcomes of babies born to mothers with primary antiphospholipid syndrome and to compare to the outcomes of babies of mothers with systemic lupus erythematosus.

Methods

A retrospective study from 2003 to 2010 assessing the clinical characteristics and psychomotor development, as well as the immunological data, of children born to mothers with antiphospholipid syndrome (APS) (group 1) and systemic lupus erythematosus (group 2).

Results

Group 1 consisted of 36 children born to mothers (n = 26) with a primary APS. Autism spectrum disorders occurred in 3 children from group 1 and all of them had persistent anti-β2GP1 IgG antibodies.Group 2 consisted of 12 children born to mothers (n = 9) with lupus erythematosus. Three children experienced cutaneous neonatal lupus, but there were no neurodevelopmental disorders. Comparing children of groups 1 and 2, no significant difference was found with regard to the parameters at birth or during follow-up. The children in group 2 had antinuclear antibodies more frequently (p < 0.05).

Conclusion

Autism spectrum disorders could be observed in babies born to mothers with antiphospholipid syndrome, but there is no risk of thrombosis.

Key messages

Neonatal lupus is well-known complication in children born to mothers with systemic lupus erythematosus, but there is no risk of thrombosis in APS-exposed children.In children of APS mothers the rate of prematurity and small-for-gestational age weight remain high even in treated pregnancy.The presence of several cases of autism spectrum disorders in APS-exposed children could be related to mother's antibodies exposition, but need to be confirmed.     

Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy

Background

Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods.In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥ 13 mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods.

Methods

In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool.

Results

362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C > A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G > A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639 + 6A > C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM).

Conclusions

In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD.     

Comparison of different invasive hemodynamic methods for AV delay optimization in patients with cardiac resynchronization therapy: Implications for clinical trial design and clinical practice

Background

Reproducibility and hemodynamic efficacy of optimization of AV delay (AVD) of cardiac resynchronization therapy (CRT) using invasive LV dp/dt_max are unknown.

Method and results

25 patients underwent AV delay (AVD) optimisation twice, using continuous left ventricular (LV) dp/dt_max, systolic blood pressure (SBP) and pulse pressure (PP). We compared 4 protocols for comparing dp/dt_max between AV delays:

Immediate absolute: mean of 10 s recording of dp/dt_max acquired immediately after programming the tested AVD,

Delayed absolute: mean of 10 s recording acquired 30 s after programming AVD,

Single relative: relative difference between reference AVD and the tested AVD,

Multiple relative: averaged difference, from multiple alternations between reference and tested AVD.

We assessed for dp/dt_max, LVSBP and LVPP, test–retest reproducibility of the optimum.Optimization using immediate absolute dp/dt_max had poor reproducibility (SDD of replicate optima = 41 ms; R² = 0.45) as did delayed absolute (SDD 39 ms; R² = 0.50). Multiple relative had better reproducibility: SDD 23 ms, R² = 0.76, and (p < 0.01 by F test).Compared with AAI pacing, the hemodynamic increment from CRT, with the nominal AV delay was LVSBP 2% and LVdp/dt_max 5%, while CRT with pre-determined optimal AVD gave 6% and 9% respectively.

Conclusions

Because of inevitable background fluctuations, optimization by absolute dp/dt_max has poor same-day reproducibility, unsuitable for clinical or research purposes. Reproducibility is improved by comparing to a reference AVD and making multiple consecutive measurements. More than 6 measurements would be required for even more precise optimization — and might be advisable for future study designs. With optimal AVD, instead of nominal, the hemodynamic increment of CRT is approximately doubled.     

The role of long-range connections on the specificity of the macaque interareal cortical network

We investigated the influence of interareal distance on connectivity patterns in a database obtained from the injection of retrograde tracers in 29 areas distributed over six regions (occipital, temporal, parietal, frontal, prefrontal, and limbic). One-third of the 1,615 pathways projecting to the 29 target areas were reported only recently and deemed new-found projections (NFPs). NFPs are predominantly long-range, low-weight connections. A minimum dominating set analysis (a graph theoretic measure) shows that NFPs play a major role in globalizing input to small groups of areas. Randomization tests show that (i) NFPs make important contributions to the specificity of the connectivity profile of individual cortical areas, and (ii) NFPs share key properties with known connections at the same distance. We developed a similarity index, which shows that intraregion similarity is high, whereas the interregion similarity declines with distance. For area pairs, there is a steep decline with distance in the similarity and probability of being connected. Nevertheless, the present findings reveal an unexpected binary specificity despite the high density (66%) of the cortical graph. This specificity is made possible because connections are largely concentrated over short distances. These findings emphasize the importance of long-distance connections in the connectivity profile of an area. We demonstrate that long-distance connections are particularly prevalent for prefrontal areas, where they may play a prominent role in large-scale communication and information integration.     

Cell membrane structures during exocytosis

Exocytosis is a key biological process that controls the neurotransmission and release of hormones from cells. In endocrine cells, hormones are packed into secretory vesicles and released into the extracellular environment via openings in the plasma membrane, a few hundred nanometers wide, which form as a result of fusion of the membranes of the granule and cell. The complex processes and dynamics that result in the formation of the fusion pore, as well as its structure, remain scantly understood. A number of different exocytosis mechanisms have been postulated. Furthermore, the possibility exists that several mechanisms occur simultaneously. We present here an investigation of the cell membrane dynamics during exocytosis in anterior pituitary cells, especially gonadotropes, which secrete LH, a hormone central to ovulation. Gonadotrope enrichment was achieved using immunolabeled magnetic nanobeads. Three complementary imaging techniques were used to realize a fine structure study of the dynamics of the exocytosis-like sites occurring during secretion. Living pituitary and gonadotrope-enriched cells were imaged with atomic force microscopy, as well as cells that had been fixed to obtain better resolution. Atomic force microscopy, along with scanning and transmission electron microscopy, studies of these cells revealed that there are at least two different site configurations: simple single fusion pores and a complex association of pores consisting of a simple primary site combined with secondary attachments.     

Induction of CXCL1 by extracellular matrix and autocrine enhancement by interleukin-1 in rat pancreatic beta-cells

As we showed previously, the extracellular matrix (ECM) derived from rat bladder carcinoma cells (804G-ECM) has positive effects on rat primary beta-cell function and survival in vitro. The aim of this study was to define beta-cell genes induced by this ECM with a specific focus on cytokines. Analysis of differential gene expression by oligonucleotide microarrays, RT-PCR, and in situ hybridization was performed to identify cytokine mRNA induced by this matrix. Four cytokines were overexpressed on 804G-ECM compared with poly-L-lysine: C-X-C motif ligand 1 (CXCL1), CXCL2, interferon-inducible protein-10, and IL-1beta. A time-course experiment indicated that maximal induction by 804G-ECM of CXCL1/2 and interferon-inducible protein-10 occurred at 4 h. Stimulation of CXCL1 release by beta-cells on 804G-ECM was confirmed at the protein level. Moreover, secreted CXCL1 was shown to be functionally active by attracting rat granulocytes. Preventing the interaction of beta1 integrins and laminin-5 (a major component of 804G-ECM) with specific antibodies resulted in a 40-50% inhibition of CXCL1 expression. Using the nuclear factor-kappaB pathway inhibitor Bay 11-7082 it is demonstrated that CXCL1 expression and secretion are dependent on nuclear factor-kappaB activation. IL-1 secreted by beta-cells plated on 804G-ECM was found to be a key soluble mediator because treatment of cells with the IL-1 receptor antagonist significantly reduced both CXCL1 gene expression and secretion. It is concluded that ECM induces expression of cytokines including CXCL1 with amplification by IL-1 acting via a positive autocrine feedback loop.