Circulating biomarkers of cognitive decline and dementia

Plasma and serum biochemical markers proposed for cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin and predementia syndromes (mild cognitive impairment and other related entities) are based on pathophysiologic processes such as lipoprotein metabolism (total cholesterol, apolipoprotein E, 24S-hydroxy-cholesterol), and vascular disease (homocysteine, lipoprotein(a)); SP formation (amyloid beta(Abeta)-protein, Abeta autoantibodies, platelet APP isoforms), oxidative stress (isoprostanes, vitamin E), and inflammation (cytokines). This review will focus on the current knowledge on circulating serum and plasma biomarkers of cognitive decline and dementia that are linked to cholesterol homeostasis and lipoprotein abnormalities, senile plaque formation and amyloid precursor protein (APP) metabolism, oxidative stress, and inflammatory reactions. Special emphasis will, however, be placed on biomarkers related to lipoprotein metabolism and vascular disease. Analytically, most plasma and serum proteins or metabolites lack reproducibility, sensitivity, or specificity for the diagnosis, risk and progression assessment, or therapeutic monitoring of AD and other dementing disorders. Measures linked to lipoprotein metabolism and vascular disease, APP metabolism, oxidative stress, or inflammation appear altered in AD relative to controls, but lack sufficient discriminatory power. Measures combining several biomarkers or incorporating a range of proteins in plasma and small molecule metabolites are promising approaches for the development of plasma or serum-based diagnostic tests for AD and other dementing disorders, as well as for predementia syndromes.     

ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern

Mutations in the X-encoded gene ATRX are known to give rise to syndromic mental retardation in male patients whereas female carriers show preferential inactivation of the mutated X chromosome and appear healthy. Here, we describe a 4-year-old girl with typical features of ATRX syndrome, carrying the recurrent R246C mutation of ATRX. We show that her pattern of X-inactivation is totally skewed and that her active X chromosome which harbors the ATRX mutation, was maternally inherited. To our knowledge, this is the first report of ATRX syndrome in a female patient. Since she was born after in vitro fertilization (IVF), we propose a possible link between assisted reproduction technologies (ART) and the unexpected X chromosome methylation pattern that we observed.     

Interpreting procedures from descriptive guidelines

Errors in clinical practice guidelines may translate into errors in real-world clinical practice. The best way to eliminate these errors is to understand how they are generated, thus enabling the future development of methods to catch errors made in creating the guideline before publication. We examined the process by which a medical expert from the American College of Physicians (ACP) created clinical algorithms from narrative guidelines, as a case study. We studied this process by looking at intermediate versions produced during the algorithm creation. We identified and analyzed errors that were generated at each stage, categorized them using Knuth's classification scheme, and studied patterns of errors that were made over the set of algorithm versions that were created. We then assessed possible explanations for the sources of these errors and provided recommendations for reducing the number of errors, based on cognitive theory and on experience drawn from software engineering methodologies.     

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.     

Health‐related quality of life of patients with juvenile dermatomyositis: Results from the paediatric rheumatology international trials organisation multinational quality of life cohort study

Objective

To investigate the health‐related quality of life (HRQOL) change over time, as measured by the Child Health Questionnaire (CHQ), and its determinants in patients with active juvenile dermatomyositis (DM).

Methods

We assessed patients with juvenile DM at both baseline and 6 months of followup, and healthy children age ≤18 years. Potential determinants of poor HRQOL included demographic data, physician's and parent's global assessments, muscle strength, functional ability as measured by the Childhood Health Assessment Questionnaire (C‐HAQ), global disease activity assessments, and laboratory markers.

Results

A total of 272 children with juvenile DM and 2,288 healthy children were enrolled from 37 countries. The mean ± SD CHQ physical and psychosocial summary scores were significantly lower in children with juvenile DM (33.7 ± 11.7 versus 54.6 ± 4.1) than in healthy children (45.1 ± 9.0 versus 52 ± 7.2), with physical well‐being domains being the most impaired. HRQOL improved over time in responders to treatment and remained unchanged or worsened in nonresponders. Both physical and psychosocial summary scores decreased with increasing levels of disease activity, muscle strength, and parent's evaluation of the child's overall well‐being. A C‐HAQ score >1.6 (odds ratio [OR] 5.06, 95% confidence interval [95% CI] 2.03–12.59), child's overall well‐being score >6.2 (OR 5.24, 95% CI 2.27–12.10), and to a lesser extent muscle strength and alanine aminotransferase level were the strongest determinants of poor physical well‐being at baseline. Baseline disability and longer disease duration were the major determinants for poor physical well‐being at followup.

Conclusion

We found that patients with juvenile DM have a significant impairment in their HRQOL compared with healthy peers, particularly in the physical domain. Physical well‐being was mostly affected by the level of functional impairment.