Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Building Babies - Chapter 16

In contrast to birds, male mammals rarely help to raise the offspring. Of all mammals, only among rodents, carnivores, and primates, males are sometimes intensively engaged in providing infant care (Kleiman and Malcolm 1981). Male caretaking of infants has long been recognized in nonhuman primates (Itani 1959). Given that infant care behavior can have a positive effect on the infant’s development, growth, well-being, or survival, why are male mammals not more frequently involved in “building babies”? We begin the chapter defining a few relevant terms and introducing the theory and hypotheses that have historically addressed the evolution of paternal care. We then review empirical findings on male care among primate taxa, before focusing, in the final section, on our own work on paternal care in South American owl monkeys (Aotus spp.). We conclude the chapter with some suggestions for future studies.Deutsche Forschungsgemeinschaft (HU 1746/2-1) Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the National Science Foundation (BCS-0621020), the University of Pennsylvania Research Foundation, the Zoological Society of San Dieg

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

GliMR: Cross-Border Collaborations to Promote Advanced MRI Biomarkers for Glioma

Purpose: There is an annual incidence of 50,000 glioma cases in Europe. The optimal treatment strategy is highly personalised, depending on tumour type, grade, spatial localization, and the degree of tissue infiltration. In research settings, advanced magnetic resonance imaging (MRI) has shown great promise as a tool to inform personalised treatment decisions. However, the use of advanced MRI in clinical practice rem

Cortical Gyrification and Sulcal Spans in Early Stage Alzheimer's Disease

Alzheimer's disease (AD) is characterized by an insidious onset of progressive cerebral atrophy and cognitive decline. Previous research suggests that cortical folding and sulcal width are associated with cognitive function in elderly individuals, and the aim of the present study was to investigate these morphological measures in patients with AD. The sample contained 161 participants, comprising 80 normal controls, 57 patients with very mild AD, and 24 patients with mild AD. From 3D T1-weighted brain scans, automated methods were used to calculate an index of global cortex gyrification and the width of five individual sulci: superior frontal, intra-parietal, superior temporal, central, and Sylvian fissure. We found that global cortex gyrification decreased with increasing severity of AD, and that the width of all individual sulci investigated other than the intra-parietal sulcus was greater in patients with mild AD than in controls. We also found that cognitive functioning, as assessed by Mini-Mental State Examination (MMSE) scores, decreased as global cortex gyrification decreased. MMSE scores also decreased in association with a widening of all individual sulci investigated other than the intra-parietal sulcus. The results suggest that abnormalities of global cortex gyrification and regional sulcal span are characteristic of patients with even very mild AD, and could thus facilitate the early diagnosis of this condition

Analysis of Area-Specific Expression Patterns of RORbeta, ER81 and Nurr1 mRNAs in Rat Neocortex by Double In Situ Hybridization and Cortical Box Method

BACKGROUND: The mammalian neocortex is subdivided into many areas, each of which exhibits distinctive lamina architecture. To investigate such area differences in detail, we chose three genes for comparative analyses, namely, RORbeta, ER81 and Nurr1, mRNAs of which have been reported to be mainly expressed in layers 4, 5 and 6, respectively. To analyze their qualitative and quantitative coexpression profiles in the rat neocortex, we used double in situ hybridization (ISH) histochemistry and cortical box method which we previously developed to integrate the data of different staining and individuals in a standard three-dimensional space. PRINCIPAL FINDINGS: Our new approach resulted in three main observations. First, the three genes showed unique area distribution patterns that are mostly complementary to one another. The patterns revealed by cortical box method matched well with the cytoarchitectonic areas defined by Nissl staining. Second, at single cell level, RORbeta and ER81 mRNAs were coexpressed in a subpopulation of layer 5 neurons, whereas Nurr1 and ER81 mRNAs were not colocalized. Third, principal component analysis showed that the order of hierarchical processing in the cortex correlates well with the expression profiles of these three genes. Based on this analysis, the dysgranular zone (DZ) in the somatosensory area was considered to exhibit a profile of a higher order area, which is consistent with previous proposal. CONCLUSIONS/SIGNIFICANCE: The tight relationship between the expression of the three layer specific genes and functional areas were revealed, demonstrating the usefulness of cortical box method in the study on the cerebral cortex. In particular, it allowed us to perform statistical evaluation and pattern matching, which would become important in interpreting the ever-increasing data of gene expression in the cortex

Nitrogen and Carbon Isotopic Dynamics of Subarctic Soils and Plants in Southern Yukon Territory and its Implications for Paleoecological and Paleodietary Studies

We examine here the carbon and nitrogen isotopic compositions of bulk soils (8 topsoil and 7 subsoils, including two soil profiles) and five different plant parts of 79 C3 plants from two main functional groups: herbs and shrubs/subshrubs, from 18 different locations in grasslands of southern Yukon Territory, Canada (eastern shoreline of Kluane Lake and Whitehorse area). The Kluane Lake region in particular has been identified previously as an analogue for Late Pleistocene eastern Beringia. All topsoils have higher average total nitrogen δ15N and organic carbon δ13C than plants from the same sites with a positive shift occurring with depth in two soil profiles analyzed. All plants analyzed have an average whole plant δ13C of −27.5 ± 1.2 ‰ and foliar δ13C of ±28.0 ± 1.3 ‰, and average whole plant δ15N of −0.3 ± 2.2 ‰ and foliar δ15N of ±0.6 ± 2.7 ‰. Plants analyzed here showed relatively smaller variability in δ13C than δ15N. Their average δ13C after suitable corrections for the Suess effect should be suitable as baseline for interpreting diets of Late Pleistocene herbivores that lived in eastern Beringia. Water availability, nitrogen availability, spacial differences and intra-plant variability are important controls on δ15N of herbaceous plants in the study area. The wider range of δ15N, the more numerous factors that affect nitrogen isotopic composition and their likely differences in the past, however, limit use of the modern N isotopic baseline for vegetation in paleodietary models for such ecosystems. That said, the positive correlation between foliar δ15N and N content shown for the modern plants could support use of plant δ15N as an index for plant N content and therefore forage quality. The modern N isotopic baseline cannot be applied directly to the past, but it is prerequisite to future efforts to detect shifts in N cycling and forage quality since the Late Pleistocene through comparison with fossil plants from the same region

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p