Location of ROIs for FA-value calculation in the septohippocampal nucleus (ROI I), in the corpus callosum (ROI II), and in the medial septal nucleus (ROI III).

<p>Directional information was incorporated by color coding the scalar FA map with the red, green and blue colors to label the left-right, ventral-dorsal, and caudal-rostral directions, respectively. FA-display threshold was 0.2.</p

FT results for seed points in the genu and along the corpus callosum, near the lateral septal nucleus, and in the olfactory path.

<p><b>Left column:</b> Location of the seed points. <b>Columns 2–4:</b> FT for mouse 1 with different scanning protocols (SP). <b>Columns 5–6:</b> FT for mice 2 and 3, respectively, with SP A (35 minute scan).</p

Brain array coil (left) vs. cryogenic cooled resonator (CCR – right).

<p><b>Upper panel:</b> (b = 0) anatomical images (axial slice and coronal reconstruction) used for signal-to-noise ratio (SNR) estimation: ROI 1 (r = 20 voxels) is located in a region without signal in order to estimate the noise, ROI 2 (r = 5 mm) is located in the ventricles in order to estimate the signal intensity in a region with high (b = 0)-signal. <b>Lower panel:</b> Directional encoded color maps of FA (axial slice and coronal reconstruction) - directional information was incorporated by color coding the scalar FA map with the red, green and blue colors to label the left-right, ventral-dorsal, and caudal-rostral directions, respectively.</p

Statistical analysis.

<p><b>Left panel</b> – ROI analysis: FA-values (standard deviation as error bars) for different mice with different scanning protocols (SP) (c<i>olors red, green, blue represent scanning protocols A,B,C, respectively)</i> and coefficients of variance (CV) averaged for 3 different ROIs in 3 different mice for the 3 scanning protocols. <b>Right panel</b> – TFAS: FA-values (standard deviation as error bars) for different mice with different scanning protocols (SP) (c<i>olors red, green, blue represent scanning protocols A,B,C, respectively)</i> and coefficients of variance (CV) averaged for 3 different TFAS in 3 different mice for the 3 scanning protocols.</p

Fumaric Acid Esters Stimulate Astrocytic VEGF Expression through HIF-1α and Nrf2

<div><p>Fumaric acid esters (FAE) are oral analogs of fumarate that have recently been shown to decrease relapse rate and disease progression in multiple sclerosis (MS), prompting to investigate their protective potential in other neurological diseases such as amyotrophic lateral sclerosis (ALS). Despite efficacy in MS, mechanisms of action of FAEs are still largely unknown. FAEs are known to activate the transcription factor Nrf2 and downstream anti-oxidant responses through the succination of Nrf2 inhibitor KEAP1. However, fumarate is also a known inhibitor of prolyl-hydroxylases domain enzymes (PhD), and PhD inhibition might lead to stabilization of the HIF-1α transcription factor under normoxic conditions and subsequent activation of a pseudo hypoxic response. Whether Nrf2 activation is associated with HIF-1α stabilization in response to FAEs in cell types relevant to MS or ALS remains unknown. Here, we show that FAEs elicit HIF-1α accumulation, and VEGF release as its expected consequence, in astrocytes but not in other cell types of the central nervous system. Reporter assays demonstrated that increased astrocytic VEGF release in response to FAEs was dependent upon both HIF-1α and Nrf2 activation. Last, astrocytes of transgenic mice expressing SOD1(G93A), an animal model of ALS, displayed reduced VEGF release in response to FAEs. These studies show that FAEs elicit different signaling pathways in cell types from the central nervous system, in particular a pseudo-hypoxic response in astrocytes. Disease relevant mutations might affect this response.</p> </div

Adipose Tissue Distribution Predicts Survival in Amyotrophic Lateral Sclerosis

<div><p>Background</p><p>amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to death within a few years after diagnosis. Malnutrition and weight loss are frequent and are indexes of poor prognosis. Total body fat and fat distribution have not been studied in ALS patients.</p><p>Objectives</p><p>Our aim was to describe adipose tissue content and distribution in ALS patients.</p><p>Design</p><p>We performed a cross-sectional study in a group of ALS patients (n = 62, mean disease duration 22 months) along with age and gender matched healthy controls (n = 62) using a MRI-based method to study quantitatively the fat distribution.</p><p>Results</p><p>Total body fat of ALS patients was not changed as compared with controls. However, ALS patients displayed increased visceral fat and an increased ratio of visceral to subcutaneous fat. Visceral fat was not correlated with clinical severity as judged using the ALS functional rating scale (ALS-FRS-R), while subcutaneous fat in ALS patients correlated positively with ALS-FRS-R and disease progression. Multiple regression analysis showed that gender and ALS-FRS-R, but not site of onset, were significant predictors of total and subcutaneous fat. Increased subcutaneous fat predicted survival in male patients but not in female patients (p<0.05).</p><p>Conclusions</p><p>Fat distribution is altered in ALS patients, with increased visceral fat as compared with healthy controls. Subcutaneous fat content is a predictor of survival of ALS patients.</p></div

Results from whole brain-based spatial statistics (WBSS) of MD-, AD-, and RD-maps of APP mice vs. wt mice at p<0.05, FDR corrected (coronal views).

<p>Reduction is displayed in hot colors. (A–E) MD reduction in the lateral septal nucleus, the dorsal hippocampues, the thalamus, the amygdala, and the internal capsule, respectively; (F–I) AD-reduction in the dorsal hippocampus (bihemispheric), the entorhinal cortex (bihemispheric), the dorsomedian hypothalamic nucleus region, and in the lateral septal nucleus, respectively; (J–M) RD-reduction in the cerebellum (bihemispheric), the lateral septal nucleus, the thalamus, and the dentate gyrus, respectively.</p

Pharmacological evidence of HIF-1α involvement in VEGF release.

<p>Wild type astrocytes were treated with 30µM DMF for indicated times. HIF1-α level was measured by Western-Blot (A) 6h after DMF treatment (B) or 16h after DMF treatment (C). The HIF1-α inhibitor YC-1 was incubated 30min before treatment with DMF. VEGF in the supernatant was quantified by ELISA (C) *p<0,05; ***p<0,001; significantly different from corresponding control. Values are mean+/-SEM of n=3 independent experiments.</p

Transcriptional effects of FAEs.

<div><p>(<b>A</b>) mRNA levels of NAD(P)H dehydrogenase quinone 1 (NQO-1) and Heme Oxygenase 1 (HO-1), two Nrf2 target genes in astrocytes, microglia, neurons and oligodendrocytes of wild type mice after vehicle (empty columns, Ctrl), or after 6 hours or 18 hours of either 30µM DEF (grey columns, DEF) or DMF (black columns, DMF). Note the robust upregulation of these two genes in all cell types except microglia.</p> <p>(<b>B</b>) mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1), two HIF1-α target genes in astrocytes, microglia, neurons and oligodendrocytes of wild type mice after vehicle (empty columns, Ctrl), or after 6 hours or 18 hours of either 30µM DEF (grey columns, DEF) or DMF (black columns, DMF). FAEs induced the expression of HIF1-α target genes in astrocytes and microglia but not in oligodendrocytes or neurons. *p<0,05; **p<0,01; ***p<0,001; significantly different from corresponding control. Values are mean+/- SEM of n=3 independent experiments.</p></div

FAEs induce HIF-1α accumulation and VEGF release in astrocytes.

<p>Wild type astrocytes were treated with 30µM DEF (A, C, E) or 30µM DMF (B, D, E) for the indicated times. HIF-1α level was measured by Western-Blot (A, B, C, D). VEGF in the supernatant was quantified by ELISA (E, F); *p<0,05; ***p<0,001; significantly different from corresponding control. Values are mean+/-SEM of n=3 independent experiments.</p