Magnetic resonance spectroscopy of normal appearing white matter in early relapsing-remitting multiple sclerosis: correlations between disability and spectroscopy

BACKGROUND: What currently appears to be irreversible axonal loss in normal appearing white matter, measured by proton magnetic resonance spectroscopy is of great interest in the study of Multiple Sclerosis. Our aim is to determine the axonal damage in normal appearing white matter measured by magnetic resonance spectroscopy and to correlate this with the functional disability measured by Multiple Sclerosis Functional Composite scale, Neurological Rating Scale, Ambulation Index scale, and Expanded Disability Scale Score. METHODS: Thirty one patients (9 male and 22 female) with relapsing remitting Multiple Sclerosis and a Kurtzke Expanded Disability Scale Score of 0–5.5 were recruited from four hospitals in Andalusia, Spain and included in the study. Magnetic resonance spectroscopy scans and neurological disability assessments were performed the same day. RESULTS: A statistically significant correlation was found (r = -0.38 p < 0.05) between disability (measured by Expanded Disability Scale Score) and N-Acetyl Aspartate (NAA/Cr ratio) levels in normal appearing white matter in these patients. No correlation was found between the NAA/Cr ratio and disability measured by any of the other disability assessment scales. CONCLUSIONS: There is correlation between disability (measured by Expanded Disability Scale Score) and the NAA/Cr ratio in normal appearing white matter. The lack of correlation between the NAA/Cr ratio and the Multiple Sclerosis Functional Composite score indicates that the Multiple Sclerosis Functional Composite is not able to measure irreversible disability and would be more useful as a marker in stages where axonal damage is not a predominant factor

Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis

Peer reviewe

The Rate of Increase of Short Telomeres Predicts Longevity in Mammals

Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice. We found that mouse telomeres shorten ∼100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity

Telomerase Reverse Transcriptase Synergizes with Calorie Restriction to Increase Health Span and Extend Mouse Longevity

<div><p>Caloric restriction (CR), a reduction of food intake while avoiding malnutrition, can delay the onset of cancer and age-related diseases in several species, including mice. In addition, depending of the genetic background, CR can also increase or decrease mouse longevity. This has highlighted the importance of identifying the molecular pathways that interplay with CR in modulating longevity. Significant lifespan extension in mice has been recently achieved through over-expression of the catalytic subunit of mouse telomerase (mTERT) in a cancer protective background. Given the CR cancer-protective effects in rodents, we set to address here whether CR impacts on telomere length and synergizes with mTERT to extend mouse longevity. CR significantly decreased tumor incidence in TERT transgenic (TgTERT) mice and extended their lifespan compared to wild-type (WT) controls under the same diet, indicating a synergy between TgTERT and CR in increasing mouse longevity. In addition, longitudinal telomere length measurements in peripheral blood leukocytes from individual mice showed that CR resulted in maintenance and/or elongation telomeres in a percentage of WT mice, a situation that mimics telomere dynamics in TgTERT cohorts. These results demonstrate that CR attenuates telomere erosion associated to aging and that synergizes with TERT over-expression in increasing “health span” and extending mouse longevity.</p> </div

Impact of long-term calorie restriction on metabolic homeostasis and age-associated pathologies.

<p>(A) Weight given as average ± SEM of WT and TgTERT mice fed with control or CR diet (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053760#s4" target="_blank">Materials and Methods</a>). One way ANOVA was used to assess statistical significance between the four groups (WT Control vs. Wt CR: p<0.0001; TgTERT Control vs. TgTERT CR: p<0.0001; WT Control vs. TgTERT Control: p = 0.72; WT CR vs. TgTERT CR: p = 0.46). (B and C) Total fat mass of the indicated cohorts was measured at 16 months of diet (B) and 24 months of diet (C). Values are given as average ± SEM, and statistical significance was determined by the two-tailed Student’s t-test. (D and E) Glucose tolerance test (GTT) was performed at 12 months of diet. Integrated AUCs (area under the curve; (D)) and curves (E) are shown. Values are given as average ± SEM, and statistical significance was determined by the two-tailed Student’s t-test. (F) Fasting plasma insulin levels, given as mean ± SEM, was measured in the different cohorts at 12 months of diet. Statistical significance was determined by the two-tailed Student’s t-test. (G) Insulin sensitivity, estimated using the homeostatic model assessment score (HOMA-IR), was performed at 12 months of diet. Values are given as average ± SEM, and statistical significance was determined by the two-tailed Student’s t-test. (H) Femur bone mineral density (BMD) variation through lifetime of WT and TgTERT mice under control and CR diets. Values are given as average ± SEM, and statistical significance was determined by the two-tailed Student’s <i>t</i>-test. (I) Representative DEXA image used for BMD and fat mass calculations. (J) Neuromuscular coordination was quantified as the percentage of mice that pass with success the tightrope test. Numbers above the bars represent the number of mice that successfully pass the test over the total number of mice tested. Student’s <i>t</i>-test was used to assess significance between control and CR mice. Values are given as average ± SEM, and statistical significance was determined by the two-tailed Student’s <i>t</i>-test.</p

Calorie restriction prevents telomere shortening in different mouse tissues and protects from telomere-mediated chromosomal aberrations in bone marrow cells.

<p>(A,B,C) Telomere fluorescence as determined by QFISH in the indicated tissues from the different mouse cohorts studied here. Histograms represent the frequency (in percentage) of telomere fluorescence per nucleus (in arbitrary units of fluorescence [auf]). Mean telomere length is indicated by a straight line, red for mice under a control diet and yellow for mice under CR. The number of mice (n) and the total number of nuclei analysed is indicated. (D,E,F) Percentage of short telomeres (fraction of telomeres presenting intensity below 50% of the mean intensity) in the indicated tissues from the different mice cohorts studied as determined by QFISH. Student´s <i>t</i>-test was used for statistical analysis. (G) Representative QFISH images for different tissues from the indicated cohorts. Blue colour corresponds to chromosome DNA stained with DAPI; red dots correspond to telomeres (TTAGGG repeats). (H) Telomere length measured in metaphase spreads of BM cells from the different cohorts after hybridization with DAPI and a fluorescent Cy3 labelled PNA-telomeric probe. (I) Frequency of signal-free ends per metaphase in BM cells from the indicated mouse cohorts. (J) Frequency of multitelomeric signals (MTS) per metaphase in BM cells from the indicated mouse cohorts. (K) Representative QFISH images of metaphases from the indicated mouse cohorts. Blue, DNA stained with DAPI; red, telomeres (TTAGGG repeats). (L) Frequency of chromosome fusions per metaphase in BM cells from the indicated mouse cohorts. (M) Representative images of chromosomal fusions. (N) Frequency of other chromosome aberrations (chromosome breaks, fragments and extrachromosomal elements) per metaphase in BM cells from the indicated mouse cohorts. (O) Representative images of the different types of chromosomal aberrations scored. Blue, DAPI staining (DNA); red dots, telomeres (TTAGGG repeats) as detected with a PNA-Cy3 probe.</p

Calorie restriction leads to telomere maintenance and/or elongation with time in a percentage of mice.

<p>(A, C and E) The behavior of mean telomere length was classified in two different profiles (“Decrease” and “Increase or Maintenance”) at different times of diet (1–22 months of diet, 5–22 months of diet and 9–22 months of diet; A, C and E, respectively) in the indicated groups. Numbers above bars indicate the number of mice showing the profile of interest over the total number of mice. Chi-squared test was used to assess the statistical significance of the differences observed. (B, D and F) The behavior in the percentage of short telomeres (<15 kb) was classified in two different profiles (“Increase” and “Decrease or Maintenance”) at different times of diet (1–22 months of diet, 5–22 months of diet and 9–22 months of diet; B, D and F respectively) in the indicated groups. Numbers above bars indicate the number of mice with the profile of interest over the total number of mice. Chi-squared test was used to assess the statistical significance of the differences observed. (G and H) Representative examples of the different assigned profiles for mean telomere length (“Increased”, “Maintained”, and “Shortened”) and percentage of short (<15 kb) telomeres (“Reduced”, “Maintained”, and “Increased”).</p

Slower age-dependent telomere shortening in mice under calorie restriction.

<p>(A and C) Mean telomere length (A) and percentage of short telomeres (C) was determined by HT QFISH on white blood cells from the indicated mice under CR and control diet. The number of mice is indicated on the top of each bar (n). Values are given as average ± SEM, and statistical significance was determined by one-tailed Student’s <i>t</i>-test. (B and D) Linear regression lines of the values obtained for mean telomere length (B) and percentage of short telomeres (D) measured in white blood cells. The slope ± SD of each regression line is indicated and represents the rate of telomere loss with time.</p

Caloric restriction increases median and maximum longevity and protects from cancer.

<p>(A–F) Kaplan-Meyer survival curves of the indicated mouse cohorts. The Log rank test was used for statistical analysis. Mice under CR were more susceptible to unexpected stresses such as the blood extraction procedure carried. 5 mice of the WT CR cohort and 6 mice of the TgTERT cohort died during the blood extraction and were excluded from the survival curves (of note, none of the WT or TgTERT mice show sensibility to the blood extraction procedure). (G–H) Realized lifespan of the 50% shortest (G) and longest (H) lived mice of each cohort. Student´s <i>t</i>-test was used for statistical analysis. (I) Percentage of mice with cancer and cancer-free mice in the different cohorts. All death mice were subjected to full histopathological analysis. (J) Percentage of mice in the different cohorts with the indicated tumours at their time of death. (K) Summary table with the findings regarding telomere length and survival of the different cohorts.</p