Cerebrospinal Fluid Biomarkers for Huntington's Disease.

Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD

Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease

INTRODUCTION: Immune system activation is involved in Huntington’s disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients. METHODS: CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed. RESULTS: CSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10−4) after adjustment for age. CONCLUSION: YKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings

Insular Celtic population structure and genomic footprints of migration

Previous studies of the genetic landscape of Ireland have suggested homogeneity, with population substructure undetectable using single-marker methods. Here we have harnessed the haplotype-based method fineSTRUCTURE in an Irish genome-wide SNP dataset, identifying 23 discrete genetic clusters which segregate with geographical provenance. Cluster diversity is pronounced in the west of Ireland but reduced in the east where older structure has been eroded by historical migrations. Accordingly, when populations from the neighbouring island of Britain are included, a west-east cline of Celtic-British ancestry is revealed along with a particularly striking correlation between haplotypes and geography across both islands. A strong relationship is revealed between subsets of Northern Irish and Scottish populations, where discordant genetic and geographic affinities reflect major migrations in recent centuries. Additionally, Irish genetic proximity of all Scottish samples likely reflects older strata of communication across the narrowest inter-island crossing. Using GLOBETROTTER we detected Irish admixture signals from Britain and Europe and estimated dates for events consistent with the historical migrations of the Norse-Vikings, the Anglo-Normans and the British Plantations. The influence of the former is greater than previously estimated from Y chromosome haplotypes. In all, we paint a new picture of the genetic landscape of Ireland, revealing structure which should be considered in the design of studies examining rare genetic variation and its association with traits

Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis

BACKGROUND: Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease. METHODS: We did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF. FINDINGS: Baseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=–0·374, p<0·0001; Stroop word reading r=–0·248, p=0·0033), total functional capacity (r=–0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001). INTERPRETATION: NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease

Comparison of Insertional RNA Editing in Myxomycetes

RNA editing describes the process in which individual or short stretches of nucleotides in a messenger or structural RNA are inserted, deleted, or substituted. A high level of RNA editing has been observed in the mitochondrial genome of Physarum polycephalum. The most frequent editing type in Physarum is the insertion of individual Cs. RNA editing is extremely accurate in Physarum; however, little is known about its mechanism. Here, we demonstrate how analyzing two organisms from the Myxomycetes, namely Physarum polycephalum and Didymium iridis, allows us to test hypotheses about the editing mechanism that can not be tested from a single organism alone. First, we show that using the recently determined full transcriptome information of Physarum dramatically improves the accuracy of computational editing site prediction in Didymium. We use this approach to predict genes in the mitochondrial genome of Didymium and identify six new edited genes as well as one new gene that appears unedited. Next we investigate sequence conservation in the vicinity of editing sites between the two organisms in order to identify sites that harbor the information for the location of editing sites based on increased conservation. Our results imply that the information contained within only nine or ten nucleotides on either side of the editing site (a distance previously suggested through experiments) is not enough to locate the editing sites. Finally, we show that the codon position bias in C insertional RNA editing of these two organisms is correlated with the selection pressure on the respective genes thereby directly testing an evolutionary theory on the origin of this codon bias. Beyond revealing interesting properties of insertional RNA editing in Myxomycetes, our work suggests possible approaches to be used when finding sequence motifs for any biological process fails

Adult exposure to ocean acidification and warming remains beneficial for oyster larvae following starvation

Climate change is expected to warm and acidify oceans and alter the phenology of phytoplankton, creating a mismatch between larvae and their food. Transgenerational plasticity (TGP) may allow marine species to acclimate to climate change; however, it is expected that this may come with elevated energetic demands. This study used the oysters, Saccostrea glomerata and Crassostrea gigas, to test the effects of adult parental exposure to elevated pCO2 and temperature on larvae during starvation and recovery. It was anticipated that beneficial effects of TGP will be limited when larvae oyster are starved. Transgenerational responses and lipid reserves of larvae were measured for 2 weeks. Larvae of C. gigas and S. glomerata from parents exposed to elevated pCO2 had greater survival when exposed to elevated CO2, but this differed between species and temperature. For S. glomerata, survival of larvae was greatest when the conditions experienced by larvae matched the condition of their parents. For C. gigas, survival of larvae was greater when parents and larvae were exposed to elevated pCO2. Larvae of both species used lipids when starved. The total lipid content was dependent on parental exposure and temperature. Against expectations, the beneficial TGP responses of larvae remained, despite starvation

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) were quantified using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. BDNF in CSF and plasma is unlikely to be a biomarker of HD progression, and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF

What do patients want from their psychiatrist? A cross- sectional questionnaire based exploratory study from Karachi

<p>Abstract</p> <p>Background</p> <p>The aspects of consultation that are important for psychiatric patients have always remained a less acknowledged area. The aim of this study was to identify these aspects.</p> <p>Methods</p> <p>A Cross-sectional, questionnaire based study was carried out in a psychiatry outpatient clinic of two tertiary care hospitals in a developing country. The patients were asked to fill out the questionnaire containing a total of 11 close-ended questions plus 1 open-ended question. They graded them as not important, important, very important or do not know. Non-psychotic patients aged 18 and above, visiting the clinic were recruited into the study before they went in for their first consultation.</p> <p>Results</p> <p>The response rate of patients was 84%. More than 90% wanted the doctor to tell them the cause of their illness, talk to them about their condition, provide symptomatic relief, let them know that how long their illness would last and make the final decision about their treatment plan. Less than 20% wanted to be part of a support network. A significant 82% wanted talking therapy as part of their treatment plan.</p> <p>Conclusion</p> <p>The three issues, most important for patients were: the doctor should listen to them, make the final decision about treatment and provide symptomatic relief. Only 20% wanted to be a part of patients' support group.</p

Community-specific evaluation of tool affordances in wild chimpanzees

The notion of animal culture, defined as socially transmitted community-specific behaviour patterns, remains controversial, notably because the definition relies on surface behaviours without addressing underlying cognitive processes. In contrast, human cultures are the product of socially acquired ideas that shape how individuals interact with their environment. We conducted field experiments with two culturally distinct chimpanzee communities in Uganda, which revealed significant differences in how individuals considered the affording parts of an experimentally provided tool to extract honey from a standardised cavity. Firstly, individuals of the two communities found different functional parts of the tool salient, suggesting that they experienced a cultural bias in their cognition. Secondly, when the alternative function was made more salient, chimpanzees were unable to learn it, suggesting that prior cultural background can interfere with new learning. Culture appears to shape how chimpanzees see the world, suggesting that a cognitive component underlies the observed behavioural patterns

Model for in vivo progression of tumors based on co-evolving cell population and vasculature

With countless biological details emerging from cancer experiments, there is a growing need for minimal mathematical models which simultaneously advance our understanding of single tumors and metastasis, provide patient-personalized predictions, whilst avoiding excessive hard-to-measure input parameters which complicate simulation, analysis and interpretation. Here we present a model built around a co-evolving resource network and cell population, yielding good agreement with primary tumors in a murine mammary cell line EMT6-HER2 model in BALB/c mice and with clinical metastasis data. Seeding data about the tumor and its vasculature from in vivo images, our model predicts corridors of future tumor growth behavior and intervention response. A scaling relation enables the estimation of a tumor's most likely evolution and pinpoints specific target sites to control growth. Our findings suggest that the clinically separate phenomena of individual tumor growth and metastasis can be viewed as mathematical copies of each other differentiated only by network structure