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Proposals - Announcements - Biomarkers -
The association of nucleolar activity with mutant huntingtin protein species in HD
Transcriptional dysregulation is known in HD. Here we will test the hypothesis that changes in ribosomal DNA (rDNA) transcription in the nucleolus are early signs of transcriptional dysregulation by mutant huntingtin (mHTT). By a systematic analysis of nucleolar transcription in HD models and tissue biopsies at different stages, we aim at identifying a sensitive metabolic marker linked to mHTT. The results could help to test the efficacy of ongoing therapeutic strategies aiming at lowering mHTT levels in specific cells. Concomitantly, the tissue-specific impact of mHTT on rRNA transcriptional dysregulation might account for the still unexplained variability in HD onset.
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The Alterations in Transcranial Sonography of Huntington Disease Patients with Psychiatric Symptoms
Transcranial sonography (TCS) is a noninvasive method that provides an insight into the pathology of movement and affective disorders. TCS findings could play a role in differential diagnostics and serve as markers of disease progression. The aim of the project is to prospectively screen a population of HD patients in search of abnormal TCD findings (altered echogenicity of nucleus raphe, substantia nigra, caudate nucleus) and to correlate them with symptoms like depression and apathy. The main goal is to check, if TCS findings may serve as a biomarker and a predictor of depression in HD patients, also those treated with dopamine depleting agents.
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The role of microRNA-34 in cancer defense- and HD pathogenic mechanisms
The frequency of cancer in HD patients is only half of what is expected from population studies, and this applies to all forms of cancer. This is also true for other polyQ disease patients, which indicates that CAG repeat expansions have protective effects against the initial steps in tumor formation. The microRNA, miR-34, is well-known as a tumor suppressor that protects against uncontrolled cell growth, and it may be involved, in some situations, in cell death. We investigate the role of miR-34 in cancer defense and neurodegeneration by studying HD patients, transgenic HD mice and a cell model.
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Apathy, cognition and oculomotor impairment in HD
Individuals with Huntington’s disease (HD) often suffer from apathy, a condition involving reduced motivation and initiation. Apathy has negative consequences for both patient and family, and has been associated with cognitive (thinking) changes in HD. In healthy adults and individuals with other conditions, apathy has been associated with abnormal eye movements while processing information. HD patients and gene carriers are known to show abnormal eye movements, but little is currently known about how changes in eye movement relate to changes in cognition and behaviour. This project will explore relationships between data on eye movements, apathy and cognitive performance in HD.
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Mitochondrial dysfunction in Huntington's disease
Mitochondria are the sub-cellular particles that are critical for the use of oxygen and glucose. A better understanding of their role in Huntington's disease could be important for the discovery of new therapeutic approaches. Hence we will investigate mitochondria in blood cells and autopsied brains from patients, as well as in brains from mice that bear the gene mutation that causes HD in humans. Our plan is to measure activity, protein and message levels of the enzymes of the tricarboxylic acid (TCA) cycle, which is critical for several biosynthetic pathways. The results could reveal peripheral and central energetic alterations that may contribute to HD pathology.
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The studies on the biochemical markers characterizing Huntington´s disease –determination of the profile of common amino acids in the serum of patients in different stages of Huntington´s disease
Decreased levels of branched amino acids (BCAA) correlate with the number of CAG repeats, UHDRS scores and weight loss in HD patients. This study will determine the profile of common amino acids in the serum of HD patients and normal controls. The results might clarify the role of certain amino acids further, lead to metabolic markers of early disease stages and could be crucial for the development of special nutrition supplements.
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Parameter optimisation for diffusion tensor imaging in Huntington’s Disease
Striatum and cortex are affected in HD. Disruption of fibres connecting these structures may play a role in symptom development. In preparation for a large Europe-wide diffusion weighted imaging study, this pilot study aims to identify suitable scanning parameters as well as post-processing methods for the analysis of cerebral white matter. In addition, we attempt to identify possible gains in sensitivity of the technique at higher MRI field strengths. To this end, HD gene mutation carriers and matched controls will be studied using different MRI hardware at the Universities of Ulm and Freiburg, Germany.
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Muscle pathology in HD as a source for biomarkers?
Peripheral manifestations of HD may provide an easily accessible and valuable source of HD biomarkers. Muscle wasting is a well-recognised phenomenon in patients with HD and worsens with disease progression. Interestingly, inflammatory processes can be linked to the development of muscle atrophy and immune activation in peripheral blood monocytes can be seen in HD. In this project, we will investigate the relationship between immune activation and muscle wasting in HD. We will study muscle pathology in relation to inflammatory cytokines in HD mouse models and in patients with juvenile onset of HD.
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Molecular mechanisms of BCAA and energy metabolism study in peripheral blood mononuclear cells of Huntington’s disease patients
Energy production impairment and mitochondrial dysfunction play an important role in the pathogenesis of Huntington’s disease (HD), within and outside the outside central nervous system. Bioenergetics defects on the cellular level and low levels of branched chain amino acids (BCAA) in serum plasma of HD patients were previously described. Difficulties of the clinical onset description and HD progress detection are also related to a lack of specific and sensitive HD biomarkers. The objective of this study is to investigate bioenergetics defects in peripheral mononuclear blood cells of HD patients on a molecular level including BCAA and energy metabolism by evaluation of the gene expression level in order to establish molecular biomarkers.
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