| 1. |
- Burgunder, J-M, et al.
(författare)
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EFNS guidelines for the molecular diagnosis of neurogenetic disorders : motoneuron, peripheral nerve and muscle disorders
- 2011
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Ingår i: European Journal of Neurology. - : Wiley-Blackwell. - 1351-5101 .- 1468-1331. ; 18:2, s. 207-E20
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. Results: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. Conclusion: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.
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| 2. |
- Burgunder, J-M., et al.
(författare)
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Molecular diagnosis of neurogenetic disorders : motoneuron, peripheral nerve and muscle disorders
- 2012. - 2
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Ingår i: European handbook of neurological management. - Oxford, UK : Wiley-Blackwell. - 9781444346268 - 9781405185349 ; , s. 97-109
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Bokkapitel (refereegranskat)abstract
- Objectives: The EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated.Search strategy: To collect data about the planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed.Results: The best level of evidence for genetic testing recommendation (Level B) can be found for the disorders with specific presentations, including familial ALS, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders a precise description of the phenotype, including the use of immunological methods in the case of myopathies, is considered good clinical practice to guide molecular genetic testing.Conclusion: These guidelines are provisional and the availability of molecular-genetic epidemiological data in the future about the neurogenetic disorders under discussion in the present paper will allow improved recommendation with an increased level of evidence.
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| 3. |
- Byrne, L. M., et al.
(författare)
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Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis
- 2017
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Ingår i: Lancet Neurology. - 1474-4422. ; 16:8, s. 601-609
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Tidskriftsartikel (refereegranskat)abstract
- 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=0602, p<0.0001; grey matter r=0.518, p<00001; 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=00036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0868, p<0.0001). Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| 4. |
- Rodrigues, F. B., et al.
(författare)
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Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- 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. CSF TNF-alpha, IL-1 beta, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed. CSF TNF-alpha and IL-1 beta 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. 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.
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| 5. |
- Rodrigues, F. B., et al.
(författare)
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Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 139:1, s. 22-25
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale ’99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p<0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p=0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r=−0.29, p=0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r=0.32, p=0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. (Figure presented.) In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9. © 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry
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| 6. |
- Rodrigues, F. B., et al.
(författare)
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Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:574
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Tidskriftsartikel (refereegranskat)abstract
- The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.
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| 7. |
- Scahill, R. I., et al.
(författare)
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Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington?s disease Young Adult Study (HD-YAS): a cross-sectional analysis
- 2020
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Ingår i: Lancet Neurology. - : Elsevier BV. - 1474-4422. ; 19:6, s. 502-512
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Tidskriftsartikel (refereegranskat)abstract
- Background Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. Methods We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0.05 deemed a significant result. Findings Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29.0 years (SD 5.6) and 29.1 years (5.7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23.6 years (SD 5.8) from predicted onset (FDR 0.22-0.87 for cognitive measures, 0.31-0.91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0.03), but this did not appear to be closely related to predicted years to onset (FDR=0.54). There were no group differences in other brain imaging measures (FDR >0.16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0.0001, =0.01, and =0.03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0.0001). Interpretation We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact.
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