Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Byrne, Lauren M.; Wild, Edward J.

doi:10.3233/jhd-160196

Cited by 66 publications

(57 citation statements)

References 74 publications

(80 reference statements)

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“…Although extensive efforts have established well characterised clinical, cognitive, and neuroimaging biomarkers of progression,2, 3, 4, 5 few biochemical markers have been identified that enable direct assessment of relevant aspects of pathology 6, 7. No prognostic biomarkers for assessing neuronal damage, disease progression, or therapeutic response have been validated, which limits the ability to test novel therapeutics, especially in mutation carriers with premanifest Huntington's disease for whom treatment is most likely to result in long-term meaningful benefits.…”

Section: Introductionmentioning

confidence: 99%

“…Many potential markers in CSF have been proposed, but only a few (eg, mHTT itself, microtubule-associated protein tau, and chitinase-3-like protein 1) have shown associations with clinical phenotype beyond established predictors, such as age and HTT CAG triplet repeat count 7, 8, 9, 10. None of the potential biomarkers has been studied longitudinally 7 .…”

Section: Introductionmentioning

confidence: 99%

“…None of the potential biomarkers has been studied longitudinally 7 . Moreover, CSF is more difficult and expensive to obtain than other fluids, but no substance detectable in a highly accessible biofluid, such as blood, has robustly reflected Huntington's disease-related alterations due to CNS pathology, either in cross-sectional or longitudinal studies.…”

Section: Introductionmentioning

confidence: 99%

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

Byrne¹,

Rodrigues²,

Blennow

et al. 2017

The Lancet Neurology

306

302

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SummaryBackgroundBlood 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.MethodsWe 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.FindingsBaseline 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).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Byrne¹,

Rodrigues²,

Blennow

et al. 2017

The Lancet Neurology

306

302

View full text Add to dashboard Cite

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“…The EBM then predicts changes in the amygdala, optic chiasm, and third ventricle. The amygdala is topologically connected to the caudate, but the literature concerning its involvement is sparse; where it exists, it focuses on functional tests 37. The optic chiasm is not expected to be pathologically involved in the disease progression, but may undergo changes in volume due to the atrophy of surrounding tissues.…”

Section: Discussionmentioning

confidence: 99%

An image‐based model of brain volume biomarker changes in Huntington's disease

Wijeratne

Young

Oxtoby

et al. 2018

Ann Clin Transl Neurol

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ObjectiveDetermining the sequence in which Huntington's disease biomarkers become abnormal can provide important insights into the disease progression and a quantitative tool for patient stratification. Here, we construct and present a uniquely fine‐grained model of temporal progression of Huntington's disease from premanifest through to manifest stages.MethodsWe employ a probabilistic event‐based model to determine the sequence of appearance of atrophy in brain volumes, learned from structural MRI in the Track‐HD study, as well as to estimate the uncertainty in the ordering. We use longitudinal and phenotypic data to demonstrate the utility of the patient staging system that the resulting model provides.ResultsThe model recovers the following order of detectable changes in brain region volumes: putamen, caudate, pallidum, insula white matter, nonventricular cerebrospinal fluid, amygdala, optic chiasm, third ventricle, posterior insula, and basal forebrain. This ordering is mostly preserved even under cross‐validation of the uncertainty in the event sequence. Longitudinal analysis performed using 6 years of follow‐up data from baseline confirms efficacy of the model, as subjects consistently move to later stages with time, and significant correlations are observed between the estimated stages and nonimaging phenotypic markers.InterpretationWe used a data‐driven method to provide new insight into Huntington's disease progression as well as new power to stage and predict conversion. Our results highlight the potential of disease progression models, such as the event‐based model, to provide new insight into Huntington's disease progression and to support fine‐grained patient stratification for future precision medicine in Huntington's disease.

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“…Changes in KYN metabolites have been observed in other neurological and psychiatric disorders, including, Huntington's disease (Forrest et al . ; Byrne and Wild ), schizophrenia (Forrest et al . ; Chiappelli et al .…”

Section: Discussionmentioning

confidence: 99%

Changes in kynurenine pathway metabolism in Parkinson patients with L‐DOPA‐induced dyskinesia

Havelund

Andersen

Binzer

et al. 2017

Journal of Neurochemistry

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L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA-induced dyskinesia.

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Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Cited by 66 publications

References 74 publications

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

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

An image‐based model of brain volume biomarker changes in Huntington's disease

Changes in kynurenine pathway metabolism in Parkinson patients with L‐DOPA‐induced dyskinesia

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