The Search for Sensitive Biomarkers in Presymptomatic Huntington Disease

Henry, Pierre Gilles; Mochel, Fanny

doi:10.1038/jcbfm.2012.17

Cited by 7 publications

(5 citation statements)

References 9 publications

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“…The disease's onset is associated with the first appearance of chorea movements but the early cognitive or psychiatric impairment is often present in clinical practice, before HD diagnosis is done (Tabrizi et al, 2011). Testing the CAG replication it's possible to predict age at onset (Rosenblatt et al, 2006), the early stage of neurodegeneration and pathophysiological changes is not evident in clinical practice (Henry and Mochel, 2012). Clinical and instrumental assessment of the presymptomatic stage may provide for a potential biomarkers, may improve the knowledge about the neuronal circuits which are affected by mutated HTT in presymptomatic phase.…”

Section: Introductionmentioning

confidence: 99%

EEG Functional Connectivity and Cognitive Variables in Premanifest and Manifest Huntington’s Disease: EEG Low-Resolution Brain Electromagnetic Tomography (LORETA) Study

et al. 2020

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BackgroundScientific literature does not offer sufficient data on electroencephalography (EEG) functional connectivity and its correlations with clinical and cognitive features in premanifest and manifest HD.AimThis study tries to identify abnormal EEG patterns of functional connectivity, in conditions of “brain resting state” and correlations with motor decline and cognitive variable in Huntington’s disease (HD), in premanifest and manifest phase, looking for a reliable marker measuring disease progression.MethodThis was an observational cross-sectional study; 105 subjects with age ≥18 years submitted to HD genetic test. Each subject underwent a neurological, psychiatric, and cognitive assessment, EEG recording and genetic investigation for detecting the expansion of the CAG trait. EEG connectivity analysis was performed by means of exact Low Resolution Electric Tomography (eLORETA) in 18 premanifest HD (pHD), 49 manifest HD (mHD), and 38 control (C) subjects.ResultsHD patients showed a Power Spectral Density reduced in the alpha range and increased in delta band compared to controls; no difference was detectable between pHD and mHD; the Global Connectivity in pHD revealed no significant differences if compared to mHD. The Current Source Density was similar among groups. No statistically significant results when comparing pHD with C group, even in comparison of mHD with Controls, and pHD with mHD. mHD compared to Controls showed a significant increase in delta, alpha1, alpha2, beta2, and beta3. Lagged Phase Synchronization in delta, alpha1, alpha2, beta2, and beta3 bands was increased in HD compared to controls (t = −3.921, p < 0.05). A significant correlation was found in Regression Analysis: statistically significant results in pHD for the “Symbol Digit Modality Test and lagged phase synchronization” in the Beta1 (r = −0.806, p < 0.05) in the prefrontal regions. The same correlation was found in mHD for the Stroop Word Reading Test (SWRT) in the Alpha2 band (r = −0.759, p < 0.05).ConclusionIncreased phase synchronization in main bands characterized EEG in HD patients, as compared to controls. pHD were not dissimilar from mHD as regard to this EEG pattern. Increased phase synchronization correlated to cognitive decline in HD patients, with a similar trend in pHD, suggesting that it would be a potential biomarker of early phenotypical expression.

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Section: Introductionmentioning

confidence: 99%

EEG Functional Connectivity and Cognitive Variables in Premanifest and Manifest Huntington’s Disease: EEG Low-Resolution Brain Electromagnetic Tomography (LORETA) Study

et al. 2020

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“…Major goals of HD research include the development of mechanistic insights and the identification of biomarker surrogates for clinical endpoints . Since striatal volume loss occurs >10 years before the onset of motor/cognitive symptoms, magnetic resonance (MR) imaging (MRI)‐measured striatal volume is one promising biomarker .…”

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confidence: 99%

“…Major goals of HD research include the development of mechanistic insights and the identification of biomarker surrogates for clinical endpoints. 4 Since striatal volume loss occurs >10 years before the onset of motor/cognitive symptoms, magnetic resonance (MR) imaging (MRI)-measured striatal volume is one ------------------------------------------------------------promising biomarker. 5 Volumetric changes (reflecting neuron death, gliosis, and other factors) are likely preceded by neurochemical changes, 6 which may be examined in vivo by MR spectroscopy (MRS).…”

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confidence: 99%

Neurochemical correlates of caudate atrophy in Huntington's disease

et al. 2014

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BACKGROUND The precise pathogenic mechanisms of Huntington disease (HD) are unknown, but can be tested in vivo using proton magnetic resonance spectroscopy (1H MRS) to measure neurochemical changes. OBJECTIVE To evaluate neurochemical differences in HD gene mutation-carriers (HGMC) vs. controls, and to investigate relationships among function, brain structure and neurochemistry in HD. Since previous 1H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two 1H MRS data analysis approaches. METHODS HGMC with pre-manifest to early HD and controls underwent evaluation of motor function, MR imaging and localized 1H MRS in caudate and frontal lobe. Analytical approaches tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). RESULTS We identified a suite of neurochemicals reduced in concentration proportionally to loss of caudate volume in HGMC. Caudate concentrations of NAA, creatine, choline, and caudate and frontal concentrations of glutamate+glutamine and glutamate correlated with caudate volume in HGMC subjects. The relative, but not the absolute quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in caudate of HGMC subjects vs. controls. CONCLUSIONS This is the first study to demonstrate correlation among structure, function and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable magnification of subtle differences between groups. Observation of decreased glutamate-glutamine signals suggests that glutamate signaling may be disrupted relatively early in HD, with important implications for therapeutic approaches.

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“…Two recent 1 H MRS studies in HD patients, one at 3 T (Sturrock et al 2010) and the other one at 7 T (van den Bogaard et al 2011), found significant differences in neurochemical profile of HD brain only after the manifestation of clinical symptoms (Henry and Mochel 2012). Nevertheless an earlier study at a lower magnetic field of 0.5 T showed some changes of metabolite concentration in premanifest HD (Reynolds et al 2005).…”

Section: Discussionmentioning

confidence: 98%

Minipig Model of Huntington´s Disease: 1H Magnetic Resonance Spectroscopy of the Brain

Jozefovičová¹,

Herynek

Jírů³

et al. 2016

Physiol Res

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Huntington’s disease (HD) is an inherited autosomal neurodegenerative disorder affecting predominantly the brain, characterized by motor dysfunctions, behavioral and cognitive disturbances. The aim of this study was to determine changes in the brain of transgenic minipigs before HD onset using 1H magnetic resonance (MR) spectroscopy. Measurements were performed on a 3 T MR scanner using a single voxel spectroscopy sequence for spectra acquisition in the white matter and chemical shift imaging sequence for measurement in the striatum, hippocampus and thalamus. A decrease of (phospho)creatine (tCr) concentration was found only in the thalamus (p=0.002) of transgenic minipigs, nevertheless we found significant changes in metabolite ratios. Increase of the ratio choline compounds (tCho)/tCr was found in all examined areas: striatum (p=0.010), thalamus (p=0.011) as well as hippocampus (p=0.027). The ratio N-acetylaspartate+N-acetylaspartylglutamate (tNAA)/tCr (p=0.043) and glutamate+glutamine (Glx)/tCr (p=0.039) was elevated in the thalamus, the ratio myo-inositol (Ins)/tCr (p=0.048) was significantly increased in the hippocampus. No significant differences were observed in the metabolite concentrations in the white matter, however we found significant increase of ratios tNAA/tCr (p=0.018) and tCho/tCr (p=0.003) ratios in transgenic boars. We suppose that the majority of the observed changes are predominantly related to changes in energy metabolism caused by decrease of tCr.

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The Search for Sensitive Biomarkers in Presymptomatic Huntington Disease

Cited by 7 publications

References 9 publications

EEG Functional Connectivity and Cognitive Variables in Premanifest and Manifest Huntington’s Disease: EEG Low-Resolution Brain Electromagnetic Tomography (LORETA) Study

EEG Functional Connectivity and Cognitive Variables in Premanifest and Manifest Huntington’s Disease: EEG Low-Resolution Brain Electromagnetic Tomography (LORETA) Study

Neurochemical correlates of caudate atrophy in Huntington's disease

Minipig Model of Huntington´s Disease: 1H Magnetic Resonance Spectroscopy of the Brain

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