Decreased frontal choline and neuropsychological performance in preclinical Huntington disease

Gómez‐Anson, Beatriz; Alegret, Montserrat; Muñoz, Esteban; Sainz, Anthony; Monté, Gemma C.; Tolosa, Eduardo

doi:10.1212/01.wnl.0000257090.01107.2f

Cited by 62 publications

(47 citation statements)

References 37 publications

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“…H magnetic resonance spectroscopy (MRS) has previously been evaluated as a biomarker modality in premanifest and early HD. [4][5][6][7][8][9][10][11] However, the literature is conflicted with regard to the utility of metabolites such as total N-acetylaspartate (tNAA), a measure of neuronal integ-*These authors contributed equally to this work. References e1-e7 are available on the Neurology Web site at www.neurology.org.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11] However, the literature is conflicted with regard to the utility of metabolites such as total N-acetylaspartate (tNAA), a measure of neuronal integ-rity, 12 as potential biomarkers in HD. In an attempt to address these discrepant findings, arising in part from small subject numbers, poorly comparable outcome measures and heterogeneity within patient cohorts, we sought to determine the potential of MRS as an HD biomarker using large numbers of subjects in defined, homogeneous clinical cohorts and examined MRS outcome measures normalized to unsuppressed water rather than metabolites such as total creatine (tCr) which are affected in HD.…”

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confidence: 99%

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Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Sturrock¹,

Laule²,

Decolongon³

et al. 2010

Neurology

105

102

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Objectives: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using 1 H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance.Methods: Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was Ͼ220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. Results:Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (ϳ15%) vs controls (p Ͻ 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (ϳ8%) and early HD (ϳ17%) vs controls (p Ͻ 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p Ͻ 0.01). In early HD, mI correlated with UHDRS motor score (R 2 ϭ 0.23, p Ͻ 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R 2 ϭ 0.30, p Ͻ 0.0001) and with disease burden score (R 2 ϭ 0.17, p Ͻ 0.005). Conclusions:We demonstrate lower putaminal tNAA in early HD compared to controls in a crosssection of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression. Neurology ® 2010;75:1702-1710 GLOSSARY AD ϭ Alzheimer disease; Cr ϭ creatine; DBS ϭ disease burden score; Glu ϭ glutamate; GPC ϭ glycerophosphocholine; HD ϭ Huntington disease; mI ϭ myo-inositol; MR ϭ magnetic resonance; MRS ϭ 1 H magnetic resonance spectroscopy; NAA ϭ N-acetylaspartate; NAAG ϭ N-acetylaspartylglutamate; PC ϭ phosphocholine; PCr ϭ phosphocreatine; pre-HD ϭ premanifest Huntington disease; SNR ϭ signal-to-noise ratio; tCho ϭ total choline; tCr ϭ total creatine; TE ϭ echo time; tNAA ϭ total N-acetylaspartate; TR ϭ repetition time; UBC ϭ University of British Columbia; UHDRS ϭ Unified Huntington's Disease Rating Scale; VBM ϭ voxel-based morphometry.The eventual development of Huntington disease (HD) symptoms can be predicted through detection of CAG trinucleotide repeat expansion in the HTT gene 1 in premanifest gene carriers. However, definitive HD biomarkers, able to objectively identify disease onset and progression, are lacking. Evaluation of potential biomarkers are the focus of longitudinal studies such as TRACK-HD 2 and PREDICT-HD. H magnetic resonance spectroscopy (MRS) has previously been evaluated as a biomarker modality in premanifest and early HD. [4][5][6][7][8][9][10][11] However, the literature is conflicted with regard to the utility of metabolites such as total N-ac...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Sturrock¹,

Laule²,

Decolongon³

et al. 2010

Neurology

105

102

View full text Add to dashboard Cite

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“…Cho/Cr ratios correlated positively with scores of neuropsychological testing in the elderly population 18,21 and in patients with preclinical Huntington disease. 34 In the latter, investigators have suggested that a decrease in Cho indicates a reduction of myelin membrane turnover that precedes neuronal death that may be responsible for the neuropsychological deficits. 34 Thus, a postoperative decrease in the Cho/Cr ratio as well as a postoperative decrease in the NAA/Cr ratio may imply neuronal damage caused by CEA, thereby resulting in postoperative cognitive impairment.…”

Section: Figmentioning

confidence: 99%

“…34 In the latter, investigators have suggested that a decrease in Cho indicates a reduction of myelin membrane turnover that precedes neuronal death that may be responsible for the neuropsychological deficits. 34 Thus, a postoperative decrease in the Cho/Cr ratio as well as a postoperative decrease in the NAA/Cr ratio may imply neuronal damage caused by CEA, thereby resulting in postoperative cognitive impairment. On the other hand, the univariate analyses showed that the ⌬Cho/Cr ratio in the cerebral hemisphere ipsilateral to the operative site was significantly higher in patients with postoperatively improved cognition than in those with postoperatively unchanged or impaired cognition, though the multivariate analysis did not demonstrate a significant difference.…”

Section: Figmentioning

confidence: 99%

Postoperative Changes in Cerebral Metabolites Associated with Cognitive Improvement and Impairment after Carotid Endarterectomy: A 3T Proton MR Spectroscopy Study

Saitō

Ogasawara²,

Nishimoto

et al. 2012

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Cognitive function can improve or decline after carotid endarterectomy. Proton MR spectroscopy can be used evaluate cerebral metabolites, such as N-acetylaspartate, choline, and creatine, in vivo. The purpose of the present study was to determine whether postoperative changes in cerebral metabolites measured by using 3T proton MR spectroscopy were associated with changes in cognitive function after CEA.

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“…However, several studies have also used two-dimensional chemical shift imaging (2D-CSI) [33,40,41]. Studies measuring changes by MRS revealed different values of metabolite concentrations in patients with HD [34,35,42,43]. Recently, several longitudinal clinical studies have been performed.…”

Section: Magnetic Resonance Imaging (Mri) and Spectroscopy (Mrs)mentioning

confidence: 99%

Porcine Model of Huntington's Disease

Rausova¹,

Vochozková²,

Vidinská³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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At present, we are probably the only research facility to be breeding transgenic Huntington's disease minipigs (TgHD). These minipigs express N-terminal part of human mutated huntingtin including 124Q under the control of human huntingtin promoter. The founder animal, born in 2009, gave birth to four subsequent generations with an equal contribution of wild-type (WT) and transgenic (TgHD) piglets in all litters. We take different approaches, some of which are unique for large animal models, to study the phenotype development comparing WT and TgHD siblings. In this chapter, we review these approaches and the phenotype progression in the minipigs. Additionally, we outline perspectives in generation of new models using novel methodology and the potential of pig models in preclinical HD studies.

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Decreased frontal choline and neuropsychological performance in preclinical Huntington disease

Abstract: As choline-containing compounds relate to membrane turnover, membrane dysfunction antedating neuronal death is suggested to occur in the frontal cortex in preclinical carriers of Huntington disease. This dysfunction may be responsible for some of the neuropsychological deficits observed.

Cited by 62 publications

References 37 publications

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Postoperative Changes in Cerebral Metabolites Associated with Cognitive Improvement and Impairment after Carotid Endarterectomy: A 3T Proton MR Spectroscopy Study

Porcine Model of Huntington's Disease

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