Heterogeneity in 1H-MRS profiles of presymptomatic and early manifest Huntington's disease

Reynolds, Norman C.; Prost, Robert; Mark, Leighton P.

doi:10.1016/j.brainres.2004.10.030

Cited by 76 publications

(82 citation statements)

References 26 publications

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“…These findings provide further evidence of the global energy metabolism failure, diffuse axonal loss, proliferation of activated microglia and astrogliosis in HD individuals (Piccolo et al 1998, Harms et al 1997, Jenkins et al 1998, Reynolds et al 2005). …”

Section: Discussionsupporting

confidence: 57%

Proton Magnetic Resonance Spectroscopy in Huntington's Disease Accompanying Neuroborreliosis

et al. 2017

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Section: Discussionsupporting

confidence: 57%

Proton Magnetic Resonance Spectroscopy in Huntington's Disease Accompanying Neuroborreliosis

et al. 2017

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“…[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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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“…75) receptors for which existing imaging tracers could potentially act as indirect markers of mHTT function in clinical studies. Energetic alterations in patients and animal models of HD (76-78) may be of relevance since energetic endpoints can be monitored non-invasively in vivo through imaging or MRS techniques (79,80). Finally, it will be vital to identify degeneration-relevant markers, such as MSN or cortically expressed proteins found in CSF, which could be used to track degeneration longitudinally.…”

Section: Pathogenic Mechanisms In Hd and Current Approaches To Intervmentioning

confidence: 99%

“…Such markers sufficiently sensitive for Phase II studies would warrant further investment for disease-modification trials. Given the widespread degeneration observed in the basal ganglia and cortical areas in manifest and advanced HD (12,14,38,39,79,(81)(82)(83), it is plausible that non-invasive techniques such as quantitative EEG (qEEG) could gauge progression. However, validating these approaches together with assessing sensitive tasks in functions important for quality of life of HD patients remains an important area of investigation for disease modification therapies.…”

Section: Pathogenic Mechanisms In Hd and Current Approaches To Intervmentioning

confidence: 99%

The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease

Muñoz-Sanjuán¹,

Bates²

2011

J. Clin. Invest.

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Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene. There are currently no effective treatments for this devastating disease. Given its monogenic nature, disease modification therapies for HD should be theoretically feasible. Currently, pharmacological therapies aimed at disease modification by altering levels of HTT protein are in late-stage preclinical development. Here, we review current efforts to develop new treatments for HD based on our current understanding of HTT function and the main pathological mechanisms. We emphasize the need to enhance translational efforts and highlight the importance of aligning the clinical and basic research communities to validate existing hypotheses in clinical studies. Human and animal therapeutic trials are presented with an emphasis on cellular and molecular mechanisms relevant to disease progression.

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Heterogeneity in 1H-MRS profiles of presymptomatic and early manifest Huntington's disease

Cited by 76 publications

References 26 publications

Proton Magnetic Resonance Spectroscopy in Huntington's Disease Accompanying Neuroborreliosis

Proton Magnetic Resonance Spectroscopy in Huntington's Disease Accompanying Neuroborreliosis

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease

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