Is there a path beyond BOLD? Molecular imaging of brain function

Koretsky, Alan P.

doi:10.1016/j.neuroimage.2012.02.076

Cited by 26 publications

(27 citation statements)

References 138 publications

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“…7). Tremendous effort has been put into developing MRI reporter agents to image gene expression, either during normal brain function or when inhibiting mRNA translation (Ifediba and Moore, 2012; Koretsky, 2012; Vandsburger et al, 2013), however these contrast-based techniques are currently far from clinical translation. Here we are using an MR modality that does not require exogenous contrast agents, is currently available in the clinic and has already been shown to sensitively detect neurochemical alterations in patients with SCAs (Öz et al, 2011a).…”

Section: Discussionmentioning

confidence: 99%

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

Öz

Kittelson

Demirgöz

et al. 2015

Neurobiology of Disease

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Suppression of transgene expression in a conditional transgenic mouse model of spinocerebellar ataxia 1 (SCA1) reverses the Purkinje cell pathology and motor dysfunction that are hallmarks of SCA1. We previously showed that cerebellar neurochemical levels measured by magnetic resonance spectroscopy (MRS) correlate with progression of pathology and clinical status of patients and that abnormal neurochemical levels normalize upon suppression of transgene expression, indicating their potential as robust surrogate markers of treatment effects. Here we investigated the relative sensitivities of MRS, histology, transgene expression and motor behavioral testing to disease reversal in conditional SCA1 mice. Transgene expression was suppressed by doxycycline administration and treated and untreated mice were assessed by MRS at 9.4 tesla before and after treatment and with an accelerating Rotarod, histology and quantitative polymerase chain reaction (qPCR) for ataxin-1 transgene expression following doxycycline treatment. The MRS-measured N-acetylaspartate-to-myo-inositol ratio (NAA/Ins) correlated significantly with the molecular layer (ML) thickness and transgene expression. NAA/Ins, ML thickness and transgene expression were highly significantly different between the treated vs. untreated groups (p<0.0001), while the Rotarod assessment showed a trend for treatment effect. MRS, qPCR and histology had high sensitivity/specificity to distinguish treated from untreated mice, all with areas under the curve (AUC) = 0.97–0.98 in receiver operating characteristic (ROC) analyses, while Rotarod had significantly lower sensitivity and specificity (AUC = 0.72). Therefore, MRS accurately reflects the extent of recovery from neurodegeneration with sensitivity similar to invasive measures, further validating its potential as a surrogate marker in pre-clinical and clinical treatment trials.

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Section: Discussionmentioning

confidence: 99%

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

Öz

Kittelson

Demirgöz

et al. 2015

Neurobiology of Disease

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“…In addition, conventional and more advanced experimental techniques also provide information on hemodynamic changes (blood flow, blood volume, tissue perfusion), metabolic changes (using MR spectroscopy, MRS, see also Chapter 8), functionality (using functional MRI, fMRI, see also Chapter 7) and cellular connectivity and tissue organization (using diffusion tensor imaging (DTI) and manganese enhanced MRI (MEMRI). [15][16][17][18][19][20] Also due to these diverse applications of MRI, it has developed into one of the most powerful tools for clinical diagnosis, the characterization of animal models and the evaluation of therapeutic strategies in biomedical research.…”

Section: Magnetic Resonance Techniquesmentioning

confidence: 99%

CHAPTER 11. Magnetic Resonance‐Based Cell Imaging Using Contrast Media and Reporter Genes

Velde¹,

Himmelreich²

2013

New Developments in NMR

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“…2,3 SCAs that respond to ions and molecules involved in neuronal signaling are of particular interest for neuroscience and could greatly help in understanding brain function. 4,5 One of the most preferred targets is Ca(II) due to its critical role in every neuronal event. Moreover, this ion is involved in muscle contraction and further insights on its physiology could aid better curing of cardiac diseases.…”

Section: ■ Introductionmentioning

confidence: 99%

Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity

et al. 2016

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Bioresponsive MRI contrast agents sensitive to Ca(II) fluctuations may play a critical role in the development of functional molecular imaging methods to study brain physiology or abnormalities in muscle contraction. A great challenge in their chemistry is the preparation of probes capable of inducing a strong signal variation that could be detected in a robust way. To this end, the incorporation of small molecular weight bioresponsive agents into nanocarriers can improve the overall properties in a few ways: (i) the agent can be delivered into the tissue of interest, increasing the local concentration; (ii) its biokinetic properties and retention time will improve; (iii) the high molecular weight and size of the nanocarrier may cause additional changes in the MRI signal and raise the chances for their detection in functional experiments. In this work, we report the preparation of the new class of liposome-based, Ca-sensitive MRI agents. We synthesized a novel amphiphilic ligand which was incorporated into the liposome bilayer. A remarkable increase of ∼420% in longitudinal relaxivity r 1 , from 7.3 mM −1 s −1 to 38.1 mM −1 s −1 at 25°C and 21.5 MHz in the absence and presence of Ca(II), respectively, was achieved by the most active liposomal formulation. To the best of our knowledge, this is the highest change in r 1 observed for Ca-sensitive agents at physiological pH and can be explained by simultaneous Ca-triggered increase in hydration and reduction of local motion of Gd(III) complex, which can be followed at low magnetic fields.

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Is there a path beyond BOLD? Molecular imaging of brain function

Cited by 26 publications

References 138 publications

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

CHAPTER 11. Magnetic Resonance‐Based Cell Imaging Using Contrast Media and Reporter Genes

Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity

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