T1ρ imaging in premanifest Huntington disease reveals changes associated with disease progression.

Huntington’s disease (HD) is a progressive, fatal, autosomal-dominant, neurodegenerative disease with no disease-modifying treatment. The disease is caused by an abnormal trinucleotide cytosine-adenine-guanine (CAG) expansion in the huntingtin gene. Detecting pathophysiological processes underlying HD before a clinical motor diagnosis offers hope for assessment of treatments and allows for early intervention, which ultimately will result in improved outcomes.1 To evaluate treatments before a clinical motor diagnosis is given, biomarkers are needed that can be objectively measured, are an indicator of disease progression, and measure a pharmacological response. To date, there are no proven biomarkers in HD and continued evaluation of potential biomarkers is needed.2 MRI provides a number of modalities that have been studied as potential biomarkers for HD progression during the premanifest phase preceding motor diagnosis, including structural imaging, diffusion imaging, magnetization transfer imaging, spectroscopy, and functional imaging, as previously reviewed in Bohanna et al.3 Weir et al.4 and van Den Bogaard et al.5 The size of the caudate and putamen have been shown to be potential biomarkers for disease progression.6,7 Based on the PREDICT-HD study, decreased volume of the striatum and white matter (WM) are detectable years to decades before estimated motor diagnosis of HD8 and are significantly atrophied close to clinical manifestation.9 The change in volume has been found to be approximately linear during the premanifest phase of the illness. Changes in brain metabolism10,11 and function12–15 have also been reported. There has been growing interest in using quantitative parametric MRI as a biomarker for neurodegenerative disorders.16–22 Quantitative imaging has a number of advantages over existing MRI techniques, including the ability to study changes in the relaxation time without the need to normalize to a standard (e.g., volumetric normalized to intracranial volume). Quantitative measurements offer the possibility to relate these changes back to pathological processes given that they reflect tissue properties at the microscopic level, instead of the macroscopic level, such as striatal volume. Coupling of multiple quantitative parametric imaging techniques facilitates the identification of the underlying mechanisms that may be responsible for the relaxation time changes. Previous studies have employed quantitative T2 and T2* mapping to study how these relaxation times change in HD19,23–25 These studies were motivated by the findings that subjects with HD have an increased iron concentration in the striatum postmortem16,26 and the known sensitivity of these relaxation parameters to metal ion concentrations. These studies have largely found decreased T2* relaxation rates within the globus pallidus (GP) and nonsignificant changes in the striatum.19,23–25 WM T2* relaxation times have been found to increase only during the early manifest stage.23 T2 mapping has been shown to largely disassociate from iron concentrations in HD,19 suggesting that other microstructural changes are largely driving the changes in T2 relaxation times. Recently, another quantitative MR parameter, T1 relaxation in the rotating frame (T1ρ), has been used to study progressive changes in Parkinson’s and Alzheimer’s disease.21,27,28 T1ρ measures proton exchange, which is influenced by metabolism (pH and glucose)29–31 and protein concentrations.32 However, T1ρ relaxation is sensitive to a number of microscopic environmental factors, including water content, which can be measured using T2 measurements. Therefore, this study was designed to collect multiple quantitative imaging parameters to better understand the underlying microscopic changes that are occurring associated with disease progression. The aims of this study were to apply multiple quantitative MRI techniques to determine whether T1ρ can serve as a unique quantitative biomarker for disease progression and examine whether T1ρ changes occur in the absence of T2 changes in terms of regional specificity and proximity to disease onset.