Elsevier

NeuroImage

Volume 51, Issue 2, June 2010, Pages 512-520
NeuroImage

Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson's disease

https://doi.org/10.1016/j.neuroimage.2010.03.005Get rights and content

Abstract

Quantitative magnetic resonance imaging is a promising in vivo imaging technique revealing insights into different aspects of brain morphology in neurodegenerative diseases based on the determination of physical tissue parameters. Using combined T1- and T2*-mapping, we investigated changes of local relaxation times in the midbrain and lower brainstem of 20 patients with early Parkinson's disease (PD) compared to 20 healthy controls. Voxelwise statistical parametric mapping disclosed a widespread reduction of midbrain T1 values contralateral to the clinically more severely affected limbs. Within the SN, the T1 decrease matched the known pattern of selective neuronal loss as examined in various post-mortem studies, suggesting that T1 is a marker for PD related tissue pathology. However, the spatial extent of T1 reductions exceeded the SN and reached non-dopaminergic areas in the pontomesencephalic junction potentially involved in early non-motor symptoms of PD. In contrast, T2*-mapping revealed a bilateral decrease of T2* values restricted to the SN, indicating a local increase in total iron content. We conclude that, particularly in longitudinal studies, quantitative T1 may be a valuable marker for the monitoring of progressive neuronal loss in PD, whereas nigral T2* reductions might be more closely associated with an increased general vulnerability for the development of the disorder.

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by asymmetric onset of motor symptoms due to a substantial damage of dopaminergic neurons in the substantia nigra pars compacta (SNc) (Hoehn and Yahr, 1967). Although the biochemical mechanisms causing selective cell death in PD are still unresolved, the formation of Lewy bodies and Lewy neurites accompanied by microglia activation and proliferation is generally considered to play a key role in PD pathology (Braak et al., 1998, Croisier and Graeber, 2006, Gibb and Lees, 1988, Imamura et al., 2003, McGeer and McGeer, 2008). Furthermore, the iron content is typically increased in the SNc of PD patients, which may also contribute to neuronal degeneration by the production of reactive oxygen species (Dexter et al., 1991, Sofic et al., 1991).

Currently, much effort is being undertaken to visualize PD related changes in tissue architecture in vivo by using novel conventional or quantitative magnetic resonance imaging (qMRI) techniques (Ordidge et al., 1994, Seppi and Schocke, 2005). In contrast to conventional imaging, qMRI aims for an unbiased quantification of distinct physical tissue properties, remarkably increasing intra- and inter-individual comparability of images and, thus, allowing the objective measurement of disease related brain changes. Longitudinal (T1) and transversal relaxation times (T2, T2* and T2’) are important parameters frequently assessed with qMRI. So far, a reduction in T2* and T2’ in the lateral SNc, likely caused by an increase in tissue iron content, was shown consistently in patients suffering from early PD stages (Gorell et al., 1995, Graham et al., 2000, Martin et al., 2008, Wallis et al., 2008). Only few studies have investigated T1-based techniques in PD (Hu et al., 2001, Hutchinson and Raff, 1999, Hutchinson and Raff, 2008), describing a lateral-to-medial gradient of signal loss within the substantia nigra (SN) which matched the spatial gradient of nigral cell loss known from histological studies (Damier et al., 1999, Fearnley and Lees, 1991). Recently, a reduced SN volume was derived from manually segmented quantitative T1-maps (Menke et al., 2009).

In this study, we used combined quantitative T1- and T2*-mapping to investigate two important issues that have not yet been addressed in imaging of early PD: (1) It is currently not known whether changes in midbrain and lower brainstem areas other than the SN can be detected using T1- or T2*-imaging, potentially reflecting morphological substrates of non-motor PD symptoms such as depression and sleep disturbance (Chaudhuri and Naidu, 2008, Grinberg et al., 2009). As T1 relaxation times of gray matter are typically longer than those of white matter (Wansapura et al., 1999) and PD is associated with gray matter loss (Fearnley and Lees, 1991), we expected a decrease in T1 in affected brain regions. (2) It is still controversial, whether iron increase represents an independent pathomechanism or just an epiphenomenon that is in some way linked to cell death (Götz et al., 2004). To address this question, we explored how alterations in T1 (as a potential marker for gray matter loss) and T2* (as a marker of iron accumulation) relate to each other using left–right asymmetry of motor symptoms as an indicator for side-specific disease state.

Section snippets

Study Subjects

Twenty right-handed patients (mean age 62.2 ± 10.2 years, mean disease duration 4.9 ± 2.4 years) diagnosed with PD in Hoehn and Yahr stage I (n = 7) and II (n = 13) were recruited from our Movement Disorders outpatient clinic (see Table 1 for epidemiological and clinical patient characteristics). All study subjects fulfilled the standard UK Brain Bank criteria for PD (Hughes et al., 1992), none had a history of head injury, stroke or other neurological diseases. PD was absent in the family history of all

Anatomy of the substantia nigra as revealed by T1- and T2*-mapping

Single subject and mean T1- and T2*-maps of three transverse sections (I-III) through the midbrain are shown in Fig. 1C–F. For comparison, stereotactic drawings based upon probabilistic data from 22 hemibrainstems (Fig. 1A) and corresponding histological slices (Fig. 1B) taken from an anatomical atlas (Afshar et al., 1978) were added. In the T1-maps (Fig. 1C and D), the SN was clearly visible as a two-layered arc of gray matter at the intercollicular level (I), which narrowed inferior to the RN

Unilateral decrease in T1

The unilateral onset of motor symptoms is characteristic for PD and side differences often persist during the entire course of the disease (Hoehn and Yahr, 1967). According to clinical symptoms, the most prominent qMRI finding in this study is a midbrain and pontine T1 decrease strictly contralateral to the clinically most affected body side. Within the affected SN, the pattern of T1 decrease matched the known caudal-to-rostral and lateral-to-medial gradient of nigral cell loss as has been

Conclusions

This combined quantitative T1 and T2* MRI study at 3 T field strength demonstrated distinct alterations in the tissue morphology of the rostral brainstem in patients with early-stage PD. Decreased T1 values likely reflecting gray matter loss were found contralateral to the most affected body side and extended from the SN down to the caudal midbrain and to the midpontine level. Within the SN, the T1 decrease matched the known pattern of dopamine cell degeneration from various post-mortem studies,

Acknowledgments

This study was supported by the Bundesministerium für Bildung und Forschung (Brain Imaging Center Frankfurt, DLR 01GO0203) and the Deutsche Forschungsgemeinschaft (ZA 233/1-1). Simon Baudrexel was partly funded by the Interdisciplinary Center for Neuroscience Frankfurt (ICNF), Frankfurt am Main. We thank Florian Beissner for his assistance in the revision of the figures.

References (66)

  • V. Napadow et al.

    Automated brainstem co-registration (ABC) for MRI

    Neuroimage

    (2006)
  • K.L. Sullivan et al.

    Prevalence and treatment of non-motor symptoms in Parkinson's disease

    Parkinson. Relat. Disord.

    (2007)
  • V.N. Uversky et al.

    Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure

    J Biol Chem

    (2001)
  • F. Afshar et al.

    Stereotaxic Atlas of the human brainstem and cerebellar nuclei

    (1978)
  • S. Baudrexel et al.

    Rapid single-scan T2*-mapping using exponential excitation pulses and image-based correction for linear background gradients

    Magn. Reson. Med.

    (2009)
  • D. Berg et al.

    Iron metabolism in Parkinsonian syndromes

    Mov. Disord.

    (2006)
  • D. Berg et al.

    Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury

    Arch. Neurol.

    (2002)
  • D. Berg et al.

    Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson's disease

    Mov. Disord.

    (2005)
  • P.A. Bottomley et al.

    A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from 1–100 MHz: dependence on tissue type, NMR frequency, temperature, species, excision, and age

    Med. Phys.

    (1984)
  • D.J. Brooks

    Morphological and functional imaging studies on the diagnosis and progression of Parkinson's disease

    J. Neurol.

    (2000)
  • K.R. Chaudhuri et al.

    Early Parkinson's disease and non-motor issues

    J. Neurol.

    (2008)
  • E. Croisier et al.

    Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration

    Acta Neuropathol.

    (2006)
  • P. Damier et al.

    The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson's disease

    Brain

    (1999)
  • S.C. Deoni et al.

    High-resolution T1 and T2 mapping of the brain in a clinically acceptable time with DESPOT1 and DESPOT2

    Magn. Reson. Med.

    (2005)
  • D.T. Dexter et al.

    Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia

    Brain

    (1991)
  • R. Djaldetti et al.

    Quantitative measurement of pain sensation in patients with Parkinson disease

    Neurology

    (2004)
  • D.R. Enzmann et al.

    Brain motion: measurement with phase-contrast MR imaging

    Radiology

    (1992)
  • J.M. Fearnley et al.

    Ageing and Parkinson's disease: substantia nigra regional selectivity

    Brain

    (1991)
  • K.J. Friston

    Testing for anatomically specified regional effects

    Hum. Brain Mapp.

    (1997)
  • N. Gelman et al.

    Interregional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents

    Magn. Reson. Med.

    (2001)
  • A. Gerhard et al.

    In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration

    Mov. Disord.

    (2004)
  • W.R. Gibb et al.

    The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease

    J. Neurol. Neurosurg. Psychiatry

    (1988)
  • J.M. Gorell et al.

    Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease

    Neurology

    (1995)
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