Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson's disease
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)
- et al.
Clinical significance of T1-weighted MR images following transient cerebral ischemia
J. Neurol. Sci.
(2006) - et al.
Neuropathological hallmarks of Alzheimer's and Parkinson's diseases
Prog. Brain Res.
(1998) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003) - et al.
Non-motor symptoms of Parkinson's disease: diagnosis and management
Lancet Neurol.
(2006) - et al.
Does hypercapnia-induced cerebral vasodilation modulate the hemodynamic response to neural activation?
Neuroimage
(2001) - et al.
The mystery of motor asymmetry in Parkinson's disease
Lancet Neurol.
(2006) - et al.
A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data
Neuroimage
(2005) - et al.
Sympathetic skin response asymmetry in early stage idiopathic Parkinson's disease
Clin. Neurophysiol.
(1999) - et al.
MRI characteristics of the substantia nigra in Parkinson's disease: a combined quantitative T1 and DTI study
Neuroimage
(2009) - et al.
Crosslinking of alpha-synuclein by advanced glycation endproducts—an early pathophysiological step in Lewy body formation?
J. Chem. Neuroanat.
(2000)
Automated brainstem co-registration (ABC) for MRI
Neuroimage
Prevalence and treatment of non-motor symptoms in Parkinson's disease
Parkinson. Relat. Disord.
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
Stereotaxic Atlas of the human brainstem and cerebellar nuclei
Rapid single-scan T2*-mapping using exponential excitation pulses and image-based correction for linear background gradients
Magn. Reson. Med.
Iron metabolism in Parkinsonian syndromes
Mov. Disord.
Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury
Arch. Neurol.
Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson's disease
Mov. Disord.
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.
Morphological and functional imaging studies on the diagnosis and progression of Parkinson's disease
J. Neurol.
Early Parkinson's disease and non-motor issues
J. Neurol.
Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration
Acta Neuropathol.
The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson's disease
Brain
High-resolution T1 and T2 mapping of the brain in a clinically acceptable time with DESPOT1 and DESPOT2
Magn. Reson. Med.
Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia
Brain
Quantitative measurement of pain sensation in patients with Parkinson disease
Neurology
Brain motion: measurement with phase-contrast MR imaging
Radiology
Ageing and Parkinson's disease: substantia nigra regional selectivity
Brain
Testing for anatomically specified regional effects
Hum. Brain Mapp.
Interregional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents
Magn. Reson. Med.
In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration
Mov. Disord.
The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease
J. Neurol. Neurosurg. Psychiatry
Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease
Neurology
Cited by (126)
Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease
2022, NeuroImage: ClinicalMagnetic resonance imaging assessment of substantia nigral iron deposition in Parkinson’s disease: a meta-analysis
2024, European Review for Medical and Pharmacological Sciences