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Role of Functional Magnetic Neuroimaging
in Diagnosis and Research
Hartwig Roman Siebner and Günther Deuschl
INTRODUCTION
Recent advances in magnetic resonance imaging (MRI) have opened up new possibilities to map
distinct aspects of human brain function in vivo. Functional magnetic resonance imaging (fMRI) is
widely used to assess changes in regional neuronal activity at high spatial and temporal resolution
(1,2). Magnetic resonance spectroscopy (MRS) provides a means to probe distinct aspects of brain
metabolism at a regional level (3,4). Water diffusion magnetic resonance imaging (dMRI) can be
used to study the integrity of white matter tracks in the brain (5). MRI has already been successfully
applied to study the pathophysiology of movement disorders such as Parkinson’s disease (PD) (6,7).
The aim of this chapter is to summarize how these innovative MRI methods may be useful for diagnosis and research of atypical parkinsonian disorders.
FUNCTIONAL MAGNETIC RESONANCE IMAGING
Neuroimaging techniques, such as single photon emission tomography (SPECT), positron emission tomography (PET), and fMRI, provide a means of mapping regional neuronal activity in vivo in
the intact human brain. Blood oxygen level-dependent (BOLD) fMRI uses echo-planar imaging (EPI)
to detect changes in the oxygenation state of the blood (8). Recent studies of the monkey brain combined BOLD-sensitive fMRI with electrophysiological measurements to demonstrate that the BOLD
signal primarily measures the input and processing of neuronal information within a brain region (2).
Since the BOLD signal is an intrinsic signal, BOLD-sensitive fMRI does not require the injection
of a contrast agent. Compared to PET and SPECT, BOLD-sensitive fMRI does not involve exposure
to radiation, is widely available, and offers a higher spatial and temporal resolution. Moreover, eventrelated fMRI protocols allow studies to investigate changes in the BOLD signal related to a single
movement, whereas SPECT and PET can only map the averaged regional cerebral blood flow (rCBF)
changes caused by multiple trials. Because of these methodological advantages, BOLD-sensitive
fMRI has largely replaced PET and SPECT of rCBF as a tool to study the functional architecture of
the human brain.
In recent years, BOLD-sensitive fMRI has been extensively used as a research tool to study the
functional consequences of nigrostriatal dopamine loss in idiopathic PD. So far, most studies have
investigated changes in BOLD signal related to volitional hand movements (9–12). These studies
have disclosed a movement-related dysfunction in basal ganglia-thalamocortical loops that are
From: Current Clinical Neurology: Atypical Parkinsonian Disorders
Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
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involved in manual motor control. However, the pattern of abnormal movement-related activity in
frontal motor areas has been variable across studies (9–12). Since these studies used motor tasks that
differed in terms of movement parameters and cognitive load, the implication is that, in PD, functional impairment of the various basal ganglia-thalamocortical motor loops is highly dependent on
the motor context. In addition to motor activation studies, BOLD-sensitive fMRI has also successfully been employed to assess nonmotor functions such as attention to action and working memory in
PD (12,13). Repeated fMRI measurements have also been used to image the acute effects of a therapeutic intervention. For instance, pharmacological fMRI studies have consistently demonstrated a
partial normalization of movement-related activation in frontal motor areas after oral administration
of levodopa (9–11).
At present, there are no fMRI studies investigating atypical parkinsonian disorders. However, the
experience with fMRI gathered in PD indicates that fMRI can successfully be applied in atypical
parkinsonian disorders. The main potential of fMRI lies in its ability to assess the functional consequences of the underlying neurodegenerative process. Activation studies with fMRI can not only
reveal regional abnormalities in task-related activity but also disclose abnomal functional integration
among brain regions that form a functional network (12). The pathology of atypical parkinsonian
disorders affects brain regions that are not subject to neurodegeneration in PD (14). Therefore, fMRI
studies may be particularly revealing if the behavioral paradigm activates a functional system that is
specifically affected by the suspected atypical parkinsonian syndrome. For instance, in patients with
progressive supranuclear palsy (PSP), fMRI studies that explore distinct aspects of voluntary control
of eye movements such as smooth pursuit and saccade generation may reveal specific functional
abnormalities in regions involved in ocular motor control. Therefore, fMRI may provide a better
understanding of the pathophysiology and help to establish a specific profile of abnormal brain activation for the various atypical parkinsonian disorders.
In contrast to PET activation studies, fMRI activation studies allow to acquire many hundreds of
brain volumes during a single session. Therefore, single-subject fMRI provides sufficient statistical
power to analyze individual activation patterns. This is of relevance in atypical parkinsonian disorders since it may be difficult to recruit a sufficient number of well-characterized patients to ensure
sufficient statistical power for between-group comparisons.
Pharmacological fMRI provides a means to objectively measure the functional effects of therapeutic agents on neuronal activity. Serial fMRI measurements of the functional response to levodopa
can be used to address the question why a subgroup of patients with multiple system atrophy (MSA)
shows a sustained levodopa response during the course of the disease. In conjunction with structural
MRI, long-term fMRI studies might be of value to monitor disease progression in patients with atypical parkinsonian disorders.
MAGNETIC RESONANCE SPECTROSCOPY
MRS provides chemical information on tissue metabolites (3,4). The molecules that can be studied by MRS in human brain tissue are hydrogen 1 (1H) and phosphorus 31 (31P). Magnetic resonance
sensitivity is far greater for protons than it is for phosphorus (3). Therefore, most commercial MR
scanners are capable of only proton MRS. Spectra are usually obtained from localized brain regions.
The brain region is defined on a single slice by placing a small voxel, on the order of 1 or 2 cm2, in the
area of interest. The compounds that can be observed in proton spectra are primarily identified by
their frequency (i.e., their position in the spectrum), expressed as the shift in frequency in pars per
million (ppm) relative to a standard. A normal spectrum shows peaks from N-acetyl groups, especially N-acetylaspartate (NAA) at 2.0 ppm, creatine (Cr), and phosphocreatine at 3.0 ppm, and choline-containing phospholipids (Ch) at 3.2 ppm (3). An additional peak at 1.3 ppm arises from the
methyl resonance of lactate and is normally barely visible above the baseline noise (3). Pathologic
conditions that involve regional neuronal loss lead to region-specific decreases in the relative NAA
Functional MRI Techniques in Atypical Parkinsonism
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concentrations (3,4). Since NAA is a marker of neuronal integrity, proton MRS provides a
noninvasive means of quantifying neuronal loss or damage in vivo. Ch and other lipids are markers of
altered neuronal membrane synthesis. Cr is a possible marker of defective energy metabolism. Typically, individual metabolic ratios obtained from peak areas of the spectrum are used as input to the
statistical analysis. Because total Cr concentration is relatively resistant to change, Cr is often used as
an internal standard to which the concentrations of other metabolites are normalized.
Proton MRS has been used by several groups to study brain metabolism in nondemented PD yielding conflicting results (15–27). In general, the majority of these studies have failed to detect consistent abnormalities for NAA, Ch, or Cr in the basal ganglia (15–19,21,24,25; but see refs. 20,26,27) or
the cerebral cortex (19,21,25; but see refs. 22,23). A multicenter study that included 151 patients with
PD and 97 age-matched controls found no overall differences in the striatal proton spectra between
groups (16). However, there was a decrease in the NAA/Cho ratio in a subgroup of elderly patients
(aged 51–70 yr) and patients that were not treated with levodopa (16). These findings suggest that
proton MRS may reveal subtle metabolic abnormalities in patients with PD depending on age and
medication. Therefore, heterogeneities of clinical features across patient groups may at least in part
account for discrepancies across studies (15–27).
Three out of four proton MRS studies have reported abnormal proton spectra in patients with
atypical parkinsonian disorders (15,18,19; but see ref. 26). Davie et al. (15) performed proton MRS
of the lentiform nucleus in seven patients with MSA-P (predominantly striatonigral variant) and five
patients with MSA-C (olivocerebellar variant). Compared with healthy controls, the NAA/Cr ratio was
significantly decreased in patients with MSA (15). Tedeschi et al. (19) found a reduced NAA/Cre ratio
in the brainstem, centrum semiovale, and frontal and precentral cortex, and a reduced NAA/Ch ratio
in the lentiform nucleus in 12 patients with PSP compared with healthy controls (Fig. 1). The same
study also included nine patients with corticobasal degeneration (CBD). CBD patients also showed
an abnormal metabolic pattern with a reduced NAA/Cre ratio in the centrum semiovale and a reduced
NAA/Ch ratio in the lentiform nucleus and the parietal cortex contralateral to the most affected side
(Fig. 1). A reduction in NAA/Ch and NAA/Cr ratios in the lentiform nucleus was also observed by
Federico et al. (18) in seven patients with MSA and seven patients with PSP. All three studies additionally examined the proton spectra in a group of PD patients and found no abnormalities in the
selected region of interest (15,18,19). It should be noted, however, that Clarke et al. failed to find any
abnormality for NAA, Ch, and Cr in six patients with probable MSA (26).
In summary, the published data suggest that proton MRS may be of potential diagnostic value in
atypical parkinsonian disorders. However, the demonstration of significant group differences in
patients with well-defined clinical features does not imply that proton MRS can reliably discriminate between PD and atypical parkinsonian disorders in individual patients. A recent study by Alexon
et al. used pattern recognition techniques (i.e., neural network and related data analyses) to analyze
proton spectra in 15 patients with probable PD, 11 patients with possible PD, 5 patients with atypical
PD, and 14 healthy age-matched controls (27). In contrast to conventional analyses, all information
within the proton spectrum can be entered in the statistical analysis simultaneously. The neuronal
networks approach allowed them to distinguish between the four groups with considerable accuracy;
approximately 88% of the predictions were correct. By contrast, conventional analysis revealed no
significant differences in metabolite ratios among groups.
Proton MRS of the basal ganglia in conjunction with statistical analyses that take into account the
pattern of the entire proton spectrum may help to distinguish PD from atypical parkinsonian disorders at initial presentation. Discriminative power may be further increased by using a multimodal
imaging approach that combines MRS with other imaging techniques such as structural MRI or
18F-6-fluorodopa PET.
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Fig 1. H-MRS findings in control subjects and patients with parkinsonian disorders.PSP, progressive supranuclear palsy; PD, Parkinson’s disease; CBD, corticobasal degeneration. Columns and error bars present means
± SD. Asterisks indicate significant differences between controls and PSP patients and between controls and
CBD (*p = 0.05, **p < 0.01, ***p < 0.001). The data were taken from Table 2 published in ref. 19.
Phosphorus MRS provides information on levels of cerebral phospholipids and high-energy phosphates. The cerebral phosphorus spectra contains at least seven resonances that can be attributed to
phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr),
and adenosine triphosphate (ATP). So far, only one group has used MRS to investigate the phosphorus spectra in 13 patients with PD and 15 patients with MSA (28). Assuming a constant cytosolic
concentration of ATP, Barbiroli et al. measured PCr and Pi and calculated cytosolic pH and free
Mg2+ (28). Compared with an age-matched control group, patients with PD showed a significant
increase in Pi and a decrease in cytosolic free Mg2+, whereas PCr was reduced and Pi was increased
in patients with MSA. In the MSA group, there was no difference in the phosphorus spectra between
the MSA-P and the MSA-C variants of MSA. A discriminant analysis that considered only the concentrations of PCr and Mg2+ provided a correct classification of MSA and PD patients in 93% of the
cases. These preliminary data suggest that, in addition to proton MRS, phosphorus MRS may be
useful to probe cerebral phosphate metabolism and ion contents in patients with atypical parkinsonian disorders.
DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING
Water diffusion-weighted MRI produces quantitative maps of microscopic displacement of water
molecules that occur as part of the physical diffusion process. This is achieved by sensitizing the
magnetic resonance signal to the random motion of water molecules by using strong magnetic field
gradients. By varying the magnetic field gradient, one can obtain different degrees of diffusionweighted images and calculate an apparent diffusion coefficient (ADC) for each voxel (5).
Since diffusion of water molecules is highly sensitive to microstructural changes in the cerebral
tissue, diffusion-weighted MRI has become a firmly established method to probe the functional integrity of brain tissue, especially in acute cerebral ischemia (29). Diffusion-weighted MRI has a high
sensitivity to detect structural abnormalities. However, it is important to bear in mind that diffusionweighted MRI has a low specificity in terms of underlying pathophysiology since various mechanisms (e.g., edema, neurotoxicity, Wallerian degeneration) can affect the diffusion process in the
cerebral tissue.
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Three studies have characterized water diffusion in patients with atypical parkinsonian disorders.
Patients with PSP showed an increase in ADCs in the prefrontal and precentral white matter (30) and
the basal ganglia (31,32). An increase in ADCs was also found in patients with the MSA-P variant of
MSA (32), but not in patients with PD (31,32). These data indicate that diffusion-weighted imaging
may help to distinguish between PD and atypical parkinsonian disorders, but fails to discriminate
between PSP and MSA.
The microstructure of the brain tissue imposes directional constraints to the diffusion of water
molecules in the brain (referred to as anisotropy). Diffusion is particularly anisotropic in white matter
tracts because water preferentially diffuses along the direction of white matter fibres. Anisotropic
diffusion is more adequately characterized by a diffusion tensor. A diffusion tensor is an array of nine
coefficients that fully characterizes the directional properties of water diffusion in space.
Diffusion tensor-encoded MRI (DT-MRI) uses different gradient orientations to characterize the
diffusion tensor in each voxel of the brain (5). The diffusion tensor is often displayed as an elipsoid
(5). The average size of the ellipsoid represents the overall displacement of the water molecules in a
given voxel (mean diffusivity). The eccentricity of the ellipsoid characterizes the degree of anisotropy. A sphere indicates isotropic diffusion whereas an elongated (cigar-shaped) or flat (pancakeshaped) ellipsoid indicates anisotropic diffusion. The main axis of the ellipsoid corresponds to the
preferential direction of diffusion.
In the white matter, the main axis of the diffusion tensor is thought to represent the prevailing
orientation of white matter bundles in each voxel. DT-MRI allows one to track white matter fibers by
connecting neighboring voxels on the basis of their main direction of the diffusion tensor (i.e., main
fiber orientation) (33). Anisotropy measurements can be used to identify subtle abnormalities in the
organization of white matter tracks that are not evident with plain, anatomical MRI (34). However, it
is worth bearing in mind that currently available DT-MRI techniques can only visualize white matter
bundles that consist of a large number of axons, limiting fiber tracking to the white matter. Furthermore, DT-MRI can not probe the directional and functional status of the information flow along the
white matter tracts. DT-MRI also has a considerable potential for functional mapping of subcortical
gray matter. A recent study employed DT-MRI to differentiate the nuclei in the thalamus and to map
their connectivity (35).
Because DT-MRI provides a unique approach to tracking anatomical connectivity in vivo, DT-MRI
can provide important new insights into the neuroanatomical basis of atypical parkinsonian disorders
linking clinical symptoms with impaired anatomical connectivity. Though no DT-MRI study has
been published on atypical parkinsonian disorders at this stage, it is safe to state that DT-MRI provides a promising tool to pinpoint characteristic patterns of abnormal connectivity, especially in
CBD and MSA. This may be used to separate atypical parkinsonian disorders from PD.
MRI-BASED MORPHOMETRY
MRI-based volumetry of structural MR images can reveal the pattern of atrophic changes in patients
with atypical parkinsonian syndromes. Using a region-of-interest (ROI) analysis, it has been shown
that the patterns of atrophy in predefined regions of interest allow the separation PD from MSA and
PSP (36) as well as PSP from CBD (37). For instance, a recent study by Gröschel and colleagues
demonstrated that the volumes of midbrain, parietal white matter, temporal gray matter, brainstem,
frontal white matter, and pons separate best between patients with PSP or CBD (37). A stepwise
linear discriminant analysis resulted in two canonical discriminant functions, which allowed for the
correct prediction of the diagnosis in 95% of healthy control subjects as well as in 76% of all PSP and
83% of all CBD patients (37). The discriminant functions revealed similar results in patients with
definite PSP/CBD and in patients with possible and probable PSP/CBD (37). Prospective studies are
now needed to show whether MRI-based volumetry will have clinical applicability.
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In recent years, voxel-based morphometry (VBM) of structural MRI data has been introduced as a
simple and objective approach for characterizing small-scale differences in white and gray matter
(36). VBM refers to a voxel-wise statistical comparison of the local concentration of gray (or white)
matter between two groups of subjects. The procedure involves spatial normalization of high-resolution MR images into the same stereotactic space followed by segmentation of the gray (or white)
matter. The smoothed gray matter segments are then compared using parametric statistical tests and
the theory of Gaussian random fields (38). Other voxel-based morphometric approaches, such as
deformation-based or tensor-based morphometry, allow the study of regional differences in brain
shapes between groups of subjects (38). In contrast to conventional ROI analyses, VBM and related
approaches provide whole-brain coverage and are highly sensitive to subtle structural changes within
a single brain region. Since VBM is an automated procedure, the analysis is highly observer independent. Finally, VBM is not affected by partial volume effects. VBM cannot only be applied to highresolution structural MRI, but VBM can also be used to investigate between-group differences of ADC
maps or fractional anisotropy maps. This allows to screen for regional changes in neuronal integrity
(i.e., VBM of ADC maps) or regional changes in fiber orientation (i.e., VBM of DT-weighted MRI).
FUTURE DIRECTIONS
Apart from proton MRS, none of the MRI approaches described in this chapter have yet been used
to study the pathophysiology of atypical parkinsonian disorders. Therefore, the potential of these
techniques for the diagnosis and research of atypical parkinsonian disorders remains to be defined.
Based on the MRI experience gathered with other neuropsychiatric disorders, we anticipate that fMRI,
MRS, and water diffusion MRI will significantly contribute to early diagnosis and advance our
understanding of pathophysiological evolution of the different atypical parkinsonian disorders.
Future advances in MR technology and new MR techniques (e.g., magnetization transfer technique)
will further increase the diagnostic and research potential of MRI in parkinsonian disorders (39).
It is important to bear in mind that these MRI techniques can readily be combined with each other
and with high-resolution structural MRI. Indeed, multimodal MRI studies that combine structural
and functional MR techniques represent the most promising approach to exploit MRI as a research
tool. Since VBM of structural MRI images maps the pattern of structural abnormalities, VBM provides complementary anatomic information for the interpretation of altered neuronal activity as
revealed by fMRI. The same applies for DT-MRI which, in combination with fMRI, might provide
important clues to altered functional connectivity in patients with atypical parkinsonism. On an individual basis, interfacing fMRI with structural MRI and DT-MRI may considerably enhance diagnostic accuracy of MRI in the differential diagnosis of the atypical parkinsonian disorders.
ROLE OF FUNCTIONAL MAGNETIC RESONANCE IMAGING
IN DIAGNOSIS AND RESEARCH OF ATYPICAL PARKINSONIAN
SYNDROMES
A. Functional magnetic resonance imaging (fMRI)
Mapping the functional consequences of neurodegeneration
Assessing the effect of therapeutic interventions
Monitoring disease progression
B. Magnetic resonance spectroscopy (MRS)
Noninvasive characterization of regional abnormalities in tissue metabolism
Discrimination between PD and atypical parkinsonian syndromes
C. Diffusion-weighted magnetic resonance imaging (dMRI)
Probing for microstructural changes in the cerebral tissue (ADC-maps)
Mapping abnormalities in the organization of white matter tracts (DT-imaging)
PD, Parkinson’s disease; ADC, apparent diffusion coefficient; DT, diffusion tensor.
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