Clinical Imaging 40 (2016) 987–996

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Clinical Imaging
journal homepage: http://www.clinicalimaging.org

Review Article

The role of magnetic resonance imaging in the diagnosis of Parkinson's

disease: a review☆
Ali M. Al-Radaideh a,⁎, Eman M. Rababah b
a
Department of Medical Imaging, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan
b
Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan

a r t i c l e i n f o a b s t r a c t

Article history: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's in elderly peo-
Received 15 October 2015 ple. Different structural and functional neuroimaging methods play a great role in the early diagnosis of neurode-
Received in revised form 9 April 2016 generative diseases. This review discusses the role of magnetic resonance imaging (MRI) in the diagnosis of PD.
Accepted 23 May 2016
MRI provides clinicians with structural and functional information of human brain noninvasively. Advanced
quantitative MRI techniques have shown promise for detecting pathological changes related to different stages
Keywords:
Parkinson's disease
of PD. Collectively, advanced MRI techniques at high and ultrahigh magnetic fields aid in better understanding
Neurodegenerative diseases of the nature and progression of PD.
Magnetic resonance imaging © 2016 Elsevier Inc. All rights reserved.
Quantitative imaging
High-field magnetic resonance imaging

1. Introduction
Neurodegenerative diseases can be defined as a group of diseases
that are characterized mainly by their slowly progressive selective loss
of neurons for unknown reasons [e.g. cerebral cortical neurons in
Alzheimer's disease (AD) and substantia nigra (SN) neurons in
Parkinson's disease (PD)]. The etiology of neurodegenerative diseases
is still ambiguous [1–3]. Recent studies suggest that genetics, environ-
mental factors, oxidative stress, and aging seem to be the most common
causes of neurodegenerative diseases [1,4–10]. However, the mecha-
nisms of neuronal death in neurodegenerative diseases are still mysteri-
ous. Apoptosis due to oxidative stress, disturbed calcium homeostasis,
mitochondrial dysfunction, and stimulation of cysteine proteases has
recently been implicated as a possible mechanism for neuronal death
in neurodegenerative diseases [4,5].
PD is the second most common neurodegenerative disease after
Alzheimer's [11,12] and the most common motor neurodegenerative
disease in old age. Its prevalence is about 0.5–1% in patients who are
65–69 years old and increases to about 1–3% in patients with age over
80 years [11]. Furthermore, the incidence of PD in men tends to be
higher than in women [13]. The mean duration of PD is about 9.4
years with a mortality rate of 2.9 times that of age-matched healthy
☆ Conflict of Interest: The authors have no conflicts of interest to declare
⁎ Corresponding author. Department of Medical Imaging, Faculty of Allied Health Sci-
ences, The Hashemite University, Zarqa, Jordan. Tel.: + 962-5-3903333x5422;
fax: +962-5-3903368.
E-mail addresses: Ali.Radaideh@hu.edu.jo, aliradaideh@yahoo.com (A.M. Al-Radaideh).
counterparts and this mortality rate was found to be higher in women
than in men [14]. Patients fulfill the clinical criteria for PD when approx-
imately 60–70% of nigrostriatal neurons are degenerated and 80% of the
striatal dopamine content is reduced [15].
Etiologically, PD can be classified into a primary or idiopathic
Parkinson's [16], secondary parkinsonism [17], hereditary or familial
Parkinson's [18], or Parkinson's associated with other syndromes or
multiple system degenerations. The latter is best known as parkinson-
ism plus syndrome [17].
Although PD is regarded as a motor syndrome, it causes several
nonmotor symptoms. Clinically, the main four motor signs are tremor,
rigidity, akinesia (bradykinesia), and postural instability [19]. Nonmotor
symptoms (neuropsychiatric symptoms) involve abnormalities in
mood, speech, cognition, behavior, and thinking [20]. Most PD patients
become demented during the course of the disease [20,21]. While de-
mentia with Lewy bodies (LBs) is best diagnosed when dementia symp-
toms appear before or at the same time as Parkinson's symptoms,
Parkinson's disease dementia is diagnosed if initial motor signs precede
cognitive symptoms by at least a year [22]. Furthermore, 60–90% of PD
patients complain of sleep disturbance [20,23]. Other autonomic dys-
functions include urinary bladder incontinence [24], sweating disorder
[19], dysphagia, and constipation [19,23].
Cell death of dopaminergic neurons in the SN (especially in its pars
compacta) is considered the main cause of motor and nonmotor symp-
toms of PD [20,25]. As a result, about 80% of neurons die [26] and LBs
start to accumulate [20,25]. The latter is the histopathological hallmark
of PD. LBs are composed mainly of α-synuclein protein that is associated
with other proteins such as ubiquitin, proteasome, and heat shock

http://dx.doi.org/10.1016/j.clinimag.2016.05.006
0899-7071/© 2016 Elsevier Inc. All rights reserved.
988 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996
proteins [20,25]. All these proteins enhance and activate neural cell death
and lead to the destruction of other proteins in neurons [20]. The forma-
tion of LBs in neural cells and thus losing the activity of ubiquitin-
proteasome system, which promotes the aggregation of α-synuclein, is
still one of the most acceptable possible cause of PD [20,25]. However, ac-
cumulation of LBs may also occur in elderly people and in other neurode-
generative diseases such as dementia with LBs and AD [25,26].
Different structural and functional neuroimaging methods play a great
role in the early diagnosis of neurodegenerative diseases that aid in con-
trolling the progression of the disease and assist the initiation of
disease-modifying therapy [27,28], thus improving the quality of patient's
life. Nowadays, structural and functional neuroimaging techniques in vivo
are extensively used in clinical diagnosis and research of neurodegenera-
tive diseases. Among these neuroimaging techniques are the structural
and quantitative magnetic resonance imaging (MRI), single-photon emis-
sion computed tomography (SPECT) and 18F-fluorodeoxyglucose-posi-
tron emission tomography ( 18F-FDG-PET) and more recently the
positron emission tomography-computed tomography (PET-CT) [29].
MRI is a noninvasive diagnostic tool that provides clinicians and re-
searchers with structural and functional information of the human
brain. The signal-to-noise ratio (SNR) in MRI increases strongly with
the magnetic field strength, and this extra SNR can be invested in ac-
quiring high-resolution images with better SNR. The magnetic reso-
nance (MR) image contrast in the brain depends on regional
differences in tissue water density (proton density) as well as on the tis-
sue relaxation times. Differences in the longitudinal (T1), transverse
(T2) relaxation time, and pseudorelaxation (T2*) values readily allow
differentiation of tissues such as gray matter and white matter in vivo.
This article will shed light on the role of both structural and quanti-
tative MRI techniques in the early diagnosis and management of PD and
excluding other mimicking diseases that cause similar clinical symp-
toms to those in PD. Furthermore, the role of high and ultrahigh MRI
in understanding the nature and progression of PD is also discussed in
the present review.
2. MRI of PD
Although brain imaging of dopaminergic dysfunction using both PET
and SPECT is currently the most frequently used biomarker to properly
diagnose PD, advanced quantitative MRI techniques have shown prom-
ise for detecting pathological changes in the SN and cortex in preclinical
patients or patients at risk of developing PD, in addition to monitoring
disease progression. Among these advanced quantitative techniques
are iron load estimation, magnetization transfer (MT) imaging, diffusion
and diffusion tensor imaging (DTI), MR spectroscopy (MRS), and
resting-state functional MRI (fMRI).
2.1. Structural MRI
Conventional MRI techniques have been used to segment the SN and
track any possible volumetric changes inside it. However, the
Fig. 1. Structural imaging of the SN. Axial 3D T1-weighted (A), T2-weighted (B), and neuromelanin sensitive (C, D) images showing the SN (arrow). Reprinted from Ref. [152] with per-
mission from John Wiley and Sons.
segmentation of the SN, particularly its pars compacta, represents a chal-
lenge for the development of effective and accurate morphological tools
due to the difficulty in visualizing its borders (Fig. 1). So, numerous efforts
have been made to develop new MR pulse sequences that are capable of
delineating the borders of the SNc. Drayer and colleagues were able to vi-
sualize the SNc depending on the iron distribution in the whole SN using
T2-weighted images [30]. In another study by Oikawa and colleagues, the
SNc and SNr were clearly visualized and delineated using combined PD-
weighted and short inversion time recovery images [31]. Different studies
adopted new MRI methods to visualize and segment the SNc as well as
the SNr [32–36]. Some of these new methods were sensitive to
neuromelanin [32]; others were based on an evaluation of T2 relaxation
times [33] while the remaining were based on using segmented inversion
recovery imaging [34–36]. Furthermore, Ziegier and others described a
new multispectral MRI method for visualizing the SNc [37]. They were
able to generate multiple weighted averages of four MRI sequences
[multiecho T1-weighted MPRAGE, multiecho PD-weighted fast low-
angle shot images, 3D T2-SPACE turbo spin echo, and 3D T2-SPACE
fluid-attenuated inversion recovery (FLAIR) turbo spin echo], each with
a unique contrast tailored to a specific group of subcortical structures
[37]. In this study, the authors claimed that their new multispectral MRI
method was able to delineate the SNc in a large cohort of PD patients
and found a significant decrease in the SNc volume in the early stages of
PD [37].
Voxel-based morphometry findings derived from structural scans in
PD were inconsistent and unconvincing. A study by Tessa and colleagues
found no differences in total brain gray and white matter volumes be-
tween controls and de novo PD (newly diagnosed patients with PD or pa-
tients not receiving L-dopa therapy) [38]. Another study by Lee et al.
found that early-stage PD without dementia is associated with volume re-
duction of subcortical gray matter but no significant cortical gray matter
changes were reported [39]. On the contrary, Jia and colleagues reported
an increase in gray matter volume of the orbitofrontal gyrus, occipital cor-
tex, limbic/paralimbic, and globus pallidus internus/putamen areas and a
decrease in the gray matter volume of the frontotemporoparietal network
and the bilateral caudate areas in PD brains when compared to those of
healthy controls [40]. Furthermore, a combined T1-weighted MR scan-
ning and neuropsychological assessment found a reduction in the cortical
volume of the posterior parietal lobe that might have a potential role in
developing freezing of gait (FOG) in PD [41]. In addition, structures of
the basal forebrain (BF) have been studied using T1-weighted [42] and
T2-weighted FLAIR images [37]. These studies revealed a significant de-
crease in the volume of the BF, mainly in demented PD patients, com-
pared to healthy controls and such volume reduction was found to
occur at late stages of PD [37,42].
Measuring the width of the middle cerebellar peduncle (MCP) using
MRI was also suggested as a valuable tool for differential diagnosis of PD
and multiple system atrophy although disease duration has contributed
to the heterogeneity of PD [43–46]. The width of MCP was found to neg-
atively correlate with PD (with tremor onset), which revealed a pro-
gressive impairment of the cerebellar and dopaminergic system [47].
 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996
2.2. Iron imaging
Brain iron concentration increases with age until the end of the sec-
ond decade at different rates in different brain regions [48]. There are
two main types of iron in the brain: heme and nonheme iron with the
latter being protein bound. The two most important nonheme com-
pounds in the brain are transferrin (used for iron transport) and ferritin
(used for iron storage) and these compounds are found in the brain in
concentrations that can be detected by MRI [49].
In healthy subjects, about 80% of the SN iron is stored as soluble fer-
ritin and insoluble hemosiderin [50] whereas the remaining 20% of the
iron is bound as neuromelanin in its ferric form [51]. In normal aging
or in PD, the SN, particularly its pars compacta, shows a decrease in
neuromelanin, loss of pigmented dopaminergic neurons [52], increase
in ferritin [53] mainly in the dopaminergic neurons [54], and increase
in iron in the forms of Fe (II) and Fe (III) [55] causing free radical forma-
tion and lipid peroxidation [56]. So, most attempts to study PD with MRI
have been based on the changes in iron homeostasis in the SN in PD.
Iron accumulation increases the transverse relaxation rate R2 due to
dipole–dipole interactions and diffusion in the increased field inhomo-
geneities and R2* due to static dephasing in the inhomogeneous field.
Increased R2 has been observed in the pars compacta of the SN of PD pa-
tients [33,57–59]. However, both R2 and R2* are also affected by other
factors such as tissue water content and water binding, complicating
the relationship between R2 and iron deposition in diseases such as
PD [60–63].
The change in the magnetic susceptibility of a tissue due to iron ac-
cumulation causes field shifts that can be detected on phase images.
These are more directly related to iron concentration than relaxation
times. Susceptibility-weighted imaging (SWI) combines T2* and phase
information, increasing the sensitivity to iron [64] as shown in Figs. 2
and 3. However, phase and susceptibility-weighted images are both
distorted by a nonlocal relationship between the underlying susceptibil-
ity distribution and the resulting field perturbation that gives rise to the
phase shifts [65–67]. Recently, quantitative susceptibility mapping
(QSM) techniques have been developed, which correct this nonlocal re-
lationship [65–70]. The magnetic susceptibility perturbations caused by
iron deposition in some structures such as the SN, red nucleus, globus
pallidus, putamen, caudate nucleus, pulvinar nucleus in multiple sclero-
sis, and PDs result in field shifts that scale with magnetic field strength,
making high and ultrahigh field MRI particularly sensitive for suscepti-
bility mapping in such diseases [71–73]. QSM may provide an indirect
marker of neuronal loss and its spatial pattern in the SN and a more
Fig. 2. High-resolution SWI acquired at 7 T MRI. Coronal view shows a clear delineation be-
tween the subthalamic nucleus (higher arrow) and the SN (lower arrow) of PD patient.
Image courtesy of Dr. Noam Harel, University of Minnesota.
989
direct measure of iron content and distribution in the SN than relaxation
times or phase maps [74].
Several 3 T and 7 T studies have shown that the detection of the ab-
normality of nigrosome 1 (the largest subregion of SN pars compacta)
can serve as a surrogate biomarker for the diagnosis of idiopathic
Parkinson's disease (IPD) [75–80]. The unilaterality of IPD was found
to correspond to neuronal nigrostriatal degeneration in the contralater-
al hemisphere. Furthermore, iron deposition, loss of neuromelanin-
containing cells, change in iron oxidation state, or a combination of
these effects were also reported to cause MRI hypointensity feature in
nigrosome 1 of the PD brains [77].
2.3. MT ratio (MTR)
MT is a novel way of generating a new contrast in MR images that re-
flects partly the tissue integrity as well as macromolecular density
found in tissue membranes, myelin, and organelles [81]. The contrast
between gray and white matter is increased in the basal ganglia and
brain stem following the application of MT presaturation pulse. So, seg-
mentation of deep-brain gray matter structures has also been improved
using the MT maps [82]. Furthermore, different studies have shown that
MTRs were reduced in specific brain areas, namely SN, red nucleus,
pons, globus pallidus, and periventricular white matter of the PD brains,
even in the early stages of the PD [83–85]. Fig. 4 shows an example of
MTR values in the left superior and right middle temporal gyri of PD
and healthy controls. A study by Tambasco and colleagues [83] revealed
that abnormalities in advanced PD involved the SNc, SNr, pons, puta-
men, lateral thalamus, and supratentorial white matter (frontal, parie-
tal, and periventricular white matter). Their results indicated a more
diffused MTR abnormalities in advanced PD compared to those in
early stages of the disease. A differential involvement of basal ganglia
nuclei in mild versus advanced PD was also observed; while the caudate
nucleus and lateral thalamus showed abnormal MTR values in advanced
PD, putamen only showed MTR abnormalities in mild PD.
Periventricular white matter involvement in PD without and with de-
mentia was also reported in other studies [86,87].
2.4. DTI
Diffusion is a physical process that involves the translational move-
ment of water molecules via thermally driven random motion, the so-
called Brownian motion [88]. The range of water's diffusion in tissues
is about 10–15 μm over a diffusion's time of 50–100 ms. Diffusion is a
3D process and can be isotropic (where there is no preferable direction
for the diffusion) or anisotropic (one preferable direction) [89].
Signal intensity on diffusion-weighted imaging (DWI) images is in-
versely proportional to the amount of diffusion, which is known as the
apparent diffusion coefficient (ADC) such that tissues with higher ADC
appear hypointense on diffusion-weighted images. DWI of the brain re-
flects the integrity of motor tracts (white matter) by estimating the
mean diffusivity (MD) [90,91]. The degree of tissue organization is in-
versely proportional to the MD. Furthermore, the directionality of fibers
is best measured by a technique known as DTI that maps the diffusion at
each spatial location using a 3×3 tensor. Fractional anisotropy (FA) is
one of the indices that can be derived from the DTI indicating the
amount of deviation from isotropicity of fibers where the FA values
range from 0 (isotropic diffusion) to 1 (anisotropic diffusion).
In the SN of PD, a reduction in FA values was found to be the most
common finding in many studies [92–96] indicating a change in anisot-
ropy property of SN tissue (Fig. 5). Surprisingly, the reduction in FA
values in the SN was inversely correlated with the severity of the clinical
status of PD patients [92,97]. However, MD values did not correlate with
any changes in the SN of PD patients [98,99].
Diffusion measures in other parts of the brain of PD patients did not
show consistent changes in diffusion measures. Some studies found that
most diffusion measures in the striatum are normal [100,101]. However,
990 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996

Fig. 3. Utility of SWI in detecting the increase in mineralization in red nucleus. It appears as an increase in hypointensity grades (0, 1, 2, 3) (indicated by the black arrows). Reprinted from
Ref. [153] with permission from Springer.

other studies reported an increase in the MD in the striatum and the
thalamus in PD [94,97]. These studies indicated overlapped and conflict
findings urging further investigations to understand the mechanism un-
derlying any changes in diffusion measures.
Tract-based spatial statistics methods have been used to compare
changes in the white matter between PD with or without freezing gait
(FOG). They showed that FOG was associated with extensive white matter
damage that extended to the intrahemispheric corticocortical, motor-
related corticofugal, and several basal ganglia white matter tracts projecting
to motor, sensory, and cognitive frontal regions in the brain [102].
2.5. MRS
While proton magnetic resonance spectroscopy ( 1H-MRS) provides
information about the levels of metabolites in the brain, phosphorus
magnetic resonance spectroscopy (13P-MRS) allows direct monitoring
of the energy metabolism in the brain [103]. Metabolites that are evalu-
ated in PD using the 1H-MRS include N-acetylaspartate (NAA; marker of
neuronal injury or loss), creatine (Cr; marker of energy metabolism),
choline-containing compound (Cho; marker of demyelination and cell
proliferation), myoinositol (mIns; marker for osmotic stress or
astrogliosis), lactate (a metabolic product of glycolysis and elevations
can indicate transient changes in physiological state), and glutathione
(GSH) as well as neurotransmitters such as glutamate/glutamine
[90,104].
Previous MRS studies showed inconsistent results that could be due
to the heterogeneity in the number of scanned PD patients, the MRS
techniques that have been used to locate and process the metabolite sig-
nals, the estimation method of metabolite concentrations, in addition to
the imaging pulse sequence factors, and the use of different magnetic
field strengths in these studies. Compared to healthy controls, MRS
studies, which were performed at 1.5 T, showed a reduction of NAA/
Cho ratios in the lentiform nucleus [105], NAA/Cr ratios in the left symp-
tomatic side of SN [106], NAA/Cr and Cho/Cr ratios in the
temporoparietal cortex [107], NAA/Cr ratios in the temporoparietal cor-
tex [108], NAA/Cr ratios in the motor cortex [109], NAA/Cr ratios in the
posterior cingulated cortex [110], and NAA/Cr ratios in the
presupplementary motor area [111] and an increase of total Cr in the
prefrontal cortex of PD [112]. Furthermore, 3 T MRS studies pointed
out a reduction of NAA/Cr and mI/Cr in the rostral SN regions and an in-
crease of NAA/Cr and mI/Cr in the caudal SN regions (Figs. 6 and 7)
[113], a reduction of NAA/Cr and Cho/Cr ratios in bilateral temporal
gray matter and an increase of total Cr in the right temporal gray matter
[114], and a reduction of Glu/Cr ratios in the posterior cingulated gyrus
of PD compared to healthy controls [115]. G. Oz and colleagues [116]
conducted an MRS study at 4 T and reported that the levels of Glu,
NAA, and glutathione were lower in the SN of PD compared to healthy
controls. On the contrary, the study showed an increase in the level of
Cho in the SN of PD. Furthermore, a higher GABA/Glu ratio in the SN
than in the cerebral cortex was also reported in the same study. Another
study was conducted at ultrahigh (7 T) magnetic field showed an in-
creased GABA level in the pons and putamen of PD brains [117].
MRS at high and ultrahigh magnetic field benefits from the increased
SNR and excellent spectral separation. The latter would result in a

Fig. 4. MTR values in the left superior temporal gyrus of PD patients were lower than those of controls (blue). However, the right middle temporal gyrus of PD showed lower MTR values
than that of controls (red). Reprinted from Ref. [154] with permission from European Society of Radiology.
 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996 991

Fig. 5. Reduced FA (Pb.01) in the SN, posterior striatum, and frontal white matter and along projection fibers to the supplementary motor areas (SMA) in PD compared to normal controls.
The reduction is illustrated as blue clusters, superimposed on the mean FA map in normalized space. Reprinted from Ref. [155] with permission from the International Society for Magnetic
Resonance in Medicine.

significant increase in the number of detectable metabolites with high
spatial specificity [118]. However, the MRS is highly sensitive to magnetic
field homogeneity and lipid artifact signals, especially in regions that are
close to the skull. So, MRS of the SN is very challenging in human due to
its location, small size, and high iron content. Technical and methodolog-
ical improvements of MRS could provide insight into biochemical abnor-
malities or changes related to pathological conditions.
2.6. fMRI
fMRI studies investigated the activity and connectivity of the senso-
rimotor areas (SMAs) using task-related and “resting-state” fMRI analy-
sis, respectively, in patients with PD to understand the potential
pathophysiological mechanisms underlying motor complications in
the advanced stage of PD.
Most task-related fMRI studies have consistently shown abnormal
activation in different areas of the motor networks in patients with
early- and late-stage PD. Abnormal task-related fMRI findings included
hypoactivation in the SMA and hyperactivation in the cerebellum and
other cortical motor regions such as premotor, primary motor, and pa-
rietal cortices compared to age-matched healthy controls [119–121].
In addition, motor task-induced hyperactivations of contralateral SMA,
primary sensorimotor, and premotor areas were also seen in PD pa-
tients receiving dopaminergic therapy when compared to age-
matched healthy controls as it can be seen in Fig. 8 [119].
The hypoactivation in SMA was related to the lack of readiness and
the difficulty in initiating voluntary movements in patients with PD as
this area is responsible for the initiation of learned motor sequences
[122–124]. The hyperactivity in corticocerebellar regions may reflect
some kind of functional compensation for the defective motor control
in basal ganglia [125].
Functional changes revealed by task-related fMRI studies may be
confounded by the fact that patients with PD have difficulty performing
motor tasks urging the use of resting-state fMRI approach to overcom-
ing this problem that provides an index of connectivity across the
whole brain. Resting-state fMRI provides a noninvasive method that fo-
cuses on a low-frequency (b0.08–0.1 Hz) spontaneous fluctuations in
the blood oxygenation level-dependent signal that occurs when an indi-
vidual is at rest. A number of studies have applied resting-state fMRI
technique to investigate SMA network connectivity in patients with
PD [126–133] and commonly demonstrated a disrupted functional inte-
gration in corticostriatal loops with greater PD-related connectivity
changes in networks linked to the preparation and initiation rather
than in those involved in the motor execution.
2.7. PET-MRI
PET is a nuclear imaging technique, which allows in vivo estimations
of important physiological parameters such as presynaptic dopamine ter-
minal function, postsynaptic dopamine receptor binding, and glucose me-
tabolism, enabling better understanding of the pathophysiology of
different neurological diseases such as PD and AD [134]. Although the
PET method is highly sensitive for biomarkers in vivo at the molecular
level, it is unable to provide accurate anatomical information. So, early at-
tempts were focused on combining the PET modality with the CT in one
scanner (PET-CT) in order to provide a complimentary functional and an-
atomical data and to correct for PET data attenuation. PET-CT has been
successfully applied in clinics for decades and the reported results were
found to be superior to those obtained using PET or CT alone. However,
CT involves using ionizing radiation and produces soft tissues images
with lower spatial resolution than that of MRI [135]. The newly emerging
hybrid PET-MRI provides anatomical, functional, biochemical, and

Fig. 6. 1H-MRS of the rostral (left) and caudal (right) voxels in the SN as well as in the midbrain tegmentum areas. Reprinted from Ref. [113] with permission from Springer.
992 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996

Fig. 7. 1H-MRS spectra in the rostral and caudal regions of the SN of a healthy control and a patient with PD acquired from 0.252 ml volumes. NAA, N-acetylaspartate; Cr, creatine; Cho,
choline; Ins, myoinositol. Reprinted from Ref. [113] with permission from Springer.

Fig. 8. fMRI with motor task (Siemens Allegra, 3.0 T). Hyperactivation of contralateral SMA, primary sensorimotor and premotor areas in a PD patient receiving dopaminergic therapy com-
pared with a control subject. Reprinted from Ref. [156] with permission from Springer.
 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996 993

Fig. 9. Two brain PET-MRI cases (A and B) with different parkinsonian syndromes. The left column shows separate dopamine transporter SPECT that revealed striatal deficits (red circles) in
both cases. The middle column shows a T2 FLAIR MRI as part of combined PET-MRI scan. The MRI scan revealed atrophy (red circles) only in case A but not in case B. In accordance with the
MRI, [18F]FDG-PET imaging (right column) of combined PET-MRI revealed striatal and thalamic glucose consumption deficits (red circles) only in case A. A differential diagnosis was made
by using multimodal brain imaging, such that patient A was diagnosed with atypical parkinsonian syndrome (progressive supranuclear palsy), whereas patient B was diagnosed with PD.
Reprinted from Ref. [136] with permission from Elsevier.

metabolic information, even at the molecular level, and it helps in both di-
agnosis and treatment of CNS diseases [135–138]. Different groups from
the University of California at Davis and King's College London
[139–141], the University of Tubingen [142,143], and the University of
Cambridge [144] were the first to explore the different approaches to in-
tegrate PET and MRI scanners and publish their results in mid to late
1990s. However, continuous efforts are still in progress to improve the
performance of the PET-MRI technology. Simultaneous PET-MRI data ac-
quisition improves the spatial as well as the temporal correlation between
signals from both imaging modalities. The most common neurological ap-
plications of PET-MRI are epileptogenic zone assessment in patients re-
fractory to drug therapy, identification of patients with cognitive
impairment who are at high risk of developing dementia, in addition to
differentiation of dementias and parkinsonian syndromes [145].
Despite the fact that SPECT is now regarded the first nuclear imaging
line for the diagnosis of PD, novel PET tracers such as those that bind to
β-amyloid, tau protein, or α-synuclein aggregates, in addition to the de-
velopment of new MR pulse sequences such as DTI, spectroscopy,
resting-state fMRI, and arterial spin labeling, might change this situation
in the future, making the PET and PET-MRI the first imaging choice and
increasing their diagnostic value of PD [136]. The use of PET-MRI as an
integrated imaging modality benefits from the exceptionally high MR
image contrast and molecular information in PET images [146] and,
thus, offers far more potential than just tracking biomarkers and
displaying anatomy. Furthermore, PET-MRI can provide a full image of
the morphological changes of dopaminergic neurons in the PD brains.
Furthermore, PET-MRI coregistration can be used in clinical differentia-
tion between parkinsonian syndromes, such as PD, progressive
supranuclear palsy, multiple system atrophy, and corticobasal degener-
ation as shown in Fig. 9 [145]. In a retrospective analysis study by Struck
and colleagues, PET-MRI was found to improve the diagnostic accuracy
of the calculation process of ROI-derived standard uptake value of
FDOPA in PD brains compared to PET measurements alone [147].
Thus, PET-MRI fusion might better predict pathology by improving the
accuracy of ROI placement.
On the other hand, PET-MRI possesses some limitations. In addition
to its relatively long scanning time and high cost [142], attenuation cor-
rection in PET-MRI is not yet optimized. It is rather based on using a
2-point Dixon MR sequence that segments tissues into four classes
(lung, air, fat, and soft tissue) [148,149] and an ultrashort echo time se-
quence that provides additional bone segmentation [150]. Moreover,
developments of new PET tracers must be performed with careful as-
sessment of their safety because static and radiofrequency fields are
likely to increase the genotoxicity of ionizing radiation [151]. Further
improvement of the PET detectors system and MRI pulse sequences
with higher temporal as well as spatial resolution would also enhance
the performance of PET-MRI and thus reduce the motion and respirato-
ry artifacts.
3. Conclusions
Although structural MRI techniques are still the first imaging line for
most neurological diseases, quantitative MRI approaches have emerged
recently as a new way to study the pathological changes in neurodegen-
erative diseases owing to their ability to detect different subtle changes
directly or indirectly by tracking some biomarkers specific to these
diseases.
MRI offers a wide range of image contrasts and high spatial resolu-
tion that make it useful for a multitude of clinical applications. MRI is
a safe, noninvasive imaging modality and does not involve any ionizing
radiations. Furthermore, the advent of high and ultrahigh magnetic
fields improved the SNR and thus allowed image acquisitions with
higher spatial resolution and better sensitivity to subtle changes in tis-
sues. Advanced quantitative MRI techniques helped the researchers
and clinicians in further investigation of the PD process and allowed
them to perform different postprocessing techniques with high specific-
ity and accuracy. The latter aided in extracting some morphological and
functional features specific to PD. However, these techniques need to be
standardized and further validated in larger cohorts of subjects in longi-
tudinal studies. It is expected that new and larger studies will improve
994 A.M. Al-Radaideh, E.M. Rababah / Clinical Imaging 40 (2016) 987–996
these techniques in this respect and widen our understanding of the na-
ture of PD and improve its diagnosis that will allow better monitoring of
its progression.
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