Professional Documents
Culture Documents
REVIEW
ARTICLE
596
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
IMAGING NIGRAL STRUCTURAL CHANGES
MRI
FIGURE 1.
IMAGING APPROACHES
TO
PD imaging algorithm.
597
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
T2-weighted sequences are influenced by local increases
in magnetic susceptibility when raised iron content is present
in brain areas. With such an approach, Michaeli et al. (9)
have been able to detect increased nigral magnetic susceptibility in PD. Again, however, midbrain relaxation times
overlapped considerably with those of a healthy group.
A potential advance involves the use of diffusion tensor
imaging to determine regional fractional anisotropy within
the nigra. In a recent study, fractional anisotropy in the
substantia nigra was measured in 14 de novo PD patients
and 14 healthy volunteers matched for age and sex (10).
Nigral fractional anisotropy values were reduced in all PD
patients, compared with the control group (Fig. 2A). The
greatest difference between the 2 groups was observed in
the caudal part of the substantia nigra. These findings are in
agreement with postmortem studies, which show greater
cell loss in the ventrocaudal nigra than in the rostral
segment of this structure. PD patients were distinguished
with 100% sensitivity and specificity from the healthy
volunteers on the basis of their fractional anisotropy value
in the caudal nigra. If confirmed in larger cohorts of PD
patients, these findings suggest that diffusion tensor imaging could be valuable for supporting a diagnosis of PD.
Transcranial Sonography
FIGURE 2. (A) Images of fractional anisotropy of midbrain. Nigral fractional anisotropy is reduced in rostral caudal gradient in
PD. (Reprinted with permission of (126).) (B) Transcranial sonography showing hyperechogenicity from lateral midbrain
(substantia nigra) in PD. (Reprinted with permission of (11).)
598
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
IMAGING STRUCTURAL CHANGE IN ATYPICAL PD
fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)tropane
(123I-FP-CIT) (DaTSCAN; GE Healthcare), 123I-altropane,
and 11C-2-carbomethoxy-3-(4-18F-fluorophenyl)tropane
(11C-CFT). Second, 18F-3,4-dihydroxyphenylalanine (18F-dopa)
PET provides a marker of terminal dopa decarboxylase
activity and dopamine turnover. Third, vesicle monoamine
transporter availability in dopamine terminals can be examined with either 11C- or 18F-dihydrotetrabenazine PET.
Early hemiparkinsonian patients show bilaterally reduced
putamen dopaminergic terminal function, activity being
more depressed in the posterior putamen contralateral to the
affected limbs (Fig. 4) (28,29). Head-of-caudate and ventral
striatal function is relatively preserved. Clinical parkinsonism occurs when PD patients have lost 40%50%
of posterior putamen dopamine terminal function (30,31).
Levels of putamen 18F-dopa uptake and DAT binding
correlate inversely with bradykinesia and rigidity of PD
patients, but interestingly, not with tremor severity (3234).
This suggests that parkinsonian tremor is not a direct
consequence of nigrostriatal degeneration.
Not all dopamine fibers are damaged in early PDsome
increase their dopamine turnover as an adaptive mechanism. At the onset of rigidity and bradykinesia, globus
pallidus interna 18F-dopa uptake is increased by up to 50%
(35). As the disease advances, pallidal 18F-dopa storage
then falls, eventually becoming subnormal. Disability is
then severe and treatment complications develop. This
observation suggests that both the putamen and the globus
pallidus interna require an intact dopaminergic input from
the nigra if limb movements are to be fluent and efficient,
and it is when both sets of projections are damaged that the
honeymoon period in PD reaches an end.
When clinically probable PD and essential tremor
patients have been compared, striatal DAT imaging with
123I-FP-CIT SPECT has been shown to differentiate these
conditions with a sensitivity and specificity of over 90%
(36). Several studies have examined the role of DAT
imaging for determining whether gray parkinsonian cases
are associated with striatal dopamine deficiency. In the
Query PD study, the standard of truth was the clinical
impression of 2 movement disorder experts after 6 mo of
clinical follow-up (37). Although referring clinicians
showed 92% sensitivity for diagnosing dopamine-deficient
parkinsonism, their baseline clinical specificity was poor
IMAGING APPROACHES
TO
599
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
600
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
them showed any clinical progression of their disorder. This
finding reinforces the viewpoint that normal dopaminergic
imaging excludes the presence of a degenerative parkinsonian syndrome.
FUNCTIONAL IMAGING AND ATYPICAL PD
FIGURE 5. 18F-FDG PET images of PD and multiplesystem atrophy patient. Multiple-system atrophy patient
shows significant striatal reduction of glucose metabolism.
MSA 5 multiple-system atrophy.
IMAGING APPROACHES
TO
601
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
Increased midbrain echogenicity has been reported in 5
of 7 asymptomatic parkin gene carriers (14) and 11 of 30
idiopathic hyposmic patients (66). Three of the 5 parkin
carriers with abnormal transcranial sonography findings
showed reduced striatal 18F-dopa uptake, whereas 5 of the
11 hyposmic patients had reduced striatal FP-CIT binding.
Midbrain hyperechogenicity detected by ultrasound in atrisk subjects, therefore, is associated with dopamine cell
dysfunction in around half of the subjects. A study from
2006 reported no correlation between levels of midbrain
hyperechogenicity in PD and reductions in striatal DAT
binding measured with 99mTRODAT SPECT. This finding
again suggests that transcranial sonography is detecting
nondopaminergic pathology present in PD such as midbrain
iron deposition (67).
MECHANISMS UNDERLYING FLUCTUATIONS
AND DYSKINESIAS
602
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
with the severity of dyskinesia. These findings are compatible with the presence of raised basal ganglia levels of
enkephalin and dynorphin in these dyskinetic PD patients.
18F-SPARQ PET is a selective marker of neurokinin 1 site
availability. In a preliminary study, thalamic neurokinin 1
availability has been shown to be reduced in dyskinetic PD
patients but normal in nondyskinetic patients (79). These in
vivo PET findings support the abnormal presence of
elevated levels of endogenous peptides in the basal ganglia
of dyskinetic PD patients.
IMAGING THE PHARMACOLOGY OF DEPRESSION
IN PD
noradrenergic and limbic dopaminergic innervation additional to the striatal dopamine deficiency present. The use
of nonselective inhibitors of monoamine transporters boosting synaptic levels of dopamine and noradrenaline would,
therefore, seem a rational approach for treating depression
in PD rather than the use of selective serotonin reuptake
inhibitors.
TREATMENT-RELATED IMPULSE
CONTROL DISORDERS
When PD patients are exposed to dopaminergic medicationparticularly agonistsa small minority develop
impulse control disorders such as pathologic gambling
and hypersexuality in the absence of any previous history.
Impulse control disorders can devastate the quality of life
of PD patients and their families; affected patients have
gambled away their life savings before the problem has
come to light. The mechanisms underlying the development
of these behavioral disturbances in PD are currently under
extensive investigation.
Using 99mTc-ethylcysteinate dimer bicisate SPECT,
a marker of regional cerebral blood flow, it has been
reported that PD patients with pathologic gambling show
resting overactivity of a right hemisphere network involved
in reward processing that includes the orbitofrontal cortex,
hippocampus, amygdala, insula, and ventral pallidum (86).
PD patients with pathologic gambling have also been
studied with 11C-raclopride PET during performance of
a gambling task. The pathologic gamblers demonstrated
greater decreases in ventral striatum D2 binding during
gambling (13.9%) than control patients (8.1%), providing
supportive evidence that excessive limbic dopaminergic
stimulation underlies the neurobiology of impulse control
disorders in PD (87).
MECHANISMS UNDERLYING DEMENTIA IN PD
IMAGING APPROACHES
TO
603
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
clinical volume loss in these areas can also be detected in
nondemented PD patients. As PDD progresses, a further
volume loss occurs from cortical association areas (91). The
boundary-shift integral approach applied to volumetric MRI
allows whole-brain volume changes to be quantitated. With
this approach, Burton et al. computed a 0.31% annual loss of
brain volume in PD (similar to healthy elderly individuals),
whereas in PDD the annual loss was 1.12%, approaching the
2% reported for Alzheimer disease (92). These workers
concluded that MRI may provide a useful tool for following
progression of PD with dementia.
Metabolic Imaging
Dopaminergic Imaging
604
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
is selectively targeted resulting in a caudateputamen
gradient of DAT binding loss, patients with DLB and
PDD showed a more uniform striatal reduction in 123IFP-CIT binding, with a reduced caudateputamen gradient.
There was a significant correlation between the Mini
Mental State Examination scores and 123I-FP-CIT binding
in PDD, supporting the hypothesis that striatal dopaminergic loss contributes to the cognitive impairment of these
patients.
The role of mesofrontal dopaminergic projections in PD
with dementia has been investigated with 18F-dopa PET
using statistical parametric mapping to localize significant
reductions in dopamine storage capacity at a voxel level.
When PD patients with and without dementia were
matched for age, disease duration, and disease severity,
interrogation of their 18F-dopa uptake images with statistical parametric mapping localized a reduced capacity for
putamen dopamine storage in both groups. However,
compared with the PD patients, the PDD patients showed
additional reductions in 18F-dopa uptake in the right
caudate and bilaterally in the ventral striatum and the
anterior cingulate (102). These findings support the concept
that dementia in PD is associated with impaired frontal and
caudate dopaminergic function. Reduced frontal 18F-dopa
uptake has been previously reported in PD patients who
showed impaired performance on tests of verbal fluency,
verbal recall, and digit span (103).
Cholinergic Function
123I-iodobenzovesamicol
IMAGING APPROACHES
TO
605
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
be detected, and this has been reported to correlate inversely with levels of posterior putamen 11C-CFT uptake,
a PET marker of DAT binding (119). Increased 11CPK11195 uptake has also been reported in the medulla
and pons, striatum, pallidum, and frontal cortex in PD
(120), in line with the known distribution of Lewy body
pathology (Fig. 8) (121). Over a 2-y follow-up period, little
change in the level of microglial activation was seen in PD
although all patients deteriorated clinically. This observation could imply that microglial activation is merely an
epiphenomenon in PD; however, postmortem studies have
shown that these cells continue to express cytokine messenger RNA, suggesting that they could be driving disease
progression while their population remains static.
IMAGING CARDIAC SYMPATHETIC DENERVATION
IN PD
606
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
Extensive microglial activation can be detected in PD
with the translocator protein marker 11C-PK11195 PET,
providing a rationale for exploring the use of antiinflammatory agents as potential neuroprotectants.
24.
25.
REFERENCES
26.
1. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of
Lewy body Parkinsons disease. Neurology. 2001;57:14971499.
2. Schneider SA, Edwards MJ, Mir P, et al. Patients with adult-onset dystonic
tremor resembling parkinsonian tremor have scans without evidence of
dopaminergic deficit (SWEDDs). Mov Disord. 2007;22:22102215.
3. Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial.
Arch Neurol. 1999;56:529535.
4. Whone AL, Watts RL, Stoessl J, et al. Slower progression of PD with ropinirole
versus L-dopa: the REAL-PET study. Ann Neurol. 2003;54:93101.
5. Geng DY, Li YX, Zee CS. Magnetic resonance imaging-based volumetric
analysis of basal ganglia nuclei and substantia nigra in patients with
Parkinsons disease. Neurosurgery. 2006;58:256262.
6. Hutchinson M, Raff U. Structural changes of the substantia nigra in Parkinsons
disease as revealed by MR imaging. Am J Neuroradiol. 2000;21:697701.
7. Hu MT, White SJ, Herlihy AH, Chaudhuri KR, Hajnal JV, Brooks DJ. A
comparison of 18F-dopa PET and inversion recovery MRI in the diagnosis of
Parkinsons disease. Neurology. 2001;56:11951200.
8. Minati L, Grisoli M, Carella F, De Simone T, Bruzzone MG, Savoiardo M.
Imaging degeneration of the substantia nigra in Parkinson disease with
inversion-recovery MR imaging. Am J Neuroradiol. 2007;28:309313.
9. Michaeli S, Oz G, Sorce DJ, et al. Assessment of brain iron and neuronal
integrity in patients with Parkinsons disease using novel MRI contrasts. Mov
Disord. 2007;22:334340.
10. Vaillancourt DE, Spraker MB, Prodoehl J, et al. High-resolution diffusion
tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology.
2009;72:13781384.
11. Berg D, Siefker C, Becker G. Echogenicity of the substantia nigra in
Parkinsons disease and its relation to clinical findings. J Neurol. 2001;248:
684689.
12. Berg D, Merz B, Reiners K, Naumann M, Becker G. Five-year follow-up study
of hyperechogenicity of the substantia nigra in Parkinsons disease. Mov
Disord. 2005;20:383385.
13. Berg D, Roggendorf W, Schroder U, et al. Echogenicity of the substantia nigra:
association with increased iron content and marker for susceptibility to
nigrostriatal injury. Arch Neurol. 2002;59:9991005.
14. Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, Dressler D. Brain
parenchyma sonography detects preclinical parkinsonism. Mov Disord.
2004;19:14451449.
15. Schweitzer KJ, Brussel T, Leitner P, et al. Transcranial ultrasound in different monogenetic subtypes of Parkinsons disease. J Neurol. 2007;254:613
616.
16. Gaenslen A, Unmuth B, Godau J, et al. The specificity and sensitivity of
transcranial ultrasound in the differential diagnosis of Parkinsons disease:
a prospective blinded study. Lancet Neurol. 2008;7:417424.
17. Vlaar AM, de Nijs T, van Kroonenburgh MJ, et al. The predictive value of
transcranial duplex sonography for the clinical diagnosis in undiagnosed
parkinsonian syndromes: comparison with SPECT scans. BMC Neurol.
2008;8:42.
18. Stockner H, Sojer M, K KS, et al. Midbrain sonography in patients with
essential tremor. Mov Disord. 2007;22:414417.
19. Walter U, Hoeppner J, Prudente-Morrissey L, Horowski S, Herpertz SC, Benecke
R. Parkinsons disease-like midbrain sonography abnormalities are frequent in
depressive disorders. Brain. 2007;130:17991807.
20. Schulz JB, Skalej M, Wedekind D, et al. Magnetic resonance imaging-based
volumetry differentiates idiopathic Parkinsons syndrome from multiple system
atrophy and progressive supranuclear palsy. Ann Neurol. 1999;45:6574.
21. Paviour DC, Price SL, Jahanshahi M, Lees AJ, Fox NC. Regional brain
volumes distinguish PSP, MSA-P, and PD: MRI-based clinico-radiological
correlations. Mov Disord. 2006;21:989996.
22. Schocke MF, Seppi K, Esterhammer R, et al. Diffusion-weighted MRI
differentiates the Parkinson variant of multiple system atrophy from PD.
Neurology. 2002;58:575580.
23. Seppi K, Schocke MF, Esterhammer R, et al. Diffusion-weighted imaging
discriminates progressive supranuclear palsy from PD, but not from the
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
IMAGING APPROACHES
TO
607
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
608
THE JOURNAL
OF
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
98. Walker Z, Costa DC, Walker RW, et al. Differentiation of dementia with
Lewy bodies from Alzheimers disease using a dopaminergic presynaptic
ligand. J Neurol Neurosurg Psychiatry. 2002;73:134140.
99. Walker Z, Jaros E, Walker RW, et al. Dementia with Lewy bodies: a comparison
of clinical diagnosis, FP-CIT SPECT imaging and autopsy. J Neurol Neurosurg
Psychiatry. 2007;78:11761181.
100. OBrien JT, McKeith IG, Walker Z, et al. Diagnostic accuracy of 123I-FP-CIT
SPECT in possible dementia with Lewy bodies. Br J Psychiatry. 2009;194:
3439.
101. OBrien JT, Colloby S, Fenwick J, et al. Dopamine transporter loss visualized
with FP-CIT SPECT in the differential diagnosis of dementia with Lewy
bodies. Arch Neurol. 2004;61:919925.
102. Ito K, Nagano-Saito A, Kato T, et al. Striatal and extrastriatal dysfunction in
Parkinsons disease with dementia: a 6-[18F]fluoro-L-dopa PET study. Brain.
2002;125:13581365.
103. Rinne JO, Portin R, Ruottinen H, et al. Cognitive impairment and the brain
dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission
tomographic study. Arch Neurol. 2000;57:470475.
104. Kuhl DE, Minoshima S, Fessler JA, et al. In vivo mapping of cholinergic
terminals in normal aging, Alzheimers disease, and Parkinsons disease. Ann
Neurol. 1996;40:399410.
105. Hilker R, Thomas AV, Klein JC, et al. Dementia in Parkinson disease: functional
imaging of cholinergic and dopaminergic pathways. Neurology. 2005;65:17161722.
106. Bohnen NI, Kaufer DI, Hendrickson R, et al. Cognitive correlates of cortical
cholinergic denervation in Parkinsons disease and parkinsonian dementia. J
Neurol. 2006;253:242247.
107. Lee PH, Yong SW, An YS. Changes in cerebral glucose metabolism in patients
with Parkinson disease with dementia after cholinesterase inhibitor therapy. J
Nucl Med. 2008;49:20062011.
108. Bacskai BJ, Frosch MP, Freeman SH, et al. Molecular imaging with Pittsburgh
Compound B confirmed at autopsy: a case report. Arch Neurol. 2007;64:431
434.
109. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimers
disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306319.
110. Edison P, Archer HA, Hinz R, et al. Amyloid, hypometabolism, and cognition
in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology.
2007;68:501508.
111. Edison P, Rowe CC, Rinne JO, et al. Amyloid load in Parkinsons disease
dementia and Lewy body dementia measured with [11C]PIB positron emission
tomography. J Neurol Neurosurg Psychiatry. 2008;79:13311338.
IMAGING APPROACHES
TO
609
Downloaded from jnm.snmjournals.org by on March 19, 2015. For personal use only.
Information about reproducing figures, tables, or other portions of this article can be found online at:
http://jnm.snmjournals.org/site/misc/permission.xhtml
Information about subscriptions to JNM can be found at:
http://jnm.snmjournals.org/site/subscriptions/online.xhtml