Review

Correspondence Imperial College London, Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK

Email david.brooks@csc.mrc.ac.uk

Introduction

The definitive diagnosis of idiopathic Parkinson's disease (PD) requires the demonstration of intracellular Lewy body inclusions via histological examination of brain tissue, which is not a viable approach in living individuals. Retrospective clinicopathological studies have shown that a clinical diagnosis of PD during life correlates with a postmortem finding of brainstem Lewy body disease in, at best, 85% of patients.¹ Atypical parkinsonian disorders, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), can mimic PD, as can severe essential and dystonic tremors. Patients with early-stage disease, in which the full constellation of parkinsonian symptoms and signs are not yet manifest, can be the most difficult to diagnose. Consequently, the ability to detect or exclude loss of nigral dopaminergic neurons or striatal dopamine terminal function by use of noninvasive imaging approaches would be a valuable tool that could not only help physicians to increase diagnostic specificity, but could also enable the appropriate management decisions to be made at the initial stages of the disease.

Lewy body pathology in parkinson's disease

In PD, the neurons that project from the lateral nigra to the posterior dorsal putamen are those most severely affected by Lewy body pathology.² It is often possible, however, to detect Lewy body inclusions in the anterior cingulate cortex and the frontal, parietal and temporal association areas at postmortem examination, even in patients who do not have dementia.³ Currently, it remains unclear whether dementia with Lewy bodies (DLB), PD with later dementia (PDD), and PD without dementia all represent a spectrum of Lewy body disease. DLB has clinical features that overlap with those of Alzheimer's disease (AD), and, at postmortem examination, most cases of DLB show a mixture of AD-like changes and cortical Lewy body inclusions.

Imaging approaches

Imaging the changes associated with the pathology of PD involves either detecting alterations in brain structure or examining functional changes in brain metabolism and receptor availability. MRI scans can reveal brain structural changes such as reductions in volume, alterations in water proton T2 relaxation signals or in water diffusion, and changes in magnetic susceptibility or in magnetization transfer. MRI also enables the exclusion of structural lesions such as basal ganglia tumors and calcification, multi-infarct disease, and hydrocephalus as causes of parkinsonism. Transcranial sonography (TCS) can detect structural midbrain and striatal changes, which manifest as hyperechogenicity, in parkinsonian disorders.

Functional imaging (PET, single-photon emission CT [SPECT], functional MRI, and proton magnetic resonance spectroscopy) provides a means of detecting and characterizing the regional changes in brain blood flow, metabolism, and receptor binding that are associated with parkinsonian disorders. Radiotracer-based PET and SPECT potentially provide a sensitive means of detecting subclinical disease in patients who are at risk for subcortical degenerations, and these techniques might also provide biomarkers for objective assessment of disease progression.

Imaging the presynaptic dopaminergic system

Transcranial sonography

In a seminal series by Berg et al., TCS was reported to detect increased midbrain echogenicity in 103 out of 112 patients with clinically established PD (Figure 1A).⁴ These researchers, however, used a threshold for abnormality of one standard deviation above the normal mean, and 10% of the healthy, elderly individuals also showed hyperechogenicity. The increased TCS signal was particularly noticeable contralateral to the more clinically affected limbs, but the signal increase did not correlate well with disability scores. In another 5-year, follow-up study of individuals with PD, there was no significant change in TCS findings during progression of disability.⁵ It has, therefore, been suggested that the presence of midbrain hyperechogenicity is a trait rather than a state marker for susceptibility to parkinsonism, and that it might reflect the presence of midbrain iron deposition.⁶

Figure 1 Visualization of midbrain structure and function in Parkinson's disease.

(A) Transcranial sonogram shows hyperechogenicity in the same region as seen in (B). The arrows indicate increased echos from the substantia nigra, and the asterisk indicates increased echos from the median raphe. Permission obtained from Steinkopff Verlag © Berg D et al. (2001) J Neurol 248: 684–689. (B) An MRI scan in which inversion recovery sequences that suppress the signal from gray and white matter are subtracted shows a loss of nigral signal in Parkinson's disease. Permission obtained from the American Society of Neuroradiology © Minati L et al. (2007) AJNR Am J Neuroradiol 28: 309–313. (C) PET is able to detect ¹⁸F-dopa uptake into brainstem structures including the substantia nigra (dopaminergic), locus ceruleus (noradrenergic), tegmentum (dopaminergic), and median raphe (serotonergic).

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MRI studies

High-field MRI, using special inversion recovery sequences that suppress the signal from gray and white matter, has been reported to detect abnormal signals from the substantia nigra compacta in patients with PD. In an initial series,⁷ all of 6 patients with established PD showed altered nigral signal, and, in a second series,⁸ 7 out of 10 patients with PD showed nigral MRI abnormalities. More recently, by use of inversion recovery sequences, Minati and co-workers⁹ demonstrated notable hypointensity of the lateral nigra on T1-weighted images in patients with PD relative to healthy controls (Figure 1B).⁹ In practice, however, there was considerable overlap between normal and PD values.

MRI sequences that directly reflect the iron content of brain areas have now been designed. By use of such an approach, Michaeli and colleagues were able to detect altered nigral magnetic susceptibility in patients with PD, although, as in the previously mentioned study, the midbrain relaxation times of these patients overlapped considerably with those of a control group.¹⁰ A volumetric MRI study failed to detect a reduction in nigral volume in PD, possibly because of difficulties in accurately defining the border of the nigra compacta.¹¹ Interestingly, however, reductions in putamen volume were detected, even in early-stage PD.

Currently, it would seem that MRI techniques cannot reliably distinguish patients with PD from those without the disease. MRI can play a valuable part, however, in distinguishing between atypical and typical PD. Volumetric MRI can reveal significant striatal, brainstem and cerebellar atrophy in patients with MSA or PSP, although the individual volumes of these structures in these patients overlap considerably with the normal range, with the exception of brainstem volumes, which fall below the normal range in patients with the cerebellar subtype of MSA.^{12, 13} In practice, it is necessary to use a discriminant function with volumetric MRI to reliably separate patients with nonataxic, atypical PD from healthy individuals and patients with typical PD.

Diffusion-weighted imaging (DWI; Figure 2A) and diffusion-tensor MRI are more-sensitive modalities for the discrimination between atypical and typical parkinsonian disorders. DWI has been reported to detect altered water diffusion in the putamen of the majority of patients with clinically probable MSA or PSP, whereas the water diffusion rate is normal in PD.^{14, 15} In addition, MSA can be discriminated from PSP by the presence of altered water diffusion in the middle cerebral peduncle in the former.¹⁶ Prospective series will be required to assess how well DWI performs at early stages of parkinsonian disorders when the clinical diagnosis is still uncertain.

Figure 2 Imaging findings of the presynaptic dopaminergic system in Parkinson's disease.

(A) Color-coded diffusion-weighted MRI and (B) striatal ¹²³I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-iodophenyl)tropane uptake for a healthy individual, a patient with Parkinson's disease (PD), and a patient with the atypical parkinsonian syndrome multiple system atrophy (MSA). The apparent diffusion coefficient (A) is normal in the striatum in PD but it is raised in MSA (arrows) because of the neuronal loss that targets the putamen. Dopamine transporter binding (B) is bilaterally reduced in the striata in both PD and MSA. In PD, the caudate is relatively spared compared with the putamen. Pictures courtesy of Gregor Wenning. Permission for panel A obtained from AAN Enterprises, Inc. © Schocke MFH et al. (2002) Neurology 58: 575–580.

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Serotonergic, noradrenergic and cholinergic function

In PD, there is loss of not only dopaminergic projections, but also serotonergic, noradrenergic and cholinergic projections. The median raphe and locus ceruleus both contain aromatic aminoacid decarboxylase and so can take up and store ¹⁸F-dopa, a process that gives an indirect insight into the functional integrity of the serotonergic and noradrenergic systems. It has been reported that ¹⁸F-dopa uptake in the median raphe is initially elevated in PD but later falls below normal as the disease advances. ¹⁸F-dopa uptake in the locus ceruleus is normal in early PD but falls at the end stage of the disease.³⁵ A more direct measure of serotonergic function is provided by use of ¹¹C-WAY-100635 PET to quantify 5-HT_1A receptor binding potential in the median raphe. One series in patients with PD showed a mean 25% loss of 5-HT_1A binding in the median raphe, which correlated with the severity of resting tremor but not with rigidity or bradykinesia.³⁶ These data suggest that midbrain tegmentum pathology might be relevant to the etiology of PD tremor.

Interestingly, no correlation between serotonergic dysfunction and depressive symptoms has been detected in patients with PD,³⁷ but there is evidence that dysfunction of noradrenergic and limbic monoaminergic projections is associated with depression. Patients with both PD and depression, when compared with patients who have equivalent disability but not depression, have been reported to show decreased levels of ¹¹C-RTI 32 uptake (a marker of norepinephrine [noradrenaline] and dopamine terminal function) in the thalamus and locus ceruleus, which probably reflects reduced noradrenergic input, along with lower signals in the limbic areas (amygdala and ventral striatum).³⁸

Cholinergic function can be assessed presynaptically with ¹²³I-benzovesamicol, a SPECT marker of vesicular acetylcholine transporter binding. In patients who have PD without dementia, there is a significant reduction of ¹²³I-benzovesamicol binding in the parietal and occipital lobes only, whereas patients with PDD show globally reduced ¹²³I-benzovesamicol binding.³⁹ Both N-¹¹C-methyl-4-piperidyl acetate (¹¹C-MP4A) PET and N-¹¹C-methylpiperidin-4-yl propionate ¹¹C-PMP PET can be used to measure acetylcholinesterase levels. Hilker and colleagues performed ¹¹C-MP4A and ¹⁸F-dopa PET studies in 17 patients with PD and 10 patients with PDD.^40 11C-MP4A binding in the cortical regions was reduced by 10% in the patients with PD and by 29.7% in the patients with PDD when compared with controls. The individual levels of striatal ¹⁸F-dopa uptake correlated with ¹¹C-MP4A binding in the cortical regions, which suggests a simultaneous loss of both transmitters. The findings reported with ¹¹C-PMP PET scans in patients with PD or PDD parallel those of ¹¹C-MP4A PET scans in these patients.⁴¹ Loss of cholinergic function is likely to be an important contributory factor to the dementia process in PD, as levels of cortical acetylcholinesterase in PD have been shown to correlate with performance on attentional and working memory tasks.⁴²

Detection of preclinical parkinson's disease

For every patient who presents with clinical PD there might be 10–15 subclinical cases with incidental brainstem Lewy body disease in the community, according to estimates from postmortem studies.⁴³ Individuals at risk of developing PD include carriers of genes known to be associated with parkinsonism, relatives of patients with PD, elderly individuals with idiopathic hyposmia, and patients with rapid eye movement sleep behavior disorder (RBD).

Subclinical midbrain hyperechogenicity detected with TCS has been reported in around 10% of healthy elderly individuals.⁴⁴ This raised echogenicity correlated with the presence of 'soft' signs of parkinsonism, such as increased muscle tone and reduced arm swing. In another study, increased midbrain echogenicity was reported in four out of seven asymptomatic carriers of PD-associated mutations in the Parkin gene. Only two of the seven carriers, however, were found to have reduced striatal ¹⁸F-dopa uptake.⁴⁵ In a third series, the same group used TCS to investigate patients with hyposmia. Out of 30 patients with idiopathic olfactory loss, 11 showed midbrain hyperechogenicity, and 5 of these 11 had reduced ¹²³I-FP-CIT binding in the striatum.⁴⁶ Increased nigral echogenicity can be detected in about a third of individuals at risk for PD, but this finding correlates with reduced dopaminergic function in fewer than 50% of patients.^{44, 45, 46}

Ponsen and colleagues collected data on 40 elderly relatives of patients with PD who had no overt parkinsonism but who manifested hyposmia on olfactory screening, and they found that seven of these relatives showed reduced ¹²³I -carbomethoxy-3-(4 iodophenyl)tropane (¹²³I--CIT) uptake in the striatum.⁴⁷ Four of these seven individuals subsequently converted to clinical PD over a 2-year period.

¹⁸F-dopa PET has been used to study asymptomatic adult relatives in familial PD kindreds.⁴⁸ In all, 25% of the asymptomatic adult relatives who were scanned showed reduced levels of ¹⁸F-dopa uptake in the putamen and a third of these subsequently developed clinical parkinsonism over a 5-year follow-up period. Parkin disease has also been investigated with ¹⁸F-dopa PET. Compound heterozygous gene carriers who are symptomatic show more-severe reductions of striatal ¹⁸F-dopa uptake than would be expected for their degree of disability, which suggests that adaptive processes might be compensating for the dopamine deficiency.^{49, 50} The pattern of dopaminergic deficit in patients with symptomatic parkin disease can mimic that of PD, in that the putamen is targeted, but the caudate nucleus and midbrain seem to be more involved in parkin disease.⁵¹ Interestingly, heterozygous Parkin mutation carriers who are asymptomatic show a mild reduction in putamen ¹⁸F-dopa uptake, but this feature does not seem to progress significantly over a 10-year period.⁵² The question of whether carrying a single Parkin mutation makes an individual more susceptible to late-onset PD is still being debated.

The most common known cause of dominantly inherited PD has emerged to be mutations in the leucine-rich repeat kinase 2 (LRRK2) gene—also known as PARK8. In a recent series, 15 family members of an LRRK2 kindred underwent ¹⁸F-dopa, ¹¹C-DTBZ and ¹¹Cd-threo-methylphenidate (¹¹C-MP) PET to assess dopamine storage, vesicle monoamine transporter density and DAT binding, respectively.⁵³ Four clinically affected LRRK2 family members showed similar results to those found in PD, two asymptomatic mutation carriers had abnormal DAT binding, and another two asymptomatic mutation carriers initially had normal levels of ¹¹C-MP uptake but experienced reductions in these levels over 4 years of follow-up. Interestingly, ¹⁸F-dopa uptake remained normal in the asymptomatic individuals, although two of them had reduced ¹¹C-DTBZ binding. The authors concluded that the in vivo neurochemical phenotype of LRRK2 mutations was indistinguishable from that of sporadic PD, and that compensatory changes, including downregulation of DAT binding and upregulation of decarboxylase activity, might act to delay the onset of parkinsonian symptoms.

RBD is a common feature of PD, and 30 patients with isolated RBD were investigated with ¹²³I-FP-CIT SPECT for the presence of dopamine deficiency.⁵⁴ Out of 11 patients with RBD who agreed to undergo SPECT, three showed reduced striatal DAT binding, and one of these had clinical parkinsonism. These proportions are considerably higher than would be expected in the general population.

Microglial activation in parkinson's disease

Microglia constitute 10–20% of the glial cells in the brain, and they form its natural defense mechanism. They are normally in a resting state, but local injury causes them to activate and swell, leading to the expression of human leukocyte antigens on the cell surface, and to release cytokines such as tumor necrosis factor and interleukins. The mitochondria of activated (but not resting) microglia express peripheral-type benzodiazepine binding sites, which might have a role, via membrane stabilization, in the prevention of cell apoptosis. The isoquinoline ¹¹CPK 11195 binds selectively to peripheral-type benzodiazepine sites and, therefore, potentially provides an in vivo PET marker of microglial activation (Figure 3). This marker suffers, however, from having high nonspecific background and vascular signals, which complicates its kinetic modeling and lowers its sensitivity in practice.

Figure 3 Visualization of microglial activation by use of ¹¹CPK 11195 PET.

(A) Only mild microglial activation is seen in the thalamus of a healthy control. (B) In a patient with Parkinson's disease, on the other hand, notably raised activation is evident in the midbrain and striata (arrows) of the patient with Parkinson's disease, along with normal levels of thalamic activation. Pictures courtesy of Alex Gerhard.

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The loss of substantia nigra neurons in PD has been shown to be associated with microglial activation, and histochemical studies have shown that, in PD, microglial activation can also be seen in other basal ganglia, along with the cingulate, hippocampus and cortical areas.⁵⁵ One series reported increased midbrain ¹¹CPK 11195 PET signal in patients with PD, which correlated inversely with the levels of DAT binding in the posterior putamen, as measured by ¹¹C-2-carbomethoxy-3-(4-fluorophenyl)tropane (¹¹C--CFT) PET.⁵⁶ In patients with advanced PD, Gerhard and co-workers reported additional microglial activation in the brainstem, striatum, pallidum and frontal cortex,⁵⁷ which is consistent with the distribution of Lewy body pathology that was reported by Braak and colleagues.⁵⁸ Interestingly, Gerhard et al. found little change in the extent of microglial activation over a 2-year follow-up period, although all the patients deteriorated clinically. This finding could imply that microglial activation is merely an epiphenomenon in PD. Postmortem studies have shown, however, that the microglia continue to express cytokine messenger RNA, which suggests that they could be driving disease progression.

Dementia and parkinson's disease

Resting brain metabolism

In patients who have PD with frank dementia, ¹⁸FDG-PET scans show an AD-like pattern of impaired resting brain glucose utilization, with posterior parietal and temporal association areas being most affected, frontal association areas being affected to a lesser degree, and primary cortical regions, basal ganglia and cerebellum being spared.⁶² Interestingly, up to a third of patients with established PD but without dementia also show reduced parietal and temporal metabolism, but to a lesser extent than in those with frank dementia, which suggests that these patients with PD might be at risk for later dementia.⁶³

Currently, it remains unclear whether the pattern of resting glucose hypometabolism in patients who have PD with dementia reflects coincidental AD, cortical Lewy body disease, loss of cholinergic projections, or some other degenerative process. Clinicopathological series suggest that there is considerable overlap in cortical ¹⁸FDG-PET findings between coincidental AD and cortical Lewy body disease, but that patients with cortical Lewy body disease show a greater reduction of resting glucose metabolism in the primary visual cortex.⁶² PET imaging agents that can be used to assess the amyloid- plaque load in patients with dementia are now available (Figure 4).⁶⁴ By use of PET with ¹¹C-Pittsburgh Compound B, a thioflavin marker of amyloid deposition, Edison and colleagues recently reported that 80% of patients with DLB but only 20% of patients with PDD have significantly raised cortical amyloid loads.⁶⁵ This finding suggests that amyloid pathology contributes to later dementia only in a minority of PD cases.

Figure 4 PET scan with ¹¹C-Pittsburgh Compound B, a thioflavin-based marker of amyloid- plaque load.

(A) An elderly individual without Parkinson's disease and (B) a patient who has Parkinson's disease with late dementia both show no significant plaque deposition in the brain when compared with (C) a patient with Alzheimer's disease in whom amyloid- deposition is extensive. Pictures courtesy of Paul Edison.

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Conclusions

Tables 1 and 2 summarize the differential imaging findings in parkinsonian syndromes and dementias, respectively.

Table 1 Differential imaging findings in parkinsonian syndromes.

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Table 2 Differential imaging findings in dementias.

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TCS and MRI can both be used to image structural changes in the substantia nigra of patients with PD. Although the altered signals that are observed do not correlate well with either clinical status or loss of dopamine terminal function in the striatum, they might prove to be valuable for revealing a susceptibility to PD. By contrast, PET and SPECT measurements of dopamine terminal function do correlate significantly with clinical disability. In patients who are suspected of having PD, a finding of normal presynaptic dopaminergic function on a PET or SPECT scan implies a good prognosis.

The severity of a parkinsonian tremor correlates better with loss of 5-HT_1A receptor binding potential in the median raphe than with nigrostriatal dysfunction, which indicates that midbrain tegmentum pathology is involved in the generation of the tremor. Surprisingly, depression in PD seems to reflect a loss of noradrenergic and limbic monoaminergic function, rather than a serotonergic etiology.

DLB can be reliably discriminated from AD by the detection of a loss of striatal DAT binding in the former. Amyloid pathology contributes notably to DLB in the majority of cases, whereas only 20% of patients who have PDD show a raised plaque load.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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