Tuesday, March 28, 2023
Differential Imaging Findings in Parkinsonian Syndromes
Differential Imaging Findings in Dementias
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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 dis ability 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]
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Figure 1. (click image to zoom) 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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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-workers[9] demonstrated notable hypo intensity 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.
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Figure 2. (click image to zoom) Imaging findings of the presynaptic dopaminergic system in Parkinson’s disease. (A) Color-coded diffusion-weighted MRI and (B) striatal 123I-2β-carbomethoxy-3β-(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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The function of dopamine terminals in PD can be examined in vivo in several ways.[17] First, dopa decarboxylase activity at dopamine terminals and dopamine turnover can both be measured with 18F-dopa PET (Figure 1C). Second, the availability of presynaptic dopamine transporters (DATs) can be assessed with PET and SPECT tracers (Figure 2B), the majority of which are tropane-based. Third, vesicle monoamine transporter density in dopamine terminals can be examined with 11C-dihydrotetrabenazine (11C-DTBZ) PET.
In early hemiparkinsonism, these radio tracer-based imaging techniques reveal bi laterally reduced putamen dopaminergic function, with activity being the most depressed in the putamen contralateral to the affected limbs. Head-of-caudate and ventral striatal function is generally spared or only mildly impaired. PET and SPECT can, therefore, detect sub clinical disease in the form of involvement of the ‘asymptomatic’ putamen contralateral to clinically unaffected limbs. It has been estimated that clinical parkinsonism occurs when patients with PD have lost around 50% of dopamine terminal function in the posterior putamen, the region most heavily targeted in PD.[18] Spiegel and colleagues compared TCS findings with 123I-2-carbomethoxy-3-(4-iodophenyl)-N(3-fluoropropyl)nortropane (123I-FP-CIT) SPECT findings in idiopathic PD and reported a lack of correlation between midbrain hyperechogenicity and loss of terminal DAT binding.[19] This finding supports the view that hyperechogenicity on TCS reflects the presence of a pathology outside the nigrostriatal dopaminergic system.
Not all populations of dopamine fibers show degeneration early in PD. Uptake of 18F-dopa in the putamen is reduced overall by 30-40% at the onset of parkinsonian rigidity and bradykinesia, but uptake of this tracer in globus pallidus interna terminals is increased (although it subsequently falls below normal as the disease advances).[20] Reduced 18F-dopa storage in the globus pallidus coincides with the onset of accelerated disability and treatment-related complications, such as fluctuating responses to levodopa, which suggests that both the putamen and the globus pallidus interna require intact dopaminergic input to facilitate efficient, fluent limb movements.
In series in which clinically probable PD and essential tremor have been compared, striatal DAT imaging with SPECT has been shown to differentiate between these conditions with a sensitivity and specificity of around 90%,[21] which indicates that a positive PET or SPECT scan might be valuable to support a diagnosis of PD when there is diagnostic doubt. Three studies have now examined the role of DAT imaging in aiding the diagnosis of such ‘gray’ parkinsonism.[22-24] All three studies concluded that the management of these cases could be rationalized and improved by the inclusion of SPECT in the diagnostic work-up, although, as the pathology still remained unclear, clinical follow-up remained the standard of truth. Around 10-15% of patients suspected of having early-stage dopamine-deficient parkinsonian syndrome turn out to have normal dopamine terminal function when studied with PET or SPECT.[25] The clinical significance of this finding remains uncertain, but a recent series by Marshall and colleagues has helped to shed light on this phenomenon.[26] The authors monitored 150 individuals over a 2-year period who had possible early parkinsonism but normal 123I-FP-CIT SPECT scans. Only four (3%) of these patients showed progression and were considered to have PD at follow-up; the other 146 patients were thought to have either a tremulous disorder or nondegenerative parkinson ism. This finding indicates that a SPECT or PET finding of normal presynaptic dopaminergic function in a patient with possible PD is likely to be associated with a good prognosis whatever the ultimate diagnosis.
PET studies of resting brain function in PD have shown increased levels of glucose metabolism in the contralateral lentiform nucleus of patients with early-stage hemi parkinsonism; however, the level of glucose metabolism is normal in PD patients with established bi lateral involvement.[27] Covariance analysis has revealed an abnormal profile of raised resting glucose metabolism in the lentiform nucleus and lowered frontal metabolism in patients who have established PD without dementia.[28] The degree of expression of this profile correlates with clinical disease severity, and it normalizes after dopaminergic and deep brain stimulation treatments have been initiated.[29,30] Eckert and colleagues performed 18F-fluoro-2-deoxy glucose PET (18FDG-PET) scans in eight patients who had suspected early parkinsonism but normal 18F-dopa PET scans.[31] These researchers found no evidence of expression of a PD-related profile of glucose metabolism in these eight individuals, and none of the the individuals studied showed any clinical progression of their disorder over a 3-year follow-up period. The authors concluded that a normal 18F-dopa PET finding excludes the presence of both typical and atypical degenerative PD.
In summary, evaluation of presynaptic dopamine terminal function has poor specificity for discriminating between typical and atypical PD,[32,33] but measurements of glucose metabolism can be very helpful. Specifically, the level of glucose metabolism in the lentiform nucleus is normal or raised in PD, but reduced in MSA and PSP.[27,34]
