PD

The predominant pathology in PD, which accounts for about 70% to 80% of PS, is the loss of dopaminergic neurons that project from the substantia nigra pars compacta in the midbrain to the striatum (putamen and caudate nucleus). The loss of neurons results in a dopaminergic deficit, which is believed to contribute to the clinical symptoms. Typically, the projections to the posterior putamen are affected earlier and to a greater extent than those to the caudate. The clinical diagnosis of PD relies on the presence of cardinal motor features and a favorable response to dopaminergic medication. However, because PD shares some major features with several other disorders, there is evidence that clinically established diagnoses may be wrong in early- and even late-stage disease. When the diagnosis is unclear, neuroimaging with PET or SPECT may help clarify it.

The biochemical hallmark of PD is the degeneration of the presynaptic nigrostriatal nerve fibers, whereas the postsynaptic side bearing the receptors remains intact, at least initially. Imaging of presynaptic terminal functions, therefore, reveals reduced radioligand uptake in the striatum of PD patients with a more pronounced decrease in the (posterior) putamen than in the caudate, and, usually, also reveals an asymmetry with more severe affection of the striatum contralateral to the limbs that are more affected, clinically. Significant correlations between disease severity and disability stages with the extent of the reduction of presynaptic terminal measures have been reported. In addition, studies in patients with early PD and those with hemi-PD (Hoehn and Yahr stage I) have concordantly shown a bilateral deficit in dopamine function. These findings were not only observed in the striatum and especially the putamen corresponding to the symptomatic limbs but also in the contralateral putamen associated with the still asymptomatic side of the body. These results strongly suggest that the aforementioned imaging techniques are capable of discriminating between subjects with early PD and healthy ones and that may also be suitable for detecting preclinical disease in sporadic and familial PD. Additionally, longitudinal imaging studies have highlighted their role in determining intraindividual disease progression. The annual rate of decline of the respective outcome measure in PD patients has been shown to range from 5% to 13% in patients with early-stage PD, whereas in those with longer disease duration, the annual decline of presynaptic outcome measures was lower (approximately 2% to 3%). In atypical PS, annual progression seems much faster; for example, in MSA patients, values of around 15% per year have been reported. Imaging of presynaptic functions has also been used in clinical trials as endpoint measures of potential disease-modifying therapies. Fluorodopa PET and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (ß-CIT) SPECT studies have demonstrated that the respective outcome measure showed a milder decline in patients receiving therapy with a dopamine agonist compared with levodopa. These trial results evoked an intense and somewhat controversial discussion on whether these imaging modalities may serve as useful surrogate markers for proving potential neuroprotective effects of newly developed drugs.

PET and SPECT with D ₂ -receptor antagonists have also been extensively used to study the postsynaptic striatal D ₂ -receptor availability of patients with PD. At least in earlier stages of the disease, uniformly elevated D ₂ -receptor binding has been reported in the striatum contralateral to the more affected limb. Characteristically, in these cases, binding is higher in the putamen than in the caudate, and even higher in the posterior than in the anterior putamen ( Fig. 2 ). This upregulation has been interpreted as the brain’s attempt to compensate for the dopaminergic deficit related to the presynaptic nerve cell loss and may be considered characteristic of PD; whereas in aPS, the postsynaptic side is also affected by neurodegeneration and displays reduced D ₂ -receptor density.

Healthy control and patient with PD. Presynaptic DAT imaging (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane [FP-CIT] SPECT) clearly reveals reduced striatal binding in the PD patient with more severe affection of the (posterior) putamen and an asymmetry with disadvantage to the right side, which is contralateral to the predominant clinical findings (left sided). Postsynaptic D ₂ -receptors (DMFP PET) show preserved and upregulated binding, which is more accentuated in the posterior putamen compared with the anterior putamen and the caudate. Note the asymmetry with higher binding in the right striatum, which is inversely related to the more severe presynaptic deficit at this location.

Some recent clinical trials using PET and SPECT imaging have found that a distinct subgroup of subjects with clinical criteria for (early-stage) PD presented with normal scans. These patients have been termed SWEDDs (subjects with scans without evidence of dopaminergic deficit). To date, SWEDDs have been mentioned in at least 3 large-scale clinical trials, the CALM-PD-CIT trial, the ELLDOPA study, and the REAL-PET study. Combining the data of these trials suggests that SWEDDs may be present in about 11% of included subjects (45 of 410 clinically diagnosed PD cases). This number is consistent with reported rates in the clinical literature of misdiagnosis of early-stage PD by movement disorder specialists. One possible and self-evident conclusion, therefore, would be that SWEDDs may simply reflect clinically misdiagnosed PD patients. Furthermore, follow-up data have shown that SWEDDs maintain the feature of noncompromised presynaptic functions over time and, thus, clearly differ from typical PD subjects. SWEDDs, therefore, may represent a distinct population within the mentioned clinical trials, and whether these subjects have PD or an alternative diagnosis has been questioned. Histopathologic diagnosis obtained in SWEDDs might be the clue to unravel their mystery; unfortunately it is still unavailable.

APS

MSA

MSA is a sporadic progressive neurodegenerative disorder that may account for up to 10% of patients with ES. Clinically, MSA is characterized by varying degrees of parkinsonism, cerebellar ataxia, and autonomic dysfunction. In terms of dependency of the predominant phenotype of the motor disorder, MSA is mainly classified into a parkinsonian type (MSA-P) and a cerebellar type (MSA-C). Pathologic studies exhibit neuronal degeneration and gliosis in the basal ganglia, brainstem, cerebellum, and spinal cord. In MSA, annual progression seems much faster compared with PD; annual loss in striatal binding around 15% per year has been reported. Because MSA is characterized by a degeneration of the pre- and postsynaptic dopaminergic system, PET and SPECT investigations of both show reduced binding ( Fig. 3 ). The major difference compared to PD, therefore, is the presence of pathologic findings on the postsynaptic level, which allows one to distinguish between MSA and PD. On the presynaptic level, reliable differential diagnosis between MSA and PD is not possible.

Healthy control and patient with MSA. Presynaptic DAT(FP-CIT SPECT) and postsynaptic D ₂ -receptor images (DMFP PET) concordantly show reduced binding of the respective tracers, both with more severe affection of the right side. The pathologic imaging results reflect degeneration of both pre- and postsynaptic fibers of the dopaminergic system within the striatum. Note that presynaptic imaging alone cannot reliably distinguish between PD (see Fig. 2 ) and MSA (as an example of aPS). Only at the postsynaptic level is there a marked difference between PD (no neurodegeneration) and aPS (neurodegeneration).

Other Neurodegenerative Extrapyramidal Syndromes

SCAs are a genetically heterogeneous group of autosomal dominant ataxias, which may present as pure cerebellar and various noncerebellar syndromes including parkinsonism. Imaging studies have shown decreased glucose metabolism in the cerebellum and various parts of the cerebral cortex, depending on the SCA subtypes. Decreased presynaptic dopaminergic terminal function has been reported in SCA2 and SCA3 and there are also some preliminary reports on reduced postsynaptic D ₂ -receptor binding potential. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder and clinically characterized by progressive cognitive impairment, neuropsychiatric symptoms, and abnormalities of movement including chorea and akinetic rigidity. Histopathologically, HD is characterized by neuronal loss and gliosis in the striatum. Accordingly PET and SPECT studies show substantial decrease in striatal perfusion, glucose metabolism, and severely compromised pre- and postsynaptic dopaminergic functions. Wilson disease (WD) is also a genetically determined disorder (autosomal recessive) that is characterized by a deficiency of biliary copper excretion resulting in pathologic copper deposition in various organs including the brain. WD goes along with extrapyramidal symptoms including parkinsonism. Similar to HD, patients with WD also present with compromised binding to pre- and postsynaptic dopaminergic targets in the striatum and show reduced striatal metabolism and perfusion, apart from the concomitant involvement of other brain areas. HD and WD are generally diagnosed clinically and genetically, with the role of functional imaging being restricted to scientific applications.

Differential Diagnosis of the Common Neurodegenerative PS

For the differential diagnosis of PD versus aPS, various nuclear medicine techniques may be applied.

As already mentioned, postsynaptic D ₂ -like receptor imaging is useful in distinguishing between PD and aPS, with the former showing preserved receptors and the latter, compromised binding because of degeneration of postsynaptic fibers. A representative case example is shown in Figs. 2 and 3 . As optimized by receiver operating characteristic (ROC) analyses, reported sensitivities and specificities were 87% and 73%, respectively for SPECT and 89% and 86%, respectively for PET investigations. Combining the information of pre- and postsynaptic dopaminergic imaging marginally increased diagnostic accuracy compared with postsynaptic imaging alone. Even though reasonable results are delivered for distinguishing PD from aPS, these imaging techniques fail to further distinguish between different types of aPS reliably.

Another molecular imaging approach for distinguishing PD from aPS addresses the sympathetic denervation of the heart, rather than focusing on the brain. For this purpose, HED and MIBG may be used as PET and SPECT tracers, respectively. Autonomic abnormalities in PD have been ascribed to postganglionic sympathetic nerve dysfunction, which is depicted by the mentioned imaging techniques. In this respect, patients with PD behave differently from those with aPS, in whom normal or only mild reduction of cardiac uptake is present. Pathologically, aPS goes along with a central and preganglionic denervation that is not targeted by the mentioned tracers. Based on this principle, a reasonable number of studies have used this type of cardiac imaging for the differential diagnosis of PD and aPS. However, the diagnostic accuracy of this approach has been criticized. Overlapping values in cardiac binding of both groups raised concerns regarding the use of these techniques as the sole method for diagnostic discrimination. Limitations and confounders of the methods have to be taken into account (eg, sympathetic denervation related to other diseases, such as diabetes mellitus or several cardiac diseases).

A third option for distinguishing PD from aPS is based on the pattern analysis of brain glucose metabolism. This is the only approach that also allows one to distinguish between the various aPS. By using modern processing tools like anatomical standardization with pixelwise evaluation or discriminant and network analyses, typical metabolic patterns may be identified, which result in high diagnostic accuracies. A recent study assessing PD, MSA, PSP, and CBD on a single-case basis reported sensitivities between 85% and 96% and specificities between 60% and 92%. The study used statistical parametric mapping to create disease-related templates in which regional features were determined and used for defining or supporting specific diseases. Briefly, hypermetabolism of the dorsolateral putamen was considered indicative of PD, bilateral hypometabolism of the putamen and cerebellum, of MSA, hypometabolism of brain stem and midline frontal cortex, of PSP, and asymmetric hypometabolism of basal ganglia and some cortical areas, of CBD.