Introduction
There are numerous neurodegenerative and symptomatic causes of parkinsonism [
1]. The many causal possibilities for parkinsonism are reflected in the suboptimal diagnostic accuracy of Parkinson’s disease (PD). A recent meta-analysis of clinicopathological studies demonstrated that the diagnostic accuracy of PD is approximately 75% among non-experts [
2].
One possible method that could be used to improve diagnostic accuracy in parkinsonism of an unknown origin is presynaptic dopaminergic functional imaging. The uptake of putaminal presynaptic dopaminergic tracers in positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging is decreased by approximately 50% in patients with early to moderate PD, with practically no overlap when compared to healthy individuals [
3]. In addition, the differentiation of patients with essential tremor (ET) from neurodegenerative parkinsonism with dopamine transporter (DAT) SPECT imaging has shown a high diagnostic accuracy [
4]. [I-123]
N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([I-123]FP-CIT) SPECT can also be used to establish the early diagnosis of neurodegenerative parkinsonism, in the differential diagnosis between dementia with Lewy bodies (DLB) and other dementias such as Alzheimer’s disease (AD), as well as between neurodegenerative parkinsonism with presynaptic dopamine loss (PD, DLB, multiple system atrophy MSA, progressive supranuclear palsy PSP and corticobasal syndrome CBS) and secondary parkinsonism, e.g., neuroleptic-induced parkinsonism [
5]. However, its aid in the differentiation between vascular parkinsonism (VP) and PD remains partly contradictory [
6]. Thus, dopaminergic imaging appears to represent a useful method for identifying neurodegenerative parkinsonism patients with striatal dopamine deficits, but the method is costly, has limited availability and is associated with radiation. Consequently, the clinical evaluation of parkinsonism patients remains the gold standard in most regions of the world.
The current evidence suggests an inverse correlation between parkinsonian motor symptom severity, particularly of bradykinesia and axial symptoms, and striatal DAT binding in patients with PD [
7], whereas rigidity appears to correlate moderately and tremor only very weakly, or not at all, with striatal DAT binding [
7,
8]. It should be noted, however, that a large proportion of the previous data has been collected in research studies that have investigated patients with established diagnoses of PD and healthy individuals, and thus, the results may convert poorly to a clinical setting when patients present with unclear or atypical parkinsonian motor symptoms. There is a lack of studies that have investigated the associations of individual parkinsonian motor signs with striatal dopamine deficiency in patients with clinical parkinsonism and tremor of an uncertain origin.
A widely used method in quantitative phenotyping of PD is the Unified Parkinson’s Disease Rating Scale (UPDRS), which revision, MDS-UPDRS was published in 2008 [
9]. In the present study, we used functional DAT imaging and MDS-UPDRS motor scoring for 221 patients with parkinsonism or tremor of an unknown origin. The aims of the study were to identify parkinsonian motor signs that point to striatal dopaminergic deficiency, and to investigate whether these associations are particularly present in certain striatal subregions in patients with striatal DAT deficits.
Discussion
The present results indicate that the presence of upper extremity rigidity and reduced facial expression are independently associated with a higher likelihood of striatal dopamine deficiency in patients with parkinsonism or tremor of an unknown origin. On the other hand, overall motor symptom severity or other common parkinsonian motor signs, such as bradykinesia or rest tremor, did not differ between parkinsonism patients with normal and abnormal DAT binding. Furthermore, parkinsonian hypomimia appears to be associated with dopamine degeneration particularly in the caudate nucleus. It should be noted that a longer duration of motor symptoms was associated with a lower likelihood of DAT deficiency. Thus, this result confirms our previous findings, probably reflecting the less progressive nature of parkinsonian symptoms in patients with normal DAT binding [
16].
The highest likelihood of DAT deficiency was observed with upper extremity rigidity in at least one body side. The OR was even higher in the subsample of patients who were not receiving antiparkinsonian medications. We are not aware of any previous studies that have investigated the association of upper extremity rigidity and DAT deficiency. The reason why in particular upper extremity rigidity was indicative of DAT loss might be due to many factors that cause and mimic increased lower extremity muscle tone and problems with gait, such as lumbar spine degenerative changes and degenerative arthritis, resulting in apparent lack of differences in the lower extremity rigidity scores between groups. It is of special interest that, unlike most other items on the motor MDS-UPDRS, the estimation of rigidity is not based on inspection but rather requires hands-on examination by the clinician. However, in accordance with earlier results of correlations between DAT and rigidity [
7], there were only mild associations between the magnitude of DAT binding and the severity of upper extremity rigidity. This may have been partially due to inter-rater variability in the rigidity severity estimates. Thus, the detection of upper extremity rigidity might serve as a clinical trigger-finding (yes/no) for neurodegenerative parkinsonism disorders associated with dopamine loss even if it cannot be used as a reflector of the magnitude of striatal dopamine deficiency.
A reduction in facial expression, as seen in reduced eye-blink frequency, masked faces, reduced spontaneous smiling and parting of the lips, was also associated with a higher likelihood of DAT deficiency. Hypomimia, the reduction of spontaneous facial movements and emotional facial expressions, is a common feature of neurodegenerative parkinsonism. Previous results have indicated that reduced facial expression in PD could be a reflection of facial bradykinesia that differs from bradykinesia in the limbs, as facial movements are not only voluntary but also involuntary (spontaneous and emotional) [
17]. The loss of spontaneous facial expression, such as a reduced blinking rate, has been suggested to be related to central dopamine deficiency and to respond well to dopaminergic medication [
18]. On the other hand, the impairment in emotional facial expressiveness seems to correlate with the impairment of facial emotions recognition both in PD [
19] and in healthy individuals [
20]. It should be noted that, as the association between hypomimia and a higher likelihood of DAT deficiency was not observed in the subsample analyses, there was a possible medication effect in hypomimia. However, the present results, also the subsample analyses, further pointed to a specific association between the decreased facial expression and the reduced dopamine function in the caudate nucleus in patients with abnormal DAT binding. It is of special interest to note that apathy, a common neuropsychiatric symptom in PD, has also been reported to be associated with caudate DAT function in early PD [
21]. Given the difficulties in emotional processing of PD patients at multiple levels [
22], the impairment in emotional facial expressiveness [
19], and the localization of hypomimia in the caudate nucleus and not in the nigrostriatally more relevant putamen, we consider that apathy and hypomimia could represent different but interconnected aspects of abnormal emotional functions in neurodegenerative parkinsonism. Further studies are needed to investigate whether the relationship between facial expression and dopamine is driven more by motor circuitry or by emotional processing.
It is noteworthy that the degree of bradykinesia, the most cardinal feature of parkinsonism and PD [
23], did not distinguish parkinsonism patients with normal and abnormal DAT uptake. Thus, the spectrum of neurodegenerative and non-neurodegenerative causes of bradykinesia may clinically appear as similar levels of bradykinesia. Slowness of movements is part of the motor dysfunction in many movement disorders, it can be present in any condition with muscle weakness, and it may also be included in the phenotype of depression [
24]. The present results cannot be interpreted to lessen the value of bradykinesia in the diagnostics of PD nor the important role of the slowness of movements in the pathophysiology of parkinsonism. Our finding rather noted the difficulties when one tries to identify patients with dopaminergic degeneration on the basis of bradykinesia. Indeed, the terminology considering bradykinesia and its different dimensions has been highly variable in the earlier literature [
25], and it has been speculated that the different dimensions of bradykinesia should be rated separately [
23]. A previous blinded video study demonstrated that the clinical symptom-based separation of tremulous patients with and without dopamine deficiency is difficult even for movement disorder specialists, and it was also noted that the true parkinsonian bradykinesia with both slowness and decrement is very hard to diagnose [
26]. In line with that study, our study underlines the similarities in tremor signs in a large number of patients by showing that the presence or the magnitude of rest, postural or kinetic tremors has minimal value in predicting striatal dopamine loss in a heterogeneous clinical sample of parkinsonism patients. Not even the tremor asymmetry index was able to differentiate between the two patient groups with and without DAT deficiency in the present study. However, it is noteworthy that the asymmetry of all bilateral motor signs, bradykinesia items and rigidity tended to be more pronounced in patients with abnormal DAT binding, and this finding needs more detailed investigation in the future studies.
The important strengths of the study were the unbiased motor evaluations (not biased by the knowledge of the imaging results) and automated semi-quantitative age- and scanner-corrected ROI analyses, along with voxel-by-voxel analyses. In addition, the scans with semi-quantitative analyses on the borderline of abnormality underwent a separate visual expert evaluation when these scans were categorized into groups of normal and abnormal DAT binding [
27]. The distribution of patients with normal and abnormal DAT binding were similar to the earlier retrospective results of patients scanned in Center 1 [
28]. Regarding limitations, the study sample consisted of patients who were scanned with SPECT due to clinical diagnostic difficulties, and therefore, the sample was probably not fully representative of typical parkinsonism patients in neurological outpatient clinics. Nevertheless, the sample represents clinical neurological diagnostic reality much better than studies where comparisons were made between patients with established PD diagnoses and healthy controls. The MDS-UPDRS part III scores were somewhat higher when compared to some previous studies of PD patients [
9], but this can be explained by the study setting and study sample that included also more advanced parkinsonism patients with also other diagnoses than PD. As a limitation, it should be noted that the MDS-UPDRS rating scale was developed for PD patients in particular and it may not be as suitable for other patient groups. The present results were limited also because they focused on motor function and were derived from motor examinations only, without possibly relevant non-motor predictive signs of striatal DAT loss. Finally, cerebrovascular disease could affect both DAT SPECT imaging and motor symptoms if there are ischemic lesions in relevant regions along the nigrostriatal tract. However, from hospital records we identified only two patients who had striatal DAT deficiency with parallel evidence of possibly relevant vascular lesions.