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Reviewed by: Philip Frank Cohen, University of British Columbia, Canada; Yashar Zeighami, McGill University, Canada
This article was submitted to Applied Neuroimaging, a section of the journal Frontiers in Neurology
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Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are clinical syndromes classified as atypical parkinsonism. Due to their overlapping symptomatology, recent research shows the necessity of finding new methods of examination of these clinical entities. PSP is a heterogenic disease. PSP Richardson-Steele Syndrome (PSP-RS) and parkinsonism predominant (PSP-P) are the most common clinical variants of progressive supranuclear palsy syndrome. The different clinical course and life expectancy of PSP-RS and PSP-P stress the need of efficient examination in the early stages. The aim of the study was to evaluate the possible feasibility of the combined use of frontal assessment battery (FAB) and single-photon emission computed tomography (SPECT) in the differentiation of PSP-RS, PSP-P, and CBS. The findings show that FAB may be interpreted as a possible supplementary tool in the differential diagnosis of PSP-P and PSP-RS. The differences in SPECT are less pronounced. The study does not show any advantages of performing combined frontal SPECT and FAB in the differential examination of PSP and CBS. Moreover, PSP-RS and CBS, in a detailed evaluation of the frontal lobe, do not show any significant differences. This is a relatively small study which, however, highlights the relevant features of clinical examination of these rare entities.
The examination of tauopathic atypical parkinsonism remains a difficult issue. The differentiation of progressive supranuclear palsy syndrome and corticobasal syndrome (CBS) is affected by significant overlaps in the diseases' symptomatology. Growing interest is associated with the search for effective tools in the assessment of four-repeat tauopathies and their clinical manifestations (
The diagnosis of PSP-P was not stressed in any of the studies. Regarding the limited feasibility of SPECT in the examination of tauopathic parkinsonism, the authors of this study intended to verify the usefulness of combined examination using assessment of frontal lobe in perfusion and neuropsychological assessment using frontal assessment battery (FAB), a short screening test that evaluates the executive functions.
According to the most recent theories, frontal lobes are responsible for the control of complex functions, such as abstract reasoning, self-regulation, motor programming, mental flexibility, inhibitory control, and environmental autonomy (
Deficits in executive functioning may be observed in PD and also in all atypical parkinsonisms (
FAB is designed to be administered at bedside in about 10 min. It consists of six tasks, each of which was designed to assess one of the main frontal lobe functions (abstract reasoning, mental flexibility, motor programming, inhibitory control, sensitivity to interference, environmental autonomy)15. It is possible to receive zero to three points for each of the test items, giving a maximal total score of 18 points. None of the tasks requires any tools. There is no need for the patient to be able to perform complex movements (which is particularly important while assessing patients with movement disorders, such as Parkinson's Disease or atypical parkinsonian syndromes) (
In this prospective study, all patients gave informed consent to participate in this research. The bioethical committee of the Medical University of Warsaw approved this study. From May 2017 to September 2020, 58 patients, in total, were enrolled. The neurological examination and diagnosis were based on the recent criteria and conducted in the Department of Neurology of the Medical University of Warsaw in all of the cases. The neuropsychological examination was performed by two neuropsychologists working (9 years of experience) in the Department of Neurology at the Medical University of Warsaw and experienced in the assessment of psychological deficiencies in atypical parkinsonism.
Due to the fact that certain patients did not accomplish the examination for various reasons, the authors of this study were forced to exclude about 29.3% of the cases primarily planned for further evaluation. Finally, the research group was based on 41 participants with clinical diagnosis of probable PSP-P, CBS, and PSP-RS and consisted of 18 patients with PSP-RS (11 male, seven female), 11 patients with PSP (six male, five female), and 12 patients with CBS (one male, 11 female). All patients were right-handed, and the duration of the disease varied from 2 to 5 years. Out of the 41 study participants, 23 (56.1%) were female and 18 (43.9%) were male. The mean age was 70.2 years (range, 54–85 years) (
Basic characteristics of research group and subgroups: progressive supranuclear palsy-Richardson–Steele syndrome (PSP-RS), progressive supranuclear palsy-parkinsonism predominant (PSP-P), and corticobasal syndrome (CBS) in relation to single-photon emission computed tomography parameters, frontal assessment battery, and subgroups comparison.
Gender | 23/18 | 7/11 | 6/5 | 11/1 | 0.7276c | 0.0121cy | 0.0509cy | ||||||||||||||||
Age | 70.2 | 54.0 | 85.0 | 6.8 (5.6–8.7) | 71.1 | 59 | 80 | 5.7 (4.3–8.5) | 70.2 | 57 | 77 | 6.9 (4.8–12.1) | 68.9 | 54 | 85 | 8.5 (6–14.5) | 0.713t | 0.4151t | 0.7009t | ||||
FAB | 12.3 | 6.0 | 18.0 | 2.9 (2.4–3.7) | 11.4 | 6 | 18 | 2.9 (2.2–4.3) | 13.9 | 11 | 17 | 1.9 (1.3–3.4) | 12.3 | 7 | 16 | 3.2 (2.2–5.4) | 0.0165t | 0.4481t | 0.1481t | ||||
( |
−1.7 | −6.9 | 2.6 | 1.8 (1.5–2.4) | −1.8 | −6.9 | 1.5 | 1.9 (1.4–2.8) | −0.7 | −3.5 | 2.6 | 2.1 (1.5–3.7) | −2.4 | −3.9 | 0.4 | 1.2 (0.9–2.1) | 0.1765t | 0.2718t | 0.0231t | ||||
( |
−1.6 | −7.2 | 2.5 | 1.8 (1.5–2.3) | −1.8 | −7.2 | 1.4 | 1.9 (1.4–2.8) | −0.6 | −3.4 | 2.5 | 2 (1.4–3.5) | −2.3 | −3.7 | 0.7 | 1.2 (0.8–2) | 0.107t | 0.433t | 0.0202t | ||||
( |
−1.5 | −6.1 | 2.6 | 1.8 (1.5–2.3) | −1.7 | −6.1 | 2 | 1.8 (1.4–2.8) | −0.4 | −3 | 2.6 | 1.9 (1.4–3.4) | −2.3 | −3.8 | 0.9 | 1.2 (0.9–2.1) | 0.1056u | 0.1624u | 0.0138u | ||||
( |
−1.7 | −8.1 | 3.1 | 2 (1.6–2.5) | −1.9 | −8.1 | 1.6 | 2.1 (1.5–3.1) | −0.8 | −3.6 | 3.1 | 2.2 (1.5–3.8) | −2.2 | −5.1 | 0.4 | 1.5 (1.1–2.6) | 0.3012u | 0.5117u | 0.1962u | ||||
( |
−2.8 | −9.6 | 2.3 | 2.3 (1.9–3) | −2.7 | −9.6 | 1.6 | 2.5 (1.8–3.7) | −1.9 | −5.2 | 2.3 | 2.5 (1.7–4.3) | −3.6 | −6.1 | 0.7 | 1.8 (1.2–3) | 0.417t | 0.252t | 0.0634t | ||||
( |
−1.3 | −9.4 | 2.8 | 2.3 (1.9–2.9) | −1.2 | −9.4 | 1.8 | 2.6 (2–3.9) | −0.4 | −4.5 | 2.8 | 2.3 (1.6–4) | −2.1 | −4 | 1 | 1.6 (1.1–2.7) | 0.4448u | 0.049u | 0.0694u | ||||
( |
−2.4 | −9.3 | 2.2 | 2.2 (1.8–2.8) | −2.5 | −9.3 | 1.2 | 2.4 (1.8–3.5) | −1.4 | −5.1 | 2.2 | 2.4 (1.7–4.3) | −3.3 | −5.2 | 0.1 | 1.4 (1–2.3) | 0.236t | 0.3317t | 0.0338t | ||||
( |
−2.6 | −6.0 | 5.2 | 2.2 (1.8–2.9) | −2.4 | −5.8 | 0.5 | 1.9 (1.4–2.8) | −1.9 | −4.3 | 1.7 | 1.9 (1.3–3.3) | −3.4 | −6 | 5.2 | 2.9 (2.1–5) | 0.6531u | 0.0515u | 0.0228u | ||||
( |
−1.5 | −5.6 | 4.8 | 2.2 (1.8–2.8) | −1.5 | −5.1 | 2.1 | 2 (1.5–3) | −1.2 | −5 | 4.8 | 2.6 (1.8–4.6) | −1.7 | −5.6 | 3.1 | 2.2 (1.5–3.7) | 0.7487t | 0.8227t | 0.6556t | ||||
( |
−2.1 | −6.4 | 3.1 | 2.4 (2–3.1) | −2.4 | −6 | 1.7 | 2.2 (1.6–3.3) | −1.7 | −5.7 | 1 | 1.9 (1.3–3.4) | −2 | −6.4 | 3.1 | 3.1 (2.2–5.3) | 0.3903t | 0.7089t | 0.764t | ||||
( |
−1,0 | −5.4 | 4.6 | 2.1 (1.7–2.7) | −1.2 | −5.4 | 3.2 | 2.1 (1.6–3.2) | −1.1 | −5.1 | 1.6 | 2 (1.4–3.4) | −0.7 | −4.2 | 4.6 | 2.2 (1.6–3.8) | 0.8667t | 0.5015t | 0.6415t | ||||
( |
−1.4 | −5.5 | 2.5 | 2.3 (1.9–2.9) | −1.1 | −5.5 | 2.5 | 2.6 (1.9–3.8) | −1.5 | −3.9 | 1.7 | 1.9 (1.3–3.4) | −1.8 | −5.3 | 2.1 | 2.3 (1.7–4) | 0.7112t | 0.4566t | 0.6913t | ||||
( |
−0.5 | −5.3 | 4.4 | 2.3 (1.9–2.9) | −0.3 | −2.9 | 4.2 | 1.9 (1.5–2.9) | −0.9 | −5.3 | 3.4 | 2.9 (2–5.1) | −0.5 | −4.7 | 4.4 | 2.3 (1.6–3.9) | 0.5684t | 0.8298t | 0.7528t | ||||
( |
−1,0 | −3.7 | 3.6 | 1.7 (1.4–2.1) | −0.8 | −3.6 | 3.6 | 1.9 (1.4–2.8) | −0.4 | −2.7 | 2.6 | 1.5 (1.1–2.7) | −1.9 | −3.7 | 0.4 | 1.1 (0.8–1.9) | 0.5015t | 0.075t | 0.0106t | ||||
( |
−1.7 | −8.5 | 3.9 | 2.4 (1.9–3) | −1.5 | −8.5 | 1.2 | 2.2 (1.7–3.4) | −0.9 | −3.3 | 3.9 | 2.4 (1.7–4.3) | −2.7 | −6.5 | 0.4 | 2.3 (1.6–3.9) | 0.9105u | 0.1384u | 0.1569u | ||||
( |
−1.3 | −5.7 | 3.4 | 2.3 (1.9–2.9) | −0.8 | −5.7 | 3.4 | 2.6 (2–3.9) | −1.2 | −4.1 | 1.8 | 1.9 (1.3–3.3) | −2.3 | −5.3 | 1.9 | 1.9 (1.4–3.3) | 0.6958t | 0.111t | 0.1822t | ||||
( |
−1.8 | −5.2 | 3.1 | 2.1 (1.8–2.7) | −1.9 | −5.2 | 3.1 | 2.4 (1.8–3.6) | −1.3 | −3.9 | 2.5 | 1.8 (1.3–3.2) | −2 | −4.1 | 3.1 | 2.1 (1.5–3.5) | 0.486u | 0.8989u | 0.1481u | ||||
( |
−1.1 | −5.7 | 3.3 | 2 (1.7–2.6) | −1.1 | −5.1 | 2.9 | 2 (1.5–3) | 0.3 | −3.4 | 3.3 | 2 (1.4–3.5) | −2.2 | −5.7 | −0.3 | 1.4 (1–2.4) | 0.0803t | 0.1344t | 0.0027t | ||||
( |
−1.2 | −6.2 | 3.1 | 1.8 (1.5–2.4) | −1.4 | −6.2 | 0.9 | 1.8 (1.3–2.7) | −0.2 | −3.9 | 3.1 | 2 (1.4–3.5) | −1.9 | −4.4 | 0.1 | 1.4 (1–2.4) | 0.0953t | 0.4544t | 0.0268t | ||||
( |
−1.1 | −3.9 | 1.5 | 1.3 (1–1.6) | −1.5 | −3.9 | 0.5 | 1.2 (0.9–1.8) | −0.2 | −1.8 | 1.5 | 1.1 (0.8–1.9) | −1.4 | −2.9 | 1.1 | 1.2 (0.8–2) | 0.0091t | 0.9354t | 0.0171t | ||||
( |
−1.2 | −6.9 | 2.2 | 1.7 (1.4–2.2) | −1.6 | −6.9 | 0.4 | 1.7 (1.3–2.6) | −0.3 | −3.7 | 2.2 | 1.9 (1.3–3.3) | −1.3 | −2.9 | 1.7 | 1.4 (1–2.3) | 0.1009u | 0.9325u | 0.1397u | ||||
( |
−1.2 | −10.4 | 2.6 | 2.5 (2–3.1) | −1 | −10.4 | 2.2 | 2.9 (2.2–4.3) | −0.6 | −4.3 | 2.6 | 1.9 (1.3–3.3) | −2.1 | −5.1 | 2.6 | 2.1 (1.5–3.6) | 0.8047u | 0.072u | 0.0489u | ||||
( |
−0.7 | −8.3 | 3.4 | 2.2 (1.8–2.9) | −0.6 | −8.3 | 2 | 2.4 (1.8–3.6) | −0.3 | −3.5 | 3.4 | 2.1 (1.4–3.6) | −1.3 | −4 | 2.7 | 2.2 (1.6–3.7) | 0.9105u | 0.0904u | 0.2184u | ||||
( |
−0.7 | −8.1 | 3.1 | 2 (1.7–2.6) | −0.7 | −8.1 | 2.9 | 2.3 (1.8–3.5) | −0.4 | −4.5 | 2.3 | 1.7 (1.2–3) | −1.1 | −3.2 | 3.1 | 2 (1.4–3.3) | 0.7192u | 0.2276u | 0.1569u | ||||
( |
−1.5 | −11.6 | 2.6 | 2.3 (1.9–3) | −1.6 | −11.6 | 2.2 | 3.1 (2.3–4.6) | −1.2 | −4 | 1 | 1.4 (1–2.4) | −1.4 | −3.5 | 2.6 | 1.9 (1.3–3.2) | 0.9642u | 0.6567u | 0.5588u |
The final research group underwent neuropsychological examination with FAB testing and perfusion assessment using SPECT 99mTc-HMPAO. Due to the fact that the software used in the study to assess perfusion in SPECT shows the results of patients compared to 20 healthy volunteers, due to ethical reasons, SPECT was not additionally conducted on the controls in this study. In order to avoid examining the controls only in neuropsychological examination, the results of the FAB test were compared with the standard results of healthy volunteers from the literature.
In this study, FAB was used due to the relevant role of frontal lobe syndrome in the symptomatology of PSP. The frontal lobe syndrome is generally associated with the Richardson–Steele variant of PSP, as patients affected by this disease often present rapidly progressing changes in behavior. In this context, FAB, regarding its simplicity and possible screening value, may be interpreted as a valuable supplement in the examination of PSP. As growing interest is related to boundaries between parkinsonian syndromes based on four-repeat tauopathies, in the opinion of the authors of the study, extended evaluation of similarities and differences regarding the frontal lobe in PSP-RS, PSP-P, and CBS seem to be an intriguing issue.
SPECT, with technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) as a radiotracer, was used for the evaluation of regional cerebral blood flow. Then, 740 MBq of radiotracer was administered in patients placed in a quiet, dimly lit room in supine position. Examinations were performed with SPECT/CT scan (Symbia T6, Siemens) on dual-head gamma camera with low-energy high-resolution parallel-hole collimator. Step and shoot acquisition mode was used, and sequences of 128 frames on a 128 × 128 matrix were obtained (64 projections per head, 30 s per projection). The photopeak was set at 140 keV with 10% window on either site of the photopeak. Iterative reconstruction (eight iterations, eight subsets, 7 mm Gauss filter), scatter correction, and CT attenuation correction were performed. Post-processing analysis was performed with Scenium software (Siemens Medical Solutions USA, Inc.). The regions of interest (ROIs) were predefined on a high-resolution T1 MRI volume scan. Perfusion in the basal ganglia, frontal lobes, hemispheres of cerebella, and thalami was subsequently examined among all patients. Values of variances from ROIs in individual parts of the frontal lobe on both sides (right and left separately) were taken for statistical analysis.
Statistical analyses were performed using Statistica software (version 13.1, Dell, Inc. Statsoft). The presented data were expressed as means with 95% confidence interval. Data distributions were assessed by Shapiro–Wilk
The mean, maximal, minimal, and standard deviation with 95% confidence interval values of age, frontal assessment battery, and SPECT parameters [divided into right (R) and left (L) sides] are listed in
In the case of PSP-RS, only the FAB turned out to be a significant parameter differentiating this subgroup from the others with AUC of 0.691 (95% CI, 0.522–0.86;
Receiver operating characteristic curve analysis of single-photon emission computed tomography parameters and frontal assessment battery (FAB).
FAB | PSP-RS | D | 12 | 0.691 | 0.522–0.86 | 0.027 | 72.2 | 65.2 | 61.9 | 75 | 68.3 |
FAB | PSP-P | S | 12 | 0.726 | 0.568–0.883 | 0.0049 | 90.9 | 43.3 | 37 | 92.9 | 56.1 |
( |
S | −1.4 | 0.73 | 0.552–0.909 | 0.0115 | 72.7 | 70 | 47.1 | 87.5 | 70.7 | |
( |
S | 0 | 0.748 | 0.567–0.93 | 0.0073 | 63.6 | 83.3 | 58.3 | 86.2 | 78 | |
( |
CBS | D | −1.2 | 0.704 | 0.536–0.872 | 0.0171 | 91.7 | 44.8 | 40.7 | 92.9 | 58.5 |
( |
D | −2.2 | 0.71 | 0.542–0.878 | 0.0145 | 75 | 95.7 | 90 | 88 | 88.6 | |
( |
D | −2.5 | 0.718 | 0.552–0.885 | 0.0103 | 66.7 | 75.9 | 53.3 | 84.6 | 73.2 | |
( |
D | −3.5 | 0.739 | 0.557–0.92 | 0.0102 | 75 | 75.9 | 56.3 | 88 | 75.6 | |
( |
D | −1.4 | 0.728 | 0.566–0.891 | 0.0058 | 83.3 | 69 | 52.6 | 90.9 | 73.2 | |
( |
D | −1 | 0.749 | 0.601–0.896 | 0.001 | 91.7 | 65.5 | 52.4 | 95 | 73.2 |
Receiver operating characteristic curve graph of frontal assessment battery (area under the ROC curve = 0.691) as a predictor for progressive supranuclear palsy-Richardson–Steele syndrome with marked cutoff value.
Receiver operating characteristic curve graphs of
Receiver operating characteristic curve graphs of
Unfortunately, for PSP-RS, it was not possible to build a model based on logistic regression in any combination of the available variables. In the case of PSP-P and CBS, models were successfully built, but only based on single variables. Any other combination and adding of the next variables did not bring any statistically significant changes. For PSP-P, the FAB turned out to be an important parameter, with OR of 29.3 (95% CI, 2.6–336.4;
Logistic regression analysis of progressive supranuclear palsy-parkinsonism predominant (PSP-P) and corticobasal syndrome (CBS) in relation to single-photon emission computed tomography and frontal assessment battery parameters.
FAB | PSP-P | 29.3 | 2.6–336.4 | 0.0311 | 72.4 |
( |
CBS | 6.0 | 1.1–33.4 | 0.0218 | 82.6 |
To the best of our knowledge, this is the first study to evaluate the examination of frontal lobe as a possible factor differentiating variants of PSP in a combined neuropsychological and perfusion assessment perspective. Our data confirm the clinical variability among patients with the two main subtypes of PSP. As the obtained results show, the impairment in executive functions could be a significant factor in the differential diagnosis of PSP variants. The analysis of the results indicate that the dysexecutive syndrome in the parkinsonian variant (PSP-P) might be less severe than in PSP-RS, with the FAB scores oscillating rather above 12 in the first and under 12 in the latter. Such differences could be correlated to distinct tau distribution in the course of PSP in each of its variants (
This study, though presenting minor differences between PSP-RS and CBS, shows that FAB and assessments of perfusion in SPECT present slightly more severe deterioration in CBS. The differences cannot be interpreted as evident as the significant differences in SPECT were observed only in one of the parameters, frontal lobe—Atlas 1 (an area automatically indicated by Scenium software). All other evaluations of the frontal lobe in SPECT did not provide significant differences. This difference does not significantly impact the clinical manifestation and the doubtful boundaries between PSP-RS and CBS. This could be partially explained by similarities of perfusion in the vast majority of ROIs. The combined assessment using FAB and SPECT examination of frontal perfusion does not provide an additional tool in differential diagnosis. The finding confirms the questionable boundaries between the clinical syndromes (
However, considering the variety of possible manifestations of CBS, a further research considering the use of other neuropsychological assessment methods should be done. The frontal–executive variant may, in fact, be hardly distinguished from PSP-RS. The other variants of CBS though (the variants with apraxia, aphasia, or visuospatial deficits dominating the clinical manifestation) (
Earlier evaluations of PSP and CBS generally did not discriminate the variant PSP-RS, which could deviate possible findings. In a study analyzing iodine-123-labeled FP-CIT SPECT, the authors indicated high sensitivity in the examination of PSP (
This study is based on the examination of relatively small groups of patients, which is a result of examining rare entities in a single department. The authors of this study are aware that the methods used in the study are non-specific, should be interpreted as possible supplementary tools, and cannot be evaluated independently when making the diagnosis. The disproportion of the number of males and females in the CBS group is a result of the need to exclude patients who did not fulfill all of the examinations planned in the study. Another limitation associated with this investigation is that the increase in familywise error rate across the reported statistical analyses was not controlled. Overall, we consider this research as a pilot study and encourage replication. The aim of the study was to choose tools which could be accessible in everyday practice.
Neuropsychological examinations of patients based on the FAB tool is important and can be helpful in the diagnosis of the subtypes of PSP: PSP-RS and PSP-P.
For CBS, SPECT shows greater differences of mean variance values from the neutral level in comparison to PSP-RS and PSP-P. This may be related to a more severe clinical course compared to PSP.
Currently, basing on the study group, the multiparametric assessment of patients with PSP-RS, PSP-P, and CBS based on SPECT features and FAB has not achieved greater overall performance than the single-parameter assessment. This implies a need for discerning clinical evaluation of the patient by an experienced clinician during the diagnostic process and use of SPECT and FAB as accessory tools.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by Ethical Committee of the Medical University of Warsaw. The patients/participants provided their written informed consent to participate in this study.
PA study design, data analysis, review of literature, and discussion. BM data analysis, statistical analysis, and discussion. NM data analysis, review of literature, and discussion. KD-W, AD, LK, and AF data analysis and discussion. IC, AS, and MS data analysis. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.