ABSTRACT
Background
The diagnostic value of midbrain atrophy for distinguishing behavioral variant frontotemporal dementia (bvFTD) from progressive supranuclear palsy (PSP) is unclear.
Objective
To investigate whether measures of midbrain atrophy differentiate PSP from bvFTD.
Methods
We included four groups: healthy controls (n = 19), PSP‐Richardson syndrome (n = 20), bvFTD (n = 19) and Parkinson's disease (PD; n = 12). The following quantitative and qualitative measures were calculated: Hummingbird sign rating scale [HBS‐RS], global midbrain atrophy [GMA], midbrain area, midbrain/pons ratio, the Magnetic Resonance Parkinsonism Index (MRPI), the MRPI 2.0 and brainstem volume.
Results
Compared to controls, PSP and bvFTD had lower values of midbrain area, HBS‐RS and GMA, and higher MRPI and MRPI 2.0. HBS‐RS, GMA, midbrain/pons ratio, midbrain area, MRPI, MRPI 2.0 and brainstem volume distinguished PSP from bvFTD with 73%, 67%, 75%, 83%, 71%, 69% and 82% accuracies, respectively.
Conclusions
Both quantitative and qualitative measures of midbrain atrophy provided modest accuracy in distinguishing PSP from bvFTD.
Keywords: progressive supranuclear palsy, frontotemporal dementia, parkinsonism, neuroimaging, midbrain atrophy
Neuroimaging is a valuable tool in the diagnostic framework of neurodegenerative diseases, especially when the distinction between diseases is hampered by overlapping clinical features. Progressive supranuclear palsy (PSP) is an example of clinical syndrome with prominent interface with other syndromes, such as behavioral variant frontotemporal dementia (bvFTD). 1 , 2 Accordingly, the differential diagnosis between PSP and bvFTD can be challenging.
PSP is a rare cause of parkinsonism with marked clinical heterogeneity, with Richardson syndrome (PSP‐RS) being the most common presentation. 3 , 4 PSP‐RS manifests as vertical supranuclear gaze palsy, early postural instability, levodopa‐resistant bradykinesia, and axial rigidity. In addition to the motor findings, PSP patients also present with cognitive changes related to frontal involvement. 3 Indeed, executive functions and social cognition are impaired in PSP, similar to bvFTD. 5 , 6 Patients with PSP may also exhibit marked frontal behavioral changes, 7 , 8 which can be mistakenly attributed to bvFTD. 9 These cognitive/behavioral features align with prefrontal/temporal atrophy, which occurs in both PSP and bvFTD. 5 , 6 , 10
While prefrontal atrophy is common to both PSP and bvFTD, midbrain atrophy has been considered a neuroimaging marker of PSP. 11 , 12 , 13 , 14 , 15 , 16 The atrophy of rostral midbrain tegmentum on mid‐sagittal MRI is described as the “penguin” or “hummingbird” sign. 15 In addition, the concavity of the lateral margin of the tegmentum associated with reduced anteroposterior diameter of the tegmentum on axial MRI is known as the “morning glory” or the “Mickey mouse” sign. 16 Both the “hummingbird” and the “morning glory” signs offer excellent diagnostic accuracy for distinguishing PSP from healthy controls. 15 Midbrain atrophy and combined measures of midbrain, pons and cerebellar peduncles (eg, the “Magnetic Resonance Parkinsonism Index” 17 ) are also helpful in distinguishing PSP from other parkinsonian disorders, such as Parkinson's disease (PD) and multiple system atrophy. 15 , 18 , 19 , 20 , 21 , 22 , 23
Previous studies have found that PSP and bvFTD may exhibit similar degrees of prefrontal atrophy. 5 , 6 However, the diagnostic significance of midbrain atrophy patterns in distinguishing bvFTD from PSP is unclear. Here, we examined whether qualitative and quantitative measures of midbrain atrophy can differentiate between both disorders. We hypothesized that midbrain measures would effectively distinguish between bvFTD and PSP, with PSP showing worse midbrain atrophy.
Methods
This study was conducted at the University Hospital of the Universidade Federal de Minas Gerais (Belo Horizonte, Brazil). The local ethics committee approved this study. All participants signed an Informed Consent Form before enrolment.
We included four groups of participants (Table 1): healthy controls (n = 19), PSP‐Richardson syndrome (n = 20), 24 bvFTD (n = 19), 9 and Parkinson's disease (PD; n = 12). 25 All participants underwent clinical and cognitive assessments. Of note, we carefully examined patients to avoid the inclusion of PSP‐frontal phenotype at the bvFTD group, and no bvFTD patient had abnormal eye movements. All patients from the PSP and PD groups were at mild to moderate stages (scores on the Hoehn & Yahr scale between stages 1–4; the minimal score of the PSP group on the Hoehn & Yahr scale was 2). All patients underwent clinical follow‐up for at least 24 months to increase diagnostic reliability. Healthy controls had no history of neurologic or psychiatric disorders.
TABLE 1.
Demographical and clinical data (mean ± standard deviation)
| Controls [n = 19] | bvFTD [n = 19] | PSP [n = 20] | PD [n = 12] | Kruskal‐Wallis Test | |
|---|---|---|---|---|---|
| Male:Female (numbers) | 6:13 | 11:8 | 10:10 | 7:5 | NA |
| Age (years) | 63.2 ± 10.1 | 63.4 ± 9 | 67.9 ± 6.9 | 61.8 ± 10 | NS |
| Education (years) | 12.6 ± 2.6 | 12.5 ± 2.7 | 12.9 ± 4.3 | 4 ± 2.2*,** | p < 0.0001 |
| Disease duration (years) | NA | 3.5 ± 2.2 | 3.7 ± 2.0 | 7.1 ± 4.1 | p < 0.0001 |
| Hoehn & Yahr scale (0–5) | NA | NA | 2.7 ± 0.8 | 2.6 ± 1.2 | NS |
| Mini‐Mental State Exam (/30) | 29 ± 0.9 | 23.9 ± 3.9* | 25.8 ± 2.5* | 23.5 ± 3.5* | p < 0.0001 |
| Frontal Assessment Battery (/18) | 15.8 ± 1.7 | 11.3 ± 3.8* | 11.1 ± 3.7* | 16 ± 1.5 | p < 0.0001 |
| Global Midbrain Atrophy (total score, 0–3) | 0.84 ± 0.8 | 1.84 ± 0.9* | 2.4 ± 0.7* | 1.25 ± 1.1 | p < 0.0001 |
| Normal | 7/19 (37%) | 1/19 (5%) | 0/20 (0%) | 2/12 (16%) | NA |
| Mild | 9/19 (47%) | 4/19 (21%) | 2/20 (10%) | 5/12 (42%) | NA |
| Moderate | 2/19 (10%) | 8/19 (42%) | 8/20 (40%) | 2/12 (16%) | NA |
| Severe | 1/19 (5%) | 5/19 (26%) | 10/20 (50%) | 2/12 (16%) | NA |
| Hummingbird sign rating scale | 2.52 ± 2 | 5.47 ± 2.3* | 7.05 ± 1.8* | 3.58 ± 2.1 | p < 0.0001 |
| Midbrain to pons ratio | 0.66 ± 0.6 | 0.61 ± 0.1 | 0.53 ± 0.1* | 0.62 ± 0.1 | p < 0.0001 |
| Brainstem volume (mm3) | 21.4 ± 2.4 | 20.9 ± 1.7 | 18.1 ± 2.6*,** | 19.8 ± 6.9 | p < 0.001 |
| MRPI | 10.6 ± 3.1 | 13 ± 4* | 15.9 ± 4.1* | 11.7 ± 2.6 | p < 0.0001 |
| MRPI 2 | 1.6 ± 0.7 | 3.0 ± 1.4* | 4.1 ± 1.7* | 2.0 ± 0.9 | p < 0.0001 |
| Midbrain area | 1.2 ± 0.2 | 0.97 ± 0.2* | 0.72 ± 0.2*,** | 1.03 ± 0.15 | p < 0.0001 |
Abbreviations: bvFTD, behavioral variant frontotemporal dementia; MRPI, magnetic resonance parkinsonism index; MRPI 2.0, MRPI: magnetic resonance parkinsonism index 2.0; NA, Not applicable; NS, Not significant; PD, Parkinson's disease; PSP, Progressive Supranuclear Palsy.
p < 0.001 (Mann–Whitney test, Bonferroni correction) versus Healthy Controls.
p < 0.001 (Mann–Whitney test, Bonferroni correction) versus bvFTD.
MRI Acquisition
All participants underwent whole‐brain MRI on a 3 T Philips scan. T1‐weighted images were acquired: multishot 256 TFE factor (TR/TE 5.4/2.4 ms, 256 × 256 matrix, FOV 256 × 256 × 180, flip angle 8°), slice thickness 1 mm, coronal orientation, voxel size 1 × 1 × 1 mm3. The delay between MRI and clinical assessment was shorter than 3 months for all participants.
Neuroimaging Measures
One neurologist with experience in movement disorders analyzed T1 MR images with RadiAnt DICOM Viewer software (Medixant, Poland). They were blinded to the diagnoses, and images were analyzed randomly. They evaluated the Hummingbird Sign Rating Scale (HBS‐RS) 13 and the scale of global midbrain atrophy (GMA). 16 Higher scores indicate more significant atrophy for both scales.
Midbrain and pons measurements were performed by a second rater with experience in neuroanatomy. The measurements were calculated using RadiAnt software, following procedures described elsewhere. 14 Briefly, the rater extracted the maximal anterior–posterior measurements of the midbrain and pons on a midsagittal slice. Once again, the investigator was blind to the diagnosis. The midbrain to pons ratio was calculated by dividing the midbrain by the pons measures. Lower ratios indicate worse midbrain atrophy. The midbrain area was measured on midsagittal slice, as previously described. 17 , 26 We also calculated the MRPI 17 and the MRPI 2.0. 18
For volumetric analysis, the MRI data were preprocessed following a standard protocol. 27 Subcortical volume estimations were obtained with Freesurfer v7 (http://surfer.nmr.mgh.harvard.edu); brainstem volumes were obtained via a whole‐brain automatic “aseg” segmentation procedure. 28
Statistical Analyses
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS 22 (IBM, USA)). The chi‐square test was used to compare categorical variables. The normal distribution of data was checked using the Kolmogorov–Smirnov test, refuting the assumption of normality. We therefore used non‐parametric tests (Kruskal‐Wallis and Mann–Whitney U tests) for comparisons. We applied Bonferroni correction for multiple comparisons, and the level of significance (α) was set at 0.006.
Results
Table 1 presents demographical, clinical, and neuroimaging data. There were no significant differences in age and sex distribution among the groups. Individuals with PD had a lower educational level than the other groups. Disease duration was similar between individuals with PSP and bvFTD, but the PD group had a longer disease duration compared to bvFTD and PSP.
Controls had lower scores on the HBS‐RS (sum of all items) than bvFTD and PSP groups (Table 1 and Fig. 1A). Patients with PD did not differ from controls on the HBS‐RS. There was no difference between PSP and bvFTD groups on the HBS‐RS (controls = PD < bvFTD = PSP).
Figure 1.
(A) Individual and groups (healthy controls, behavioral variant frontotemporal dementia [FTD], Parkinson's disease [PD] and Progressive Supranuclear Palsy [PSP]) scores on the Hummingbird Sign—Rating Scale (HBS‐RS). (B) Individual and groups (controls, FTD, PD and PSP) scores on the scale of global midbrain atrophy. (C) Individual and groups (controls, FTD, PD and PSP) scores on the midbrain to pons ratio. (D) Individual and groups (controls, FTD, PD and PSP) brainstem volumes. (E) Individual and groups (controls, FTD, PD and PSP) scores on the Magnetic resonance Parkinsonism Index (MRPI). (F) Individual and groups (controls, FTD, PD and PSP) scores on the MRPI 2.0. (G) Individual and groups (controls, FTD, PD and PSP) measures of midbrain atrophy.
Patients with bvFTD and PSP displayed higher GMA index scores than control and PD groups (Fig. 1B). No difference was found between bvFTD and PSP, while individuals with PD had similar scores to controls (controls = PD < bvFTD = PSP). Severe GMA was observed in 10/20 (50%) and 5/19 (26%) of the individuals with PSP and bvFTD, respectively (Table 1, Fig. 1B).
Patients with PSP displayed higher MRPI and MRPI 2.0 scores than control and PD groups (Fig. 1E,F); no difference was found between bvFTD and PSP. Individuals with PD did not differ from controls in these indexes.
PSP group had lower midbrain area than controls, PD and bvFTD groups (Fig. 1G). Patients with bvFTD had lower midbrain area than controls, while individuals with PD did not differ from controls.
Compared to controls, PSP had significantly lower midbrain:pons ratios (Fig. 1C). No difference was found between PD and controls, bvFTD and controls, or bvFTD and PSP.
Individuals with PSP had lower brainstem volumes than all groups (Fig. 1D). No difference was found between PD and controls (PSP < controls = PD = bvFTD).
Table S1 presents diagnostic accuracies for all measures. The midbrain area provided the best diagnostic accuracies in distinguishing PSP from controls, and PSP from PD. Qualitative and quantitative measures provided limited diagnostic accuracy (67–83%) in differentiating PSP from bvFTD (Fig. S1).
Discussion
This study pioneered the investigation of the diagnostic value of midbrain measures in distinguishing PSP from bvFTD. By using a multimodal approach, we found that measures of midbrain atrophy only slightly helped to differentiate between PSP and bvFTD, contrarily to our hypothesis.
Midbrain atrophy is commonly observed in PSP, 12 , 13 , 14 , 15 , 16 , 20 even at early stages. 29 Qualitative and quantitative measures of midbrain atrophy help distinguish PSP from PD. 15 , 17 , 18 , 20 , 22 , 23 , 30 In our study, the midbrain area, the MRPI 2.0 and the HBS‐RS provided optimal accuracies (94–96%) for differentiating PSP from PD. This is in line with previous data 15 , 18 , 26 , 31 showing that these measures are helpful in clinical settings, facilitating the discrimination between PSP and PD.
However, midbrain atrophy is not a pathognomonic hallmark of PSP, being observed in several other neurological conditions, such as dementia with Lewy bodies, idiopathic normal pressure hydrocephalus, vascular parkinsonism and corticobasal syndrome. 32 , 33 , 34 , 35 , 36 , 37 , 38 Our findings indicate that midbrain atrophy is also found in bvFTD. Controls differed from bvFTD patients on midbrain measures. Previous data found that bvFTD patients with extrapyramidal signs have brainstem atrophy. 39 In the present study, patients with bvFTD did not manifest parkinsonism and, as an original contribution, we found that midbrain atrophy may be observed in bvFTD even in the absence of extrapyramidal signs.
Taken together, these results reinforce the idea that while midbrain atrophy is often associated with PSP, it should not be considered a specific marker of PSP. Indeed, a clinicopathological study demonstrated that midbrain atrophy is present in patients with clinical features of PSP, regardless of their pathological findings. 36 On the contrary, patients with confirmed PSP pathology, but with no clinical features of PSP, did not present midbrain atrophy. 36
PSP and bvFTD showed no major differences in midbrain atrophy measures, except for brainstem volumes and midbrain area, which were lower in PSP patients. Although the group difference was statistically significant, the clinical significance of this finding is uncertain and should be interpreted cautiously. It is important to note that these measures require extensive and time‐consuming processing of neuroimaging data, which limits its clinical applicability. Semi‐automatized tools for segmentation are available on clinical settings, but their diagnostic accuracy for differentiating bvFTD and PSP warrants confirmation.
While structural neuroimaging is a helpful tool in the diagnostic framework of neurodegenerative diseases, our findings reinforce that imaging markers should always be considered in light of medical history and careful neurological examination. The future development of fluid biomarkers of neurodegenerative diseases may provide optimal distinction between PSP and bvFTD by targeting specific underlying pathophysiological mechanisms of these diseases. 40
We are aware of the study's limitations, mainly the small sample size. Even if our sample is similar to other studies, 6 , 26 , 32 our findings should be confirmed in a larger series. We did not analyze other measures such as basal ganglia volumes, cerebral/cerebellar pedunculi, midbrain volume and cortical thickness, which may help differentiating bvFTD from PSP. 20 , 35 Here we included patients with Richardson presentation of PSP; future studies should also include other phenotypic presentations. A major limitation is that qualitative tools were performed by only one rater. The next studies should provide measures and classification performances from at least two different raters, checking for the inter‐rater reliability.
Despite these caveats, our results are meaningful to clinical settings for the differential diagnosis between bvFTD and PSP. Additionally, our findings contribute to the growing evidence of the connection between PSP and bvFTD, highlighting their complex relationship.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
M.C.Q.S.C.:1A, 1C, 3B.
S.C.:1A, 1C, 3B.
V.R.J.: 1C, 3B.
N.P.R.: 2C, 3B.
A.L.T.: 3B.
T.O.M.: 1C, 3B.
E.P.F.R.: 2C, 3B.
F.E.C.C.: 1C, 3B.
P.C.: 1C, 3B.
L.C.S.: 1A, 1C, 2A, 2B, 3A.
All authors read and approved the final manuscript.
Disclosures
Ethical Compliance Statement: The local ethics committee of the Universidade Federal de Minas Gerais approved this study protocol (number of approval: CAAE 17850513.2.0000.5149). All participants gave written informed consent prior to inclusion. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: PC is supported by Brazilian National Council for Scientific and Technological Development (CNPq—bolsa de produtividade em pesquisa). VRJ is supported by CNPq (bolsa de iniciação científica). ALT is supported by the Orme Chair in Alzheimer's and Neurodegenerative Disease Research. SC has received an award from The Michael J. Fox Foundation. NPR receives research funds from the Diana & Conrad Weil, Jr. Family Foundation, the Huntington's Disease Society of America, and the Alzheimer's Association. This work was partially supported by CNPq (402853/2012‐1 and 474748/2012‐0). The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: EPFR received honoraria from Proneuro for the preparation of educational materials, from Novo Nordisk for conference attendance, and from Roche for participation in educational activities. PC has received honoraria for participation in advisory boards for Aché, Danone, Eurofarma, Knight Therapeutics and for preparation of material for continuous medical education and participation as speaker in symposia sponsored by Aché, Danone, Grupo Fleury e Novo Nordisk. LCS has received honoraria for participation in advisory boards for Biogen and Lilly, and for the development of continuing medical education material and participation as speaker in symposia sponsored by Abbott, Biogen, Knight, and Novo Nordisk; he is a principal investigator in a clinical trial for PassageBio. MCQSC, SC, VRJ, NPR, ALT, TOM and FECC declare that there are no additional disclosures to report.
Supporting information
Figure S1. (A) Receiver Operator Characteristic (ROC) curve for the Hummingbird Sign—Rating Scale (HBS‐RS), for the diagnostic distinction between the behavioral variant of frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP). (B) ROC curve for the scale of global midbrain atrophy for the diagnostic distinction between FTD and PSP. (C) ROC curve for the pons to midbrain ratio for the diagnostic distinction between FTD and PSP. (D) ROC curve for the brainstem volumes for the diagnostic distinction between FTD and PSP. (E) ROC curve for the Magnetic resonance Parkinsonism Index (MRPI) for the diagnostic distinction between FTD and PSP. (F) ROC curve for the MRPI 2.0 for the diagnostic distinction between FTD and PSP. (G) ROC curve for the midbrain area for the diagnostic distinction between FTD and PSP.
Table S1. Diagnostic accuracy for qualitative and quantitative measures. Results are presented as area under the curve (95% confidence interval; p value). AUC, Area under the curve; bvFTD, behavioral variant frontotemporal dementia; GMA, Global Midbrain atrophy; HBS‐RS, Hummingbird sign rating scale; MRPI, magnetic resonance parkinsonism index; MRPI 2.0, MRPI, magnetic resonance parkinsonism index 2.0; NA, Not applicable; NS, Not significant; PD, Parkinson's disease; PSP, Progressive Supranuclear Palsy.
Acknowledgments
We thank our patients and their families for their generous contribution to scientific research. We also thank Leonardo Dornas de Oliveira, MD; Maciel Eduardo Pontes, MD, and Rodrigo Santiago Gomez, MD, for referring PSP patients for this study. We thank the reviewers for their critical insights on the first version of the manuscript.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
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Supplementary Materials
Figure S1. (A) Receiver Operator Characteristic (ROC) curve for the Hummingbird Sign—Rating Scale (HBS‐RS), for the diagnostic distinction between the behavioral variant of frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP). (B) ROC curve for the scale of global midbrain atrophy for the diagnostic distinction between FTD and PSP. (C) ROC curve for the pons to midbrain ratio for the diagnostic distinction between FTD and PSP. (D) ROC curve for the brainstem volumes for the diagnostic distinction between FTD and PSP. (E) ROC curve for the Magnetic resonance Parkinsonism Index (MRPI) for the diagnostic distinction between FTD and PSP. (F) ROC curve for the MRPI 2.0 for the diagnostic distinction between FTD and PSP. (G) ROC curve for the midbrain area for the diagnostic distinction between FTD and PSP.
Table S1. Diagnostic accuracy for qualitative and quantitative measures. Results are presented as area under the curve (95% confidence interval; p value). AUC, Area under the curve; bvFTD, behavioral variant frontotemporal dementia; GMA, Global Midbrain atrophy; HBS‐RS, Hummingbird sign rating scale; MRPI, magnetic resonance parkinsonism index; MRPI 2.0, MRPI, magnetic resonance parkinsonism index 2.0; NA, Not applicable; NS, Not significant; PD, Parkinson's disease; PSP, Progressive Supranuclear Palsy.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.