Atrophy in midbrain & cerebral/cerebellar pedunculi is characteristic for progressive supranuclear palsy - A double-validation whole-brain meta-analysis

Abstract

Objective: Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome characterized by vertical gaze palsy and postural instability. Midbrain atrophy is suggested as a hallmark, but it has not been validated systematically in whole-brain imaging.

Methods: We conducted whole-brain meta-analyses identifying disease-related atrophy in structural MRI. Eighteen studies were identified (N = 315 PSP, 393 controls) and separated into gray or white matter analyses (15/12). All patients were diagnosed according to the National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP criteria, Litvan et al. (1996a)), which are now considered as PSP-Richardson syndrome (Höglinger et al., 2017). With overlay analyses, we double-validated two meta-analytical algorithms: anatomical likelihood estimation and seed-based D mapping. Additionally, we conducted region-of-interest effect size meta-analyses on radiological biomarkers and subtraction analyses differentiating PSP from Parkinson's disease.

Results: Whole brain meta-analyses revealed consistent gray matter atrophy in bilateral thalamus, anterior insulae, midbrain, and left caudate nucleus. White matter alterations were consistently detected in bilateral superior/middle cerebellar pedunculi, cerebral pedunculi, and midbrain atrophy. Region-of-interest meta-analyses demonstrated that midbrain metrics generally perform very well in distinguishing PSP from other parkinsonian syndromes with strong effect sizes. Subtraction analyses identified the midbrain as differentiating between PSP and Parkinson's disease.

Conclusions: Our meta-analyses identify gray matter atrophy of the midbrain and white matter atrophy of the cerebral/cerebellar pedunculi and midbrain as characteristic for PSP. Results support the incorporation of structural MRI data, and particularly these structures, into the revised PSP diagnostic criteria.

Keywords: Anatomical likelihood estimation; Cerebellar pedunculi; Cerebral pedunculi; Imaging biomarker; Meta-analysis; Midbrain; Progressive supranuclear palsy; Seed-based D mapping.

Fig. 1

Brain regions consistently associated with progressive supranuclear palsy. Analysis of gray matter (GM, dark blue) included 257 patients contrasted to 334 healthy subjects. White matter analysis (WM, light blue) included 210 patients contrasted to 265 healthy subjects. Upper image shows effect size estimates (seed-based D mapping, SDM) and bottom image anatomical likelihood estimate (ALE) meta-analyses. Abbreviation: L left. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Overlap analysis. Overlay analysis for impaired brain regions in progressive supranuclear palsy as revealed by anatomical likelihood estimate (ALE) and effect size estimates (seed-based D mapping, SDM) meta-analyses. Results of ALE are shown in red. Results of SDM are shown in green. Yellow clusters indicate overlap of both analyses (ALE and SDM). Upper image displays gray matter (GM) atrophy, bottom image displays white matter (WM) atrophy. Abbreviation: L left. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Brain regions consistently associated with progressive supranuclear palsy in comparison to Parkinson's disease. Analysis of gray matter (GM, dark blue) included 257 patients with PSP contrasted to 809 patients with PD. White matter analysis (WM, light blue) included 210 patients with PSP contrasted to 75 patients with PD. Image shows subtraction anatomical likelihood estimate (ALE) meta-analyses. Abbreviation: L left, PD Parkinson's disease, PSP progressive supranuclear palsy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Effect size (Hedges' g) meta-analyses of radiological biomarkers of progressive supranuclear palsy (PSP) based on Whitwell et al. (2017) and additional literature search. (1) Measurement using 1.5 Tesla, (2) measurement using 3 Tesla, (3) pathologically confirmed, and (4) clinically diagnosed groups. Abbreviation: CI confidence interval, df degrees of freedom, RE random effects, PD Parkinson's disease, MSA multiple system atrophy, MRPI Magnetic Resonance Parkinsonism Index.

Fig. 5

Meta-analyses confirm proposed pathognomonic imaging markers of progressive supranuclear palsy (PSP). Left column shows meta-analytic results (green seed-based D mapping – SDM – analysis, red anatomical likelihood estimation analysis – ALE –, and yellow overlay). Right column depicts individual examples of corresponding structural magnetic resonance images of individual PSP patients with midbrain atrophy. Images in the middle are the silhouettes of a penguin, a hummingbird, and Mickey Mouse projected onto these patients' brain images. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)