Staging of progressive supranuclear palsy-Richardson syndrome using MRI brain charts for the human lifespan

Abstract

Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy-Richardson syndrome. We combined multiple datasets (n = 8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n = 62 MRI of progressive supranuclear palsy-Richardson syndrome patients from the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI)) to extrapolate lifetime volumetric models of healthy and progressive supranuclear palsy-Richardson syndrome brain structures. We then mapped in time and space the sequential divergence between healthy and progressive supranuclear palsy-Richardson syndrome charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe, and (vi) occipital lobe. The three structures with the most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in progressive supranuclear palsy-Richardson syndrome, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.

Keywords: MRI; Richardson syndrome; brain charts; progressive supranuclear palsy; staging.

Graphical abstract

Figure 1

Lifespan trajectories based on z-scores of normalized brain volumes for cognitively normal (CN) subjects (in black) and patients with PSP-RS (in blue). Black dots represent all healthy individuals and blue dots patients with PSP-RS. The orange curves represent the distance between the healthy and PSP-RS models. The orange areas indicate the time period where confidence intervals at 95% of both models do not overlap. Only models detected as significantly different between healthy aging and PSP-RS are presented in this figure. In AssemblyNet, the ventral diencephalon regroups the hypothalamus, the mammillary bodies, the subthalamic nuclei, the substantia nigra, the red nuclei and the geniculate nuclei. Suppl: Supplementary; Inf: Inferior.

Figure 2

The MRI staging scheme of PSP-RS. The upper panel maps the progression of atrophy in the three axes (all brain structures identified in Fig. 1). The lower panel is a timeline representing the sequential divergence of significantly atrophied structures between healthy and PSP-RS volumetric trajectories. The effect-size of structural divergence is color-coded according to the bar at the bottom right of the figure. In AssemblyNet, the ventral diencephalon regroups the hypothalamus, the mammillary bodies, the subthalamic nuclei, the substantia nigra, the red nuclei and the geniculate nuclei. Suppl: Supplementary; Inf: Inferior; CN: cognitively normal.