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. 2024 Sep;39(9):1493-1503.
doi: 10.1002/mds.29887. Epub 2024 Jun 17.

Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy

Edoardo Gioele Spinelli  1   2   3 , Alma Ghirelli  1   2   3 , Ilaria Bottale  1   2   3 , Silvia Basaia  1 , Elisa Canu  1 , Veronica Castelnovo  1 , Maria Antonietta Volontè  3 , Sebastiano Galantucci  3 , Giuseppe Magnani  3 , Francesca Caso  3 , Giordano Cecchetti  1   3   4 , Paola Caroppo  5 , Sara Prioni  5 , Cristina Villa  5 , Keith A Josephs  6 , Jennifer L Whitwell  7 , Massimo Filippi  1   2   3   4   8 , Federica Agosta  1   2   3
Affiliations

Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy

Edoardo Gioele Spinelli et al. Mov Disord. 2024 Sep.

Abstract

Background: Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances.

Objective: This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS).

Methods: Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution.

Results: The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001).

Conclusions: This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: MRI; RS fMRI; SFC; progressive supranuclear palsy; resting‐state functional MRI; stepwise functional connectivity.

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Conflict of interest statement

Potential conflicts of interest. EG Spinelli was co-financed by the Next Generation EU [DM 1557 11.10.2022]. The views and opinions expressed are only those of the authors and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.J Whitwell reports support from the US National Institutes of Health (R01-NS89757) and the Dana Foundation F Agosta reports support from European Research Council (StG-2016_714388_NeuroTRACK) and Foundation Research on Alzheimer Disease.

Figures

Figure 1.
Figure 1.. Identification of disease epicenter.
(A) Results of voxel-based morphometry analysis showing regions of significant brain atrophy in path-proven PSP-RS patients of the Mayo Clinic cohort when compared with healthy controls. Significant clusters are overlaid on the axial sections of the Montreal Neurological Institute (MNI) standard brain. Analyses were corrected for age, sex, and total intracranial volume. Statistical threshold for significance was p<0.05, FWE-corrected for multiple comparisons. (B) A 10-mm radius sphere overlaid on the MNI standard brain shows the identified peak of atrophy in the left midbrain. Abbreviations: FWE= Family-Wise Error; L= left hemisphere; PSP-RS = Progressive Supranuclear Palsy – Richardson’s Syndrome; R= right hemisphere.
Figure 2.
Figure 2.. Stepwise functional connectivity alterations in PSP-RS patients.
Cortical and subcortical differences between PSP-RS patients and age-matched healthy controls (HC-old) from the main cohort in stepwise functional connectivity of the left midbrain (red-yellow = lower functional connectivity, blue-green = higher functional connectivity). Statistical threshold for significance was p<0.05, FWE-corrected for multiple comparisons. Abbreviations: FWE= Family-Wise Error; HC= healthy controls; L= left hemisphere; PSP-RS = Progressive Supranuclear Palsy – Richardson’s Syndrome; R= right hemisphere; SFC= stepwise functional connectivity.
Figure 3.
Figure 3.. SFC architecture from disease epicenters in young healthy subjects.
Average stepwise functional connectivity maps in young healthy controls (HC-young) using the left midbrain as seed ROI. Results are depicted in surface space. Red-yellow indicates high strength of connectivity; blue-violet indicates low strength of connectivity. Abbreviations: SFC= stepwise functional connectivity.
Figure 4.
Figure 4.. Correlation analysis
between average step distance from the left midbrain in HC-young subjects and average volume in PSP-RS patients from the main cohort for each of the 90 brain regions of the AAL atlas. Color legend represents regional distribution of each AAL label. Abbreviations: AAL= Automated Anatomical Labeling; HC= healthy controls; PSP-RS= Progressive Supranuclear Palsy – Richardson’s Syndrome.
See this image and copyright information in PMC

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