In:
Brain, Oxford University Press (OUP), ( 2024-06-06)
Abstract:
4-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R-tauopathies are progressive-supranuclear-palsy (PSP) and corticobasal-degeneration (CBD) characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aβ-negative patients with clinically diagnosed PSP variants (n=26) or Corticobasal Syndrome (CBS; n=25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol, to determine an early 0.5-2.5 min post-tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post-tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early-window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlasses. We determined tau epicenters as subcortical regions with highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicenters to cortical ROIs using a resting-state fMRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether i) higher subcortical tau-PET was associated with reduced cortical perfusion and ii) whether cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicenters. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicenters aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.
Type of Medium:
Online Resource
ISSN:
0006-8950
,
1460-2156
DOI:
10.1093/brain/awae174
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2024
detail.hit.zdb_id:
1474117-9
SSG:
12
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