Primary Hypothesis: 4R-tau pathology in PSP initiates in specific brainstem nuclei (particularly the sublaterodorsal nucleus and cholinergic tegmental nuclei) before spreading to subcortical structures and ultimately the cortex in a predictable pattern that correlates with clinical phenotypes.
Secondary Hypotheses:
The specific initiation zone determines whether patients develop PSP (brainstem predilection) vs CBS (cortical predilection)
Functional connectivity patterns facilitate templated propagation along specific neural networks
The presence of specific genetic variants (MAPT H1/H2, GWAS hits) modifies the initiation zone
Open Question Source
This experiment addresses the critical understanding gap identified in the [CBS/PSP Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap) Phase 2:
"Where does tau initiate and how does it spread through networks?"
Also complements existing experiments:
[Tau Spreading Network Mapping via Spatial Transcriptomics](/experiments/tau-spreading-network-mapping-psp) (existing experiment 22, focuses on molecular signatures)
This experiment focuses on anatomical initiation and propagation patterns
Validation Protocol
Study Design
...
Tau Pathology Initiation Zone
Hypothesis
Primary Hypothesis: 4R-tau pathology in PSP initiates in specific brainstem nuclei (particularly the sublaterodorsal nucleus and cholinergic tegmental nuclei) before spreading to subcortical structures and ultimately the cortex in a predictable pattern that correlates with clinical phenotypes.
Secondary Hypotheses:
The specific initiation zone determines whether patients develop PSP (brainstem predilection) vs CBS (cortical predilection)
Functional connectivity patterns facilitate templated propagation along specific neural networks
The presence of specific genetic variants (MAPT H1/H2, GWAS hits) modifies the initiation zone
Open Question Source
This experiment addresses the critical understanding gap identified in the [CBS/PSP Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap) Phase 2:
"Where does tau initiate and how does it spread through networks?"
Also complements existing experiments:
[Tau Spreading Network Mapping via Spatial Transcriptomics](/experiments/tau-spreading-network-mapping-psp) (existing experiment 22, focuses on molecular signatures)
This experiment focuses on anatomical initiation and propagation patterns
Validation Protocol
Study Design
Type: Multi-center cross-sectional + longitudinal post-mortem and imaging study
Cohort:
Early-stage PSP (n=50): PSP-RS, disease duration <3 years
Early-stage CBS (n=30): Probable CBS, disease duration <3 years
Advanced PSP (n=30): Disease duration >5 years
Controls (n=30): Age-matched, no neurodegenerative pathology
Phase 1: Post-Mortem Mapping
Tissue Collection
Brain regions (systematic sampling):
Brainstem: Sublaterodorsal nucleus, pedunculopontine nucleus, dorsal raphe, locus coeruleus