Immune Cell Infiltration Distinguishes PSP from Other Parkinsonian Disorders

Couto B, Forrest SL, Fearon C, Lee S, Knott S, Li J, Fox SH, Tartaglia MC, Lang AE, Kovacs GG. Midbrain cytotoxic T cells as a distinct neuropathological feature of progressive supranuclear palsy. Brain 2025;148(8):2650-2657. doi: 10.1093/brain/awaf135.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy defined by four-repeat tau deposition in neurons and glia, particularly affecting the substantia nigra and midbrain tegmentum. Unlike infectious or autoimmune encephalitides, neurodegenerative diseases generally lack lymphocytic infiltrates. However, immune activation and altered T-cell profiles have been reported in PSP, suggesting a potential autoimmune contribution.

Hypothesis: This study hypothesized that cytotoxic T-cell infiltration is a distinctive neuropathological feature of PSP, potentially linked to tau pathology and microglial activation, and greater in PSP than in Parkinson’s disease (PD) or control brains.

Methods: The authors analyzed post mortem brain samples from nine PSP patients, ten PD patients and six controls. Serial midbrain sections were immunostained for phosphorylated tau, α-synuclein, CD8 and HLA-DR. Cytotoxic T cells were quantified stereologically using Stereo Investigator with an unbiased Fractionator probe, and microglial and protein-pathology loads were measured via HALO image analysis. Statistical comparisons and correlations assessed relationships among CD8 counts, microglia, and pathology load.

Results: CD8-positive cell counts in the substantia nigra were significantly higher in PSP than PD or controls. CD8 cells often contacted neurons in PSP, and their density was greatest in the red nucleus/superior cerebellar peduncle. Microglial activation was also higher in PSP than in controls. CD8-cell counts were independent of disease duration, age or tau load.

Conclusions: These findings identify midbrain cytotoxic T-cell infiltration as a distinctive feature of PSP, suggesting an autoimmune component in its pathogenesis and providing a potential target for future therapeutic exploration.