Abstract
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.
Highlights
perivascular vesicular astrocytes (PVA) were morphologically and immunophenotypically distinct from the tufted astrocytes seen in Progressive supranuclear palsy (PSP), granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in Corticobasal degeneration (CBD)
Neither sibling had mutations in microtubule-associated protein tau (MAPT) or valosin-containing protein (VCP) which are the only known genes linked to autosomal dominant forms of primary tauopathy [11]
Gosuranemab treatment was not associated with obvious clearance of FTLD-tau aggregates
Summary
Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 613A Stellar Chance Laboratories, 422. Penn Memory Center, Department of Neurology, Perelman. Parkinson’s Disease and Movement Disorders Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative disorder that causes motor deficits including gait disturbance, postural instability, and vertical gaze palsy, as well as cognitive dysfunction [13]. PSP is a 4-repeat (4R) tauopathy and is a subtype of frontotemporal lobar degeneration with tau inclusions (FTLD-tau) which are primary tauopathies where tau protein accumulation is central to disease pathogenesis [15]. Corticobasal degeneration (CBD) is a 4R tauopathy characterized by
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