Pathomechanisms of Cognitive Impairment in Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by early postural instability and falls, oculomotor dysfunction (vertical supranuclear gaze palsy), parkinsonism with poor response to levodopa, pseudobulbar palsy, and cognitive impairment. This four-repeat tauopathy is morphologically featured by accumulation of tau protein in neurons and glia causing neuronal loss and gliosis in the extrapyramidal system associated with cortical atrophy and white matter lesions. Cognitive impairment being frequent in PSP and more severe than in multiple system atrophy and Parkinson disease, is dominated by executive dysfunction, with milder difficulties in memory, and visuo-spatial and naming dysfunctions. Showing longitudinal decline, it has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, such as involvement of cholinergic and muscarinergic dysfunctions, and striking tau pathology in frontal and temporal cortical regions associated with reduced synaptic density. Altered striatofrontal, fronto-cerebellar, parahippocampal, and multiple subcortical structures, as well as widespread white matter lesions causing extensive connectivity disruptions in cortico-subcortical and cortico-brainstem connections, support the concept that PSP is a brain network disruption disorder. The pathophysiology and pathogenesis of cognitive impairment in PSP, as in other degenerative movement disorders, are complex and deserve further elucidation as a basis for adequate treatment to improve the quality of life of patients with this fatal disease.