Characterisation of cortical pathology and clinicopathological correlates in progressive supranuclear palsy

This thesis characterises the cortical pattern of degeneration in progressivesupranuclear palsy (PSP) and its consequences. Global atrophy was first examinedusing a recently developed staging scheme in pathologically-proven PSP casescompared with other tauopathies: gross atrophy was not observed in PSP.Quantification of regional volume loss throughout the brain was then used todetermine the magnitude of more focal tissue atrophy in PSP, cortical dysfunction wasinvestigated by measuring cerebral blood flow (CBF) changes, and several corticalcellular pathologies were analysed. Any changes observed were related to each otherand clinical assessments of motor, cognitive and behavioural abnormalities.At mid-stage PSP, frontal and subcortical atrophy related to decreased CBF inthe frontal cortex and cognitive decline. Parietocerebellar CBF increases were alsoidentified (related to frontal CBF deficits) and related to motor and non-motor deficits.By end-stage PSP, focal atrophy had advanced from frontal and subcortical structuresto include atrophy in the parietal lobe. Parietal lobe atrophy related to behaviouralabnormalities. Histopathological analysis at end-stage revealed that the corticalatrophy and cell loss does not relate to tau deposition. The focal cortical cell lossrelated exclusively to motor deficits whilst the more widespread cortical tau depositionrelated to cognitive and behavioural impairments. Both the tau deposition and thesenon-motor impairments increased in severity over time. The results show that frontalatrophy and dysfunction occurs rapidly and early in PSP and relate to increasingcognitive deficits. Such deficits appear to cause compensatory CBF enhancement inparietocerebellar regions which then also undergo rapid and severeneurodegeneration. These later changes occur in concert with the more classic PSPsymptoms, such as oculomotor features. Throughout the disease, the progressiveincrease in frontotemporal tau deposition contributes to cognitive and behaviouraldeficits which become most marked late in the disease.The findings strongly suggest that progressive clinical dysfunction in PSP isdirectly related to progressive cortical degeneration. Cortical degeneration appears tooccur in two independent functional networks. Increased CBF in PSP may be a usefulearly indicator for future neurodegeneration, although the cellular mechanism leadingto cell death requires further investigation