Abstract
AimsSince the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardson's syndrome (PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS.MethodsWe sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions.ResultsIn addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a ‘cortical’ PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups.ConclusionsA better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies.
Highlights
Tsuboi et al quantified tau load in four selected cortical regions including cingulate gyrus, mid-frontal cortex, motor cortex and inferior-parietal cortex in three progressive supranuclear palsy (PSP)-Corticobasal syndrome (CBS) cases and eight randomly chosen PSP-RS cases [12]. They reported an increased tau pathology in the mid-frontal and inferiorparietal cortices in PSP with corticobasal syndrome presentation (PSP-CBS) compared with PSP-RS and concluded that the CBS presentation of PSP was either caused by a concurrent cortical pathology from a secondary process such as Alzheimer’s disease or primary PSP tau pathology involving the cortical regions [12]. It is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS
The aims of this study were: (i) to validate the findings reported by Tsuboi et al in a significantly larger cohort of PSP-CBS cases and to quantitatively assess tau distribution in more cortical regions and other brain regions including the basal ganglia, brainstem and cerebellum; (ii) to determine the cellular lesions which contribute to the tau pathology were characteristic of PSP pathology rather than Alzheimer-type neurofibrillary tangle pathology; and (iii) to assess neuronal loss of the substantia nigra and subthalamic nuclei and pathological involvement of the corticospinal tract
PSP-CBS (Tables 1a and 2) All patients had been diagnosed with CBS/corticobasal degeneration (CBD) by neurologists during life
Summary
Other wellrecognized clinical variants of PSP are PSP-parkinsonism. Clinicopathological studies have since demonstrated a close correlation between topographical severity of tau pathology and clinical phenotypes of PSP. Severe tau pathology was identified in the inferior frontal gyrus in PSP-PNFA [8] and frontal and temporal cortices in PSP-bvFTD [13]. Similar clinicopathological correlation was identified in another closely related 4-repeat (4R) tauopathy, corticobasal degeneration (CBD) and its clinical phenotypes [14]
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