Clinicopathological Correlates in Tauopathy and Aging

Abstract

Cognitive decline can result from both neurodegenerative or normal aging processes. Definitive diagnosis of many neurodegenerative diseases, such as Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP), requires post-mortem neuropathological examination and focuses on the identification of structural changes and protein aggregation in the brain, in addition to a clinical presentation consistent with the disease during life. Herein, we examined clinicopathological correlates of cognitive decline in sporadic and familial tauopathy, and normal aging. We hypothesized that structural neuropathological changes would be insufficient to explain symptomology in these cases, and that alternate mechanisms, such as cholinesterase expression, may bridge the gap between observed neuropathological changes and clinical symptoms in regions that are important to cognition, including the rostral prefrontal cortex (rPFC) and hippocampal formation. In cognitively normal (CN) octogenarians and older, there is an accumulation of β-amyloid plaque, tau neurofibrillary tangle, and phosphorylated TAR DNA-binding protein pathology comparable to AD. Butyrylcholinesterase (BChE), however, remains specific to AD pathology and lower acetylcholinesterase and BChE deposition in these pathological structures may contribute to their preserved cognition. In PSP, there are low levels of AD-associated neuropathological aggregation and cholinesterase-positive neuropathology in the rPFC, comparable to CN individuals. This suggests that disruption of rPFC function in this condition may occur through alternate means. Finally, in familial tauopathy caused by the IVS10 + 14 MAPT mutation, there was a high degree of intra- and inter-familial phenotypic heterogeneity, with one case presenting severe cognitive symptoms which did not correspond to the mild neuropathology observed in regions associated with cognition. Our findings support the need to explore alternate diagnostic and therapeutic targets for neurodegeneration as the protein aggregates do not always accurately reflect clinical phenotype in tauopathy and aging.