Proteopathies include diseases such as Creutzfeldt-Jakob disease, Alzheimer's disease, Parkinson's disease, and a wide range of other disorders. A particular class of proteopathies concerns tauopathies. Tauopathies are characterized by the aggregation of the tau protein into neurofibrillary or gliofibrillary tangles (NFT) in the human brain.
Corticobasal degeneration (CBD) is a rare neurodegenerative disease. Symptoms of CBD usually start in people 50 to 70 years old, and the average duration of the disease is six years. It is characterized by marked disturbances in movement and cognition. Diagnosis is difficult because symptoms are often similar to those of other disorders, such as Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies.
Distinct tau neuronal and glial pathologies define corticobasal degeneration and progressive supranuclear palsy, but copathologies of Alzheimer's disease, TDP-43 and Lewy bodies are common.
A hyperphosphorylated, ubiquitinated and cleaved form of TDP-43 is the main protein responsible for frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Lewy bodies are abnormal aggregations of proteins that develop inside nerve cells, contributing to Parkinson's disease (PD), dementia with Lewy bodies, multi-system atrophy, and other disorders.
The interaction of these copathologies with clinical symptoms remains uncertain because individuals may have corticobasal syndrome, frontotemporal dementia, progressive supranuclear palsy or atypical parkinsonism and may have additional secondary impairments.
The authors of this article report clinical, pathological and genetic interactions in a cohort of corticobasal degeneration and progressive supranuclear palsy. Neurofibrillary tangles and plaques were common. Carriers of apolipoprotein E (APOE) ε4 had more plaques while carriers of progressive supranuclear palsy APOEε2 had fewer plaques.
Two of the authors are Virginia Man-Yee Lee and her husband, John Q. Trojanowski.
Both are known in particular for challenging the theory that Alzheimer's disease is caused by protein plaques called beta-amyloid, arguing that a key culprit may be the Tau protein aggregates, they have also discovered the significance of TDP-43 in ALS and FTD.
The copathology of TDP-43 was present and associated with age in 14% of progressive supranuclear palsy, and independent of age in 33% of corticobasal degeneration. Lewy's body copathology ranged from 9% to 15% and was not associated with age. The primary FTD-Tau burden - a sum of neural, astrocytic and oligodendrocyte tau - was not related to age, APOE or MAPT.
In progressive supranuclear palsy, FTD-Tau, independent of copathology, associated with executive, language, motor and visuospatial impairments, while progressive supranuclear palsy with Parkinsonism had a lower FTD-Tau load, but it was not the case in corticobasal degeneration.
Overall, the researchers' results indicate that the burden of primary tauopathy is the strongest correlate of clinical progressive supranuclear palsy, while copathologies are mainly determined by age and genetic risk factors.