A new nosology for neurodegenerative dementias: cognitive proteinopathies - Shifting from “Where” to “What”

Abstract

Over the next 100 years, the neuropathology of each of these diseases was studied in greater detail. For instance, alpha-synuclein was identified in Parkinson's disease, beta-amyloid and phospho-tau in Alzheimer's disease, and tau and TDP-43 in Pick's disease. At the same time, typical and atypical forms of these pathologies began to be described. In frontotemporal disease, for instance, the classic behavioral variant and the rare aphasic variant have been described. Similarly, Alzheimer's disease has both classical (amnesic) and atypical variants including frontal, posterior cortical, aphasic and, more recently, Down's disease. Alpha-synuclein is the most important factor in Parkinson's disease, which is associated with Lewy bodies disease. However, in parkinsonian syndromes such as progressive supranuclear palsy or corticobasal degeneration, the change is a tauopathy. Therefore, these phenotypes, which only describe “where” the lesion is located cannot be maintained. For example, a patient presenting with a behavioral disturbance such as apathy and disinhibition may have tauopathy, or TDP-43-opathy, or even beta amyloidosis. Over the last 10 years, neuropathological, and genetic research, as well as the emergence of biomarkers, has enabled us to diagnose the syndrome and identify the protein change that causes it during life. This is insignificant in the context of the new diagnostic criteria, and the new treatments targeting abnormal proteins or altered pathways, such as anti-amyloid, anti-tau, anti-sortilin antibodies. In the coming years, we will therefore move from diagnosing “where” to diagnosing “what” disease produces these symptoms.