Continued effort is necessary to investigate the earliest brain regions involved in tau seeding and the mechanistic pathways from tau aggregation and propagation to neuronal dysfunction and cell death. 27 The answers to these questions hold the key to the development of antemortem diagnostic biomarkers and effective mechanistic‐based therapy.
Six tau isoforms are expressed by alternative mRNA splicing of exons 2, 3, and 10 of the MAPT gene located on chromosome 17. 10 The extra repeat domain, which is expressed in 4R tau, is coded by exon 10 of MAPT. Tau filaments in PSP and CBD are made up of predominantly 4R tau. Western blots of insoluble filamentous tau extracted from affected brain regions of PSP and CBD show two major bands of 68 and 64 kDa, made of hyperphosphorylated 4R tau isoforms. In contrast, three major bands of 60, 64, and 68 kDa are detected in Alzheimer’s disease representing a mixture of 3R and 4R tau.
More than 50 pathogenic mutations of the MAPT gene have been identified. 14 These autosomal dominant tau mutations cause an inherited form of frontotemporal dementia with parkinsonism, which is now collectively classified as FTDP‐17T. 14 Their discovery established the causal relationship between tau dysfunction and neurodegeneration and the clinical manifestation of cognitive and motor impairments.
Financial Disclosures for the previous 12 months: The author H.L. is supported by a research grant from CBD Solutions (grant code: 512385) and receives honorarium for consultancy work for Adivo Associates and Adelphi Group Company.
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.
Animal studies demonstrated that intracerebral injection of brain homogenates from humans with autopsy‐confirmed PSP and CBD produced distinct tau lesions in mouse brains reminiscent of the hallmarks of the respective human tauopathies (i.e., tufted astrocytes in PSP and astrocytic plaques in CBD). 22 , 23 , 24 The injection of brain homogenates does not only induce the formation of tau inclusions at the injection sites but also leads to their subsequent spread to distant brain regions connected by specific neural networks, which vary between tauopathies. 22 , 23 , 24 These findings support the notion that PSP and CBD have distinct tau strains and represent different pathological processes. 25 , 26
Although the majority of PSP and CBD cases are sporadic, certain MAPT mutations can result in clinical phenotypes and pathological features that are indistinguishable from PSP or CBD and may be considered as the monogenetic causes of PSP and CBD. 14 The genetic‐pathological correlations demonstrated by these FTDP‐17T cases serve as strong evidence of the fundamental mechanistic difference between PSP and CBD. The assessment of clinical and family history, genetic tests, and in postmortem cases, neuropathological characterization is necessary to distinguish FTDP‐17T from sporadic PSP or CBD.
H.L.: 1A, 1B, 1C, 3A, 3B
Ethical Compliance Statement: The authors confirm that she has read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
The diagnosis must be made or confirmed by a consultant with expertise in PSP. This will usually be a neurologist (a specialist in conditions affecting the brain and nerves).
Treatment will be tailored to meet the needs of each individual:
Difficulty swallowing can cause choking or inhaling food or liquid into the airways. This can lead to pneumonia, which can be life threatening.
PSP occurs when brain cells in certain parts of the brain are damaged as a result of a build-up of a protein called tau.
You may need to have a brain scan to look for other possible causes of your symptoms, as well as tests of your memory, concentration and ability to understand language.
Treatments for PSP
Good care and assistance can help someone with PSP to be more independent and enjoy a better quality of life, but the condition will eventually put them at risk of serious complications.
In people with PSP, it isn’t broken down properly and forms harmful clumps in brain cells.