The tau protein is important in the normal function of the brain. It is associated with structures within brain cells called microtubules which help one cell to speak to another cell. In its normal state tau helps to stabilize microtubules but when tau clumps together in the abnormal state, microtubules are destabilized leading to death of brain cells. This process can happen selectively in frontal and temporal regions of the brain causing the behavioural or language symptoms of FTD. When we find abnormal tau in brain cells at post-mortem in patients with FTD we call this frontotemporal lobar degeneration-tau, or FTLD-tau.
There are multiple types of FTLD-tau with the most common being corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD) and Pick’s disease. These types of pathology are sporadic in nature, which means that they do not strongly run in families. However, FTLD-tau can also occur as a result of mutations in the microtubule-associated protein tau (MAPT) gene when it is strongly inherited in families.
In a study by Thal and colleagues, the brains of 373 individuals who had passed away from a variety of conditions including those with and without dementia were examined. The key questions they were seeking to answer were: can several different co-existing pathologies be observed in people with FTLD-tau and how does age impact the presence of FTLD-tau and other pathologies?
Several interesting observations were made in their study:
1) Increasing age was associated with the presence of Alzheimer’s disease brain changes in patients with AGD but not CBD, PSP or Pick’s disease.
2) Disease of the small brain vessels representing ‘silent strokes’ (cerebral small vessel disease) was also more common and severe in Pick’s disease but not CBD, PSP or AGD.
3) Small haemorrhages in the brain due to a pathology called cerebral amyloid angiopathy were more commonly associated with Alzheimer’s disease than with FTLD-tau.
4) Several brains from people without dementia showed changes consistent with FTLD-tau indicating that this pathology can exist in some individuals before they show any signs of disease. The older someone was the more likely this was to be seen.
The findings of this paper are consistent with similar observations in late onset forms of Alzheimer’s disease, specifically that increasing age contributes to co-existing pathologies including small vessel disease. These important findings have implications for the development of novel drugs in the pipeline that target FTLD-tau pathology. For example, people that have genetic forms of FTLD-tau due to mutations in the MAPT gene, i.e. a more pure form of FTLD-tau, may have a better chance of responding to a drug targeting tau than older individuals who may have several different co-pathologies. The development of strategies for predicting ‘pure disease’ vs. ‘mixed disease’ should therefore be a research priority when designing clinical trials of novel therapeutic agents in FTLD-tau.
Thal DR, von Arnim CA, Griffin WS, Mrak RE, Walker L, Attems J, Arzberger T. Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. J Neural Transm. 2015 Jan 4. [Epub ahead of print]