Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies

<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Frontotemporal dementia (<jats:styled-content style="fixed-case">FTD</jats:styled-content>) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new <jats:styled-content style="fixed-case">FTD</jats:styled-content>‐causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of <jats:styled-content style="fixed-case">FTD</jats:styled-content> to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, <jats:styled-content style="fixed-case">TDP</jats:styled-content>‐43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of <jats:styled-content style="fixed-case">FTD</jats:styled-content>, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies.</jats:p></jats:sec><jats:sec><jats:label /><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13588-fig-0004-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> Most cases of <jats:styled-content style="fixed-case">FTD</jats:styled-content> can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these <jats:styled-content style="fixed-case">FTD</jats:styled-content> molecular subtypes <jats:italic>in vivo</jats:italic> will likely be crucial for the development and use of targeted therapies. </jats:p><jats:p><jats:bold>This article is part of the</jats:bold> <jats:styled-content><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1471-4159/homepage/special_issues.htm">Frontotemporal Dementia special issue</jats:ext-link>.</jats:styled-content></jats:p></jats:sec>