Objective:

To systematically characterise thalamus pathology in frontotemporal dementia (FTD) phenotypes

Background:

FTD is classically associated with distinctive cortical atrophy patterns. However, the spectrum of cognitive and behavioural manifestations in FTD arise from multi-synaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit; the anterior cingulate circuit; and the orbitofrontal circuit.

Design/Methods:

Thalamus pathology was quantitatively evaluated at a nuclear, vertex and morphometric level in a prospective, multimodal imaging study using a standardised neuroimaging protocol. 10 patients with behavioural FTD (bvFTD), 15 patients with non-fluent variant primary progressive aphasia (nfvPPA) and 5 patients with semantic variant PPA (svPPA) were evaluated with reference to 100 healthy controls. All patients underwent detailed clinical and neuropsychological profiling and whole-genome sequencing.

Results:

Volumetric analyses revealed widespread bilateral thalamic nuclear volume loss in bvFTD; selective bilateral with left-sided predominant thalamic degeneration was captured in nfvPPA; and more focal, left-lateralised thalamic volume loss identified in svPPA. Vertex analyses showed diffuse thalamic surface changes in bvFTD and nfvPPA, but not svPPA. Morphometric analyses demonstrated extensive symmetric intra-thalamic changes in nfvPPA, and mostly right-sided changes in both bvFTD and svPPA.

Conclusions:

FTD is associated with considerable focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei associated with behaviour and language functions are preferentially involved. FTD is not solely associated with cortical atrophy. The manifestations of FTD are likely to stem from cortico-subcortical circuitry dysfunction and not exclusively driven by focal cortical changes.