The neural basis of frontotemporal dementia (FTD): insights from ALE meta-analyses of four FTD subtypes encompassing 8,057 patients

Frontotemporal dementia (FTD) is a complex neurodegenerative syndrome primarily affecting the frontal and temporal lobes, resulting in deficits in behaviour, executive function, and language. As the leading cause of early-onset dementia, FTD includes several subtypes, notably behavioural variant FTD (bvFTD) and primary progressive aphasia (PPA). PPA is further subdivided into three main variants: non-fluent variant PPA (nfvPPA), semantic variant PPA (svPPA)/semantic dementia (SD), and logopenic variant PPA (lvPPA), each characterised by distinct language and cognitive impairments. However, despite these clinical distinctions, increasing evidence suggests overlapping behavioural symptoms and neural abnormalities across FTD syndromes, challenging the traditional view of them as mutually exclusive. To explore the neural basis of FTD, we conducted an activation likelihood estimation meta-analysis, synthesising data from structural and functional neuroimaging studies across four major FTD subtypes. Our analysis included coordinate-based data from 114 studies comprising 8,057 FTD patients. Results revealed widespread brain abnormalities in FTD compared to healthy controls, encompassing the frontal, temporal, and parietal lobes, as well as subcortical and limbic regions such as the basal ganglia and thalamus. This widespread degeneration aligns with the broad spectrum of cognitive and behavioural symptoms seen in FTD. Each FTD subtype demonstrated distinct, yet partially overlapping, patterns of degeneration. BvFTD showed prominent degeneration in the frontal and medial temporal lobes, insula, cingulate cortex, and limbic system, consistent with impairments in social cognition and disinhibition. SvPPA/SD exhibited focal atrophy in the anterior temporal lobes, disrupting the semantic network and impairing semantic processing. NfvPPA was associated with degeneration in the speech production network, particularly the insula and inferior frontal gyrus. LvPPA displayed left-lateralised abnormalities in the posterior temporal and inferior parietal lobes, affecting language function. Additionally, FTD subtypes exhibited overlapping patterns of degeneration, contributing to shared cognitive and language deficits. For example, svPPA/SD and bvFTD both showed degeneration in the anterior temporal lobe and amygdala, linked to socio-emotional impairments. BvFTD and nfvPPA shared degeneration in the left frontal cortex and insula, suggesting common executive dysfunction. Similarly, lvPPA and svPPA/SD both showed abnormalities in the left lateral temporal lobe, linking these regions to semantic cognition deficits observed in both variants. These findings highlight the mixture of clinical heterogeneity of each FTD subtype as well as their overlapping features. This study offers new insights into the neural bases of recent proposals that FTD spans a transdiagnostic multidimensional phenotype-geometry and may aid in refining diagnostic criteria and developing targeted interventions for this group of neurodegenerative disorders.