The neural bases of frontotemporal dementia and primary progressive aphasia subtypes: insights from activation likelihood estimation meta-analyses of 8,057 patients

Abstract Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) are a complex, partially overlapping neurodegenerative syndromes primarily affecting the frontal and temporal lobes, resulting in deficits in behaviour, executive function, and language. FTD is among the leading causes of early-onset dementia and has several subtypes including behavioural-variant FTD (bvFTD) and semantic dementia (SD). PPA is 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. Although these syndromes are clinically distinguishable, overlapping cognitive, behavioural and neuroanatomical features are common. To provide a comprehensive quantitative synthesis of the associated neuroimaging findings for each subgroup, we conducted an activation likelihood estimation (ALE) meta-analysis of structural and functional neuroimaging studies across bvFTD and the major PPA syndromes. The analysis included coordinate-based data from 114 studies comprising 8,057 patients. Across syndromes, patients showed widespread brain abnormalities relative to healthy controls, involving frontal, temporal and parietal cortices as well as subcortical and limbic regions including the basal ganglia and thalamus. 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. In addition to these prototypical patterns, overlapping regions were observed between specific syndromes, including shared involvement of anterior temporal and limbic regions in bvFTD and svPPA/SD, frontal–insular regions in bvFTD and nfvPPA, and lateral temporal regions in svPPA/SD and lvPPA. Together, these findings provide a robust, synthesis of distinct and overlapping neuroanatomical alterations across FTD and PPA syndromes, clarifying how syndrome-specific and shared patterns of degeneration may contribute to clinical heterogeneity.