Striatal dopaminergic patterns and clinical features in frontotemporal dementia

Frontotemporal dementia is a group of neurodegenerative disorders mainly characterized by behavioural and language impairments. While the precise pathophysiology remains elusive, emerging evidence points to an important role of dopamine dysfunction, particularly within the caudate nucleus. Moreover, a theoretical model proposes that frontotemporal dementia manifestations result from a deficit in goal-directed behaviour, which may be related to altered dopamine control of the frontostriatal circuitry. However, no study has investigated the gradient of striatal dopamine transporter levels in frontotemporal dementia using neuroimaging and their correlation with clinical features. This study used ¹²³I-Ioflupane Single Photon Emission Computed Tomography imaging to measure striatal dopamine transporter levels and their distribution patterns in frontotemporal dementia, compared to Parkinson's disease and healthy controls. Additionally, we explored the correlation between dopamine transporter uptake and two key domains affected in frontotemporal dementia: social cognition and language abilities. We hypothesized that frontotemporal dementia would show a predominant dopaminergic deficit in the caudate, and that this would correlate with the severity of clinical core features. The study comprised 139 participants, including 34 sporadic and genetic frontotemporal dementia, 68 Parkinson's disease individuals, and 37 age- and sex-matched healthy controls. Among the frontotemporal dementia group, 22 cases had clinically probable behavioural variant frontotemporal dementia, and 12 had primary progressive aphasia. Social cognition was assessed with the abbreviated version of the Social and Emotional Assessment, which includes a Theory of Mind test and a Facial Emotion Recognition Task. Language skills were evaluated with the Screening for Aphasia in NeuroDegeneration battery. We found that dopamine transporter levels were reduced in frontotemporal dementia compared to healthy controls (P < 0.001) and that frontotemporal dementia showed a higher putamen-to-caudate ratio than Parkinson's disease (P < 0.001), particularly notable in patients with identified disease-causing mutation. We also found that dopamine transporter levels were correlated with parkinsonian motor features and general cognition in frontotemporal dementia. Notably, both social cognition-especially facial emotion recognition-and language abilities exhibited associations with dopamine transporter levels in both the putamen and the caudate. These findings suggest that the pattern of dopamine transporter uptake could serve as a valuable biomarker for frontotemporal dementia, shedding light on the role of the dopaminergic system and the striatum in some fundamental clinical aspects. This opens new avenues for further investigating the underlying mechanisms and potential therapeutic targets of the dopaminergic projections in frontotemporal dementia.