Abstract
ObjectiveWe aimed to investigate mutation‐specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72,MAPT, and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study.MethodsOne hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72,MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers.ResultsDiffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC.InterpretationThis study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network‐based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease‐tracking and ‐staging in presymptomatic to early‐stage familial FTD.
Highlights
Genetic FTD with an autosomal dominant inheritance pattern has a heterogeneous clinical profile, including behavioral variant FTD and primary progressive aphasia (PPA)
Interpretation: This study demonstrates the presence of early and widespread White matter (WM) integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network-based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for diseasetracking and -staging in presymptomatic to early-stage familial FTD
CBI-R scores were significantly higher in microtubule-associated protein tau (MAPT) and C9orf[72] mutation carriers compared to noncarriers, and compared to GRN mutation carriers (MAPT P = 0.002, C9orf[72] P = 0.003)
Summary
Genetic FTD with an autosomal dominant inheritance pattern has a heterogeneous clinical profile, including behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). White matter (WM) alterations, as measured by diffusion tensor imaging (DTI) are found to be early and widespread in the symptomatic phase of FTD, extending beyond the zones of GM atrophy,[7,8,9] with distinct profiles in clinical and genetic subtypes.[7,10,11,12,13,14] The pattern of WM integrity loss includes the uncinate fasciculus (UF), cingulum, (anterior) corpus callosum, fornix, superior and inferior longitudinal fasciculi, thalamic radiation, and corona radiata.[7,12,14,15,16] previous studies in presymptomatic FTD caused by GRN and MAPT mutations demonstrated, respectively, lower integrity of the UF,[17,18] and inferior frontooccipital fasciculus,[17] whereas studies into presymptomatic C9orf[72] have shown more inconsistent results.[19,20,21] This underlines that, a promising candidate, larger studies are needed in order to validate DTI as a neuroimaging biomarker for presymptomatic FTD
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