Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Abstract

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…We conducted whole-brain cluster-level inference for all analyses, reporting clusters significant at α = 0.05 using familywise error (FWE) correction and a cluster-forming threshold of P = 0.005 (uncorrected). Our statistical thresholds were determined a priori based on our own previous work investigating the effects of intranasal spray OT on rCBF in humans 16 and are standardly applied in pharmacological ASL studies measuring rCBF [91][92][93][94][95][96] . For the paired t-tests, in recognition of the increased risk of false positives given the large number of paired t-tests (3 × 8 = 24), we mark clusters that do not survive correction for multiple testing following adjustment of the Pvalue using conservative Bonferroni correction for the 24 paired-t-tests performed with an asterisk (*) (P adjusted = 0.05/24 = 0.002) (see Tables 2-4).…”

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…and are standardly applied in pharmacological ASL studies measuring rCBF(102)(103)(104)(105)(106)(107). For the paired T-tests, in recognition of the increased risk of false positives given the large number of paired t-tests (3 x 8 = 24), we mark clusters that do not survive correction for multiple testing following adjustment of the P value using conservative Bonferroni correction for the 24 paired-T tests performed with an asterisk (*) (P adjusted =0.05/24=0.002) (see.…”

Investigating resting brain perfusion abnormalities and target-engagement by intranasal oxytocin in women with bulimia nervosa and binge-eating disorder and healthy controls

“…We used cluster-level inference at α = 0.05 using familywise error (FWE) correction for multiple comparisons and a cluster-forming threshold of P=0.005 (uncorrected). These statistical thresholds had been determined a priori based on our own work investigating the effects of intranasal OT on rCBF in humans 40,42 and are standardly applied in ASL studies measuring rCBF [55][56][57][58][59][60] .…”