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. 2023 Jan 11;43(2):333–345. doi: 10.1523/JNEUROSCI.1448-22.2022

Figure 3.

Figure 3.

Peripheral C9orf72 expression captures unique, disease-relevant information related to clinical severity. A, C9orf72 expression is significantly decreased in HRE carriers versus noncarrier controls (p = 5.56 × 10−4) in a multiple regression model covarying for age, sex, education, CDR-SB score, and sample processing batch. B, C9orf72 expression associates with clinical impairment, as measured by CDR-SB score (p = 1.84 × 10−4), even after correcting for age, sex, education, and batch. Given our finding of significantly lower total thalamic volumes in HRE carriers compared with controls (Figure 1A; p = 1.57 × 10−6), we explored the relationship among C9orf72 expression, thalamic volumes, and CDR-SB scores. We found that thalamic volumes also predicted CDR-SB scores, again accounting for relevant covariates (p = 2.94 × 10−6; covariates: age, sex, education, MRI scanner type, and TIV). Both variables remained significant in a combined model, C9orf72 expression (p = 0.04) and thalamic volumes (p = 1.47 × 10−4), suggesting that C9orf72 expression and thalamic volumes provide distinct, disease-relevant information. C–F, Three-dimensional brain renderings depict results of multiple regression analyses (covarying for age, sex, education, clinical severity, MRI scanner type, and TIV) evaluating the relationship between cortical thickness and R MDl nucleus volumes (C), CDR-SB scores (D), C9orf72 HRE carrier status (E), and C9orf72 expression (F). R MDl nucleus volumes associate with cortical thickness in multiple FTD-relevant regions such as prefrontal cortex and orbitofrontal cortex (C). CDR-SB scores track global atrophy with relative sparing only of medial occipital cortex (D). C9orf72 carrier status associates with bifrontal thinning in HRE carriers with notable sparing of bilateral motor cortex (E). C9orf72 expression associates with left prefrontal cortex and left parietal cortex volumes with less prominent involvement of left orbitofrontal cortex and middle frontal gyrus (F). Extended Data Figures 3-1, 3-2, 3-3, 3-4, and 3-5 show full results from the regression analyses described above. Indep, Independent; Thal, Thalamic; Exp, Expression; Vol, Volume.