AbstractBackground and purposeThalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia–amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high‐order thalamic nucleus and timekeeper for large‐scale cortical networks, has been hypothesized to be involved in C9orf72‐related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region.MethodsWe studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild‐type ALS (ALSC9−) and ALS mimic (ALSmimic) patients using structural and resting‐state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed‐to‐voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation.ResultsPulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9− (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9− showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital–temporal–parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9− patients showed reduced pulvinar–occipital connectivity for anterior and inferior pulvinar seeds.ConclusionsPulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar–cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild‐type patients.