Semantic Deficits in ALS Related to Right Lingual/Fusiform Gyrus Network Involvement: A Case-Control Study

Background: The clinicopathological continuity between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is well known. Although patients with ALS demonstrate similar language symptoms to patients with FTLD, including semantic dementia, word reading impairments in ALS have not been well studied. "Jukujikun" are kanji-written words with irregular pronunciation that applies to "exception words" and are useful for detecting semantic deficits in Japan. We investigated Jukujikun reading impairments and related changes in resting-state networks in patients with ALS. Methods: We enrolled 140 participants, including 71 ALS patients and 69 healthy controls. We examined demographic and comprehensive neuropsychological factors, including Jukujikun. We also performed resting-state functional magnetic resonance imaging with voxel-based graph analysis on a subset of participants who agreed to participate in the imaging study to investigate the hub regions and related networks associated with Jukujikun impairments in ALS. Findings: Fifty-two percent of ALS patients (N=37) exhibited a significantly reduced score in Jukujikun reading compared with controls. We classified those patients as ALS with positive Jukujikun deficit (ALS-JD+) and the other patients as ALS with negative deficit (ALS-JD-). Resting-state network analysis showed significantly decreased degree centrality in the right fusiform/lingual gyrus and increased degree centrality in the left inferior/middle temporal gyrus in ALS-JD+ compared with ALS-JD- and controls. Seed-based analysis also revealed that the hub dysfunction in the right fusiform/lingual gyrus depended on decreased connectivity with regions associated with visual word perception, semantic processing, and speech. On the other hand, the observed increased degree centrality in the left inferior/middle temporal gyrus was derived from regions related to semantic processing. Interpretation Dysfunction of the "hub" in the right fusiform/lingual gyrus can affect semantic deficit in ALS. Considering neuropsychological symptoms as network impairments is vital for understanding various diseases. Funding MHLW and MEXT, Japan. Funding Statement: MHLW and MEXT, Japan. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study conformed to the Ethical Guidelines for Medical and Health Research Involving Human Subjects endorsed by the Japanese government. The study protocol was approved by the Ethics Review Committee of the Nagoya University Graduate School of Medicine, and written informed consent was obtained from all participants.