Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy

• Published in: NeuroImage clinical 2024, Vol.43, p.103649, Article 103649
• Main Authors: R. K. Roy, Ashlin, Noohi, Fate, Morris, Nathaniel A., Ljubenkov, Peter, Heuer, Hilary, Fong, Jamie, Hall, Matthew, Lario Lago, Argentina, Rankin, Katherine P., Miller, Bruce L., Boxer, Adam L., Rosen, Howard J., Seeley, William W., Perry, David C., Yokoyama, Jennifer S., Lee, Suzee E., Sturm, Virginia E.
• Format: Article
• Language: English
• Subjects: Aged; Autonomic nervous system; Behavioral variant frontotemporal dementia; C9orf72; C9orf72 Protein - genetics; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Cognitive Dysfunction - diagnostic imaging; Cognitive Dysfunction - etiology; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Cognitive Dysfunction - physiopathology; DNA Repeat Expansion - genetics; Empathy - physiology; Female; Frontotemporal Dementia - diagnostic imaging; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Frontotemporal Dementia - physiopathology; Heterozygote; Humans; Insula; Magnetic Resonance Imaging - methods; Male; Middle Aged; Parasympathetic Nervous System - physiopathology; Prosocial behavior; Respiratory Sinus Arrhythmia - physiology; Thalamus - diagnostic imaging; Thalamus - pathology; Thalamus - physiopathology
• ISSN: 2213-1582; 2213-1582
• DOI: 10.1016/j.nicl.2024.103649

•Basal parasympathetic activity is impaired in C9+ FTD.•Parasympathetic activity in C9+ carriers is lower in those with greater symptoms.•Diminished parasympathetic activity in C9+ carriers correlates with lower empathy.•Frontoinsular and thalamic atrophy relates to lower parasympathetic activity.•Baseline respiratory sinus arrythmia may be a potential biomarker for early FTD. Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants’ current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morpho