Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation

Eur J Neurol. 2025 Jul;32(7):e70261. doi: 10.1111/ene.70261.

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs both upper and lower motor neurons. Mutations in the neurofilament heavy (NEFH) gene are associated with a higher risk for ALS. This study aimed to evaluate the brain metabolism in patients with ALS and NEFH gene mutations (NEFH-ALS) and assess its correlation with emotional and cognitive changes.

Methods: This prospective study enrolled 119 patients with ALS and 128 age- and gender-matched health controls. Study assessments included demographic data collection, questionnaires for motor function, cognition, and depression, and brain F-18 FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)) scan. Correlation between brain metabolism and clinical questionnaire scores was performed. Chain-mediation model analysis for the NEFH-ALS group was conducted. Cox regression and Kaplan-Meier survival analysis were also performed.

Results: There were 26 NEFH-ALS patients. Patients with NEFH-ALS showed brain glucose hypometabolism in the cortex-striatum/limbic system-brainstem circuit when compared with healthy controls (p < 0.05). Decreased brain glucose metabolism was correlated with impairments of motor function (r = 0.477, p = 0.014, FDR corrected p = 0.014), cognitive scores (r = 0.549, p = 0.004, FDR corrected p = 0.009), and depression (r = -0.523, p = 0.009, FDR corrected p = 0.009). This study showed that brain glucose hypometabolism could lead to impairment of motor function, which was mediated by cognition and depression. Survival analysis showed that brain glucose metabolism was an independent prognostic factor for patients with ALS.

Conclusions: Reduced brain glucose metabolism in the cortex-striatum/limbic system-brainstem circuit may potentially serve as an independent prognostic factor for patients with ALS and NEFH mutation.

Keywords: 18F‐FDG‐PET/CT 18F‐fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT); amyotrophic lateral sclerosis; brain glucose metabolism; mediation effect; neurofilament heavy (NEFH) gene.

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis* / diagnostic imaging
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / mortality
  • Brain* / diagnostic imaging
  • Brain* / metabolism
  • Female
  • Fluorodeoxyglucose F18
  • Glucose / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neurofilament Proteins* / genetics
  • Positron Emission Tomography Computed Tomography
  • Prospective Studies

Substances

  • Neurofilament Proteins
  • neurofilament protein H
  • Fluorodeoxyglucose F18
  • Glucose