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Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder
Greet Vanderlinden1, Charles Carron1,2, Donatienne Van Weehaeghe1,2,3
1Nuclear Medicine and Molecular Imaging, Imaging and Pathology, KU Leuven, Leuven Brain Institute, Leuven, Belgium.
Annals of Clinical and Translational Neurology
|May 7, 2025
Summary
Positron emission tomography tracer [18F]EKZ-001 showed lower binding in people with amyotrophic lateral sclerosis (ALS) compared to controls. This PET tracer may help understand HDAC6 roles in ALS and frontotemporal spectrum disorder (FTSD).
Area of Science:
- Neuroscience
- Radiochemistry
- Molecular Biology
Background:
- Histone deacetylase 6 (HDAC6) is crucial for intracellular transport and clearance of misfolded proteins.
- HDAC6 modulation is a potential therapeutic target for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
- Cognitive impairment, part of the ALS-frontotemporal spectrum disorder (ALS-FTSD), affects a subset of people with ALS (pwALS).
Purpose of the Study:
- To assess the binding of the novel PET tracer [18F]EKZ-001 in pwALS with varying degrees of cognitive impairment.
- To investigate the relationship between [18F]EKZ-001 binding and cognitive status in ALS.
- To explore potential mechanisms underlying altered tracer binding in ALS.
Main Methods:
- Twenty-four pwALS and 12 healthy controls (HC) underwent dynamic PET-MR imaging with arterial sampling.
- PwALS were categorized into cognitively normal (ALS-CN) and those with ALS-FTSD based on the Edinburgh cognitive and behavioral ALS screen (ECAS).
- Regional distribution volumes (VT) of [18F]EKZ-001 were calculated using Logan graphical analysis.
Main Results:
- [18F]EKZ-001 VT was significantly reduced in pwALS compared to HC across brain regions.
- Reductions were most pronounced in the brainstem for ALS-CN and more widespread in gray and white matter for ALS-FTSD.
- No significant differences in VT were observed between ALS patients with or without C9orf72 mutations, nor were VT values correlated with ECAS scores, age, or disease duration.
Conclusions:
- Brain-wide [18F]EKZ-001 binding is decreased in pwALS, suggesting altered HDAC6 availability or function.
- This reduction may reflect compensatory mechanisms for intracellular transport defects or HDAC6 sequestration within protein aggregates in ALS.
- The PET tracer [18F]EKZ-001 shows potential for investigating HDAC6-related pathophysiology in ALS and ALS-FTSD.
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