Work

Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis‐Frontotemporal Spectrum Disorder

Year: 2025

Type: article

Abstract: ABSTRACT Objective [18F]EKZ‐001 is a positron emission tomography (PET) tracer targeting histone deacetylase 6 (HDAC6), an enzyme responsible for intracellular transport and clearance of misfolded proteins. HDAC6 modulation is a promising treatment strategy in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Apart from motor symptoms, people with ALS (pwALS) can show a variable degree of cognitive impairment as part of the ALS‐frontotemporal spectrum disorder (ALS‐FTSD). This work assessed [18F]EKZ‐001 binding in pwALS with variable involvement of FTSD. Methods Twenty‐four pwALS (13M/11F, 61 ± 10 years) and 12 healthy controls (HC) (6M/6F, 58 ± 3 years) were included. Thirteen pwALS were cognitively normal (ALS‐CN), and eleven pwALS presented with FTSD (ALS‐FTSD) ranging from mild cognitive or behavioral impairment to FTD, according to their performance on the Edinburgh cognitive and behavioral ALS screen (ECAS). All subjects underwent dynamic PET‐MR imaging with arterial sampling, and regional distribution volumes (VT) were calculated using a Logan graphical analysis. Results [18F]EKZ‐001 VT was significantly lower in pwALS compared to HC. For ALS‐CN, the largest reduction was found in the brainstem. For ALS‐FTSD, reductions were more widespread in both gray and white matter. No differences in VT were found between pwALS with and without a C9orf72 mutation. [18F]EKZ‐001 VT was not correlated with ECAS scores, age, or disease duration. Interpretation [18F]EKZ‐001 binding is lower throughout the brain in pwALS compared to HC. This may be related to a compensatory mechanism to repair intracellular transport defects in ALS or to reduced HDAC6 enzyme availability for [18F]EKZ‐001 binding due to sequestration of HDAC6 within protein aggregates.

Source: Annals of Clinical and Translational Neurology

DOI: 10.1002/acn3.70067