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

OBJECTIVE

[F]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 [F]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 (V) were calculated using a Logan graphical analysis.

RESULTS

[F]EKZ-001 V 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 V were found between pwALS with and without a C9orf72 mutation. [F]EKZ-001 V was not correlated with ECAS scores, age, or disease duration.

INTERPRETATION

[F]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 [F]EKZ-001 binding due to sequestration of HDAC6 within protein aggregates.