{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:59:36Z","timestamp":1787662776488,"version":"build-2736575974"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003607","name":"Association for Frontotemporal Degeneration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003607","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013013","name":"Target ALS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020462","name":"Eikonizo Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020462","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>[<jats:sup>18<\/jats:sup>F]EKZ\u2010001 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\u2010frontotemporal spectrum disorder (ALS\u2010FTSD). This work assessed [<jats:sup>18<\/jats:sup>F]EKZ\u2010001 binding in pwALS with variable involvement of FTSD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010four pwALS (13M\/11F, 61\u2009\u00b1\u200910\u2009years) and 12 healthy controls (HC) (6M\/6F, 58\u2009\u00b1\u20093\u2009years) were included. Thirteen pwALS were cognitively normal (ALS\u2010CN), and eleven pwALS presented with FTSD (ALS\u2010FTSD) 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\u2010MR imaging with arterial sampling, and regional distribution volumes (<jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub>) were calculated using a Logan graphical analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>[<jats:sup>18<\/jats:sup>F]EKZ\u2010001 <jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub> was significantly lower in pwALS compared to HC. For ALS\u2010CN, the largest reduction was found in the brainstem. For ALS\u2010FTSD, reductions were more widespread in both gray and white matter. No differences in <jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub> were found between pwALS with and without a <jats:italic>C9orf72<\/jats:italic> mutation. [<jats:sup>18<\/jats:sup>F]EKZ\u2010001 <jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub> was not correlated with ECAS scores, age, or disease duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>[<jats:sup>18<\/jats:sup>F]EKZ\u2010001 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 [<jats:sup>18<\/jats:sup>F]EKZ\u2010001 binding due to sequestration of HDAC6 within protein aggregates.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70067","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T12:49:14Z","timestamp":1746622154000},"page":"1350-1359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis\u2010Frontotemporal Spectrum Disorder"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-4121","authenticated-orcid":false,"given":"Greet","family":"Vanderlinden","sequence":"first","affiliation":[{"name":"Nuclear Medicine and Molecular Imaging, Imaging and Pathology KU Leuven, Leuven Brain Institute  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Carron","sequence":"additional","affiliation":[{"name":"Nuclear Medicine and Molecular Imaging, Imaging and Pathology KU Leuven, Leuven Brain Institute  Leuven Belgium"},{"name":"Division of Nuclear Medicine University Hospitals UZ Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatienne","family":"Van Weehaeghe","sequence":"additional","affiliation":[{"name":"Nuclear Medicine and Molecular Imaging, Imaging and Pathology KU Leuven, Leuven Brain Institute  Leuven Belgium"},{"name":"Division of Nuclear Medicine University Hospitals UZ Leuven  Leuven Belgium"},{"name":"Nuclear Medicine Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joke","family":"De Vocht","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospitals Leuven  Leuven Belgium"},{"name":"Department of Neurosciences, Experimental Neurology KU Leuven, Leuven Brain Institute  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fouke","family":"Ombelet","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospitals Leuven  Leuven Belgium"},{"name":"Department of Neurosciences, Experimental Neurology KU Leuven, Leuven Brain Institute  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pegah","family":"Masrori","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospitals Leuven  Leuven Belgium"},{"name":"Department of Neurosciences, Experimental Neurology KU Leuven, Leuven Brain Institute  Leuven Belgium"},{"name":"Department of Neurology Cliniques Universitaires Saint\u2010Luc Institute of Neuroscience, UCLouvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caro","family":"De Weerdt","sequence":"additional","affiliation":[{"name":"Nuclear Medicine and Molecular Imaging, Imaging and Pathology KU Leuven, Leuven Brain Institute  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"James","sequence":"additional","affiliation":[{"name":"Eikonizo Therapeutics, Inc.  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