Assessment of cholesterol homeostasis in the living human brain.

Autor: Haider A; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Zhao C; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Wang L; Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China., Xiao Z; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Rong J; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Xia X; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China., Chen Z; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA., Pfister SK; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA., Mast N; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Yutuc E; Institute of Life Science, Swansea University Medical School, SA2 8PP Swansea, Wales, UK., Chen J; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Li Y; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Shao T; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA., Warnock GI; Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland.; Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland., Dawoud A; Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt., Connors TR; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.; Massachusetts Alzheimer's Disease Research Center, Boston, MA 02129, USA., Oakley DH; Harvard Medical School, Boston, MA 02115, USA.; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114-2696, USA.; C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA 02114, USA.; Massachusetts Alzheimer's Disease Research Center, Charlestown, MA 02129, USA., Wei H; Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China., Wang J; Department of Pharmacy, First Affiliated Hospital of Jinan University, Guangzhou 510630, China., Zheng Z; Guangdong Province Pharmaceutical Association, Guangzhou 510080, China., Xu H; Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China., Davenport AT; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA., Daunais JB; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA., Van RS; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA., Shao Y; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA., Wang Y; Institute of Life Science, Swansea University Medical School, SA2 8PP Swansea, Wales, UK., Zhang MR; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Gebhard C; Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland.; Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland., Pikuleva I; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Levey AI; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA., Griffiths WJ; Institute of Life Science, Swansea University Medical School, SA2 8PP Swansea, Wales, UK., Liang SH; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2022 Oct 05; Vol. 14 (665), pp. eadc9967. Date of Electronic Publication: 2022 Oct 05.
DOI: 10.1126/scitranslmed.adc9967
Abstrakt: Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18 F-CHL-2205 ( 18 F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer's disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.
Databáze: MEDLINE