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Louis Sokoloff Papers 1923-2016
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Biographical/Historical Note

Dr. Louis Sokoloff spent most of his career as a neurochemical researcher with the National Institute of Mental Health (NIMH). From 1957 until his retirement more than 40 years later, he served as Chief of the Section (later Laboratory) of Cerebral Metabolism. In 1981 he won the Albert Lasker Award for Clinical Research for developing methods of visualizing biochemical activity in neural pathways that led to development of positron-emission tomography (PET).

Louis Sokoloff was born in Philadelphia in 1921. He earned the B.A., M.A., and M.D. degrees at the University of Pennsylvania. Influenced by Lewis V. Heilbrunn and other faculty, he decided on a career in scientific research, more specifically mammalian physiology and biochemistry. His experiences during a medical internship at Philadelphia Medical Hospital and on active duty in the Army Medical Corps at Camp Lee, Va., from 1946 to 1949, fostered an interest in physiological and biochemical mechanisms of the brain in mental disease. In 1949 he began grant-funded research at the University of Pennsylvania under former instructor and neuroscientist, Dr. Seymour S. Kety. During his four years there his primary research projects were studies of peripheral circulation, and, with Benton King and Richard Wechsler, the effects of epinephrine and norephinephrine and epinephrine on cerebral blood flow (CBF) and cerebral 02 consumption (MCR02).

In 1953 Sokoloff joined Dr. Kety at the National Institute of Mental Health, Bethesda, Md., where Kety had relocated as NIMH's first scientific director. As Associate Chief, Section on Cerebral Metabolism, Laboratory of Neurochemistry, Sokoloff spent the next six years studying thyroid hormones. Collaborating with Seymour Kaufman, he demonstrated that thyroid hormones stimulated protein synthesis. His study of thyroid mechanisms gradually broadened into interests in the relationship between biochemical processes and physiological functions in the nervous system.

Sokoloff's thyroid studies during the 1950s were conducted using the N20 method. Developed by Dr. Kety and C. S. Schmidt in 1948, this method enabled researchers to measure the average blood flow in the brain as a whole. By the late 1950s his research interests had progressed beyond cerebral blood flow to looking at brain metabolism, specifically glucose metabolism, which provided the brain's energy. However, the N20 method could not produce evidence of changes in cerebral energy metabolism during changes in mental function, even including functional psychoses.

A new technique arose during the mid-1950s when Drs. Kety, William Landau and Walter Freygang used isotopes of iodine to develop the [131]triflouroiodomethane ([131]CF31) method to study local cerebral blood flow and, indirectly, metabolic rates. Sokoloff attempted to adapt this method but by 1959 had not found a glucose compound that worked well. By 1965, however, NIMH's Dr. Martin Reivich modified the CF3I method in a way that allowed better autoradiographic resolution. This technique, using [14C]iodoantipyrine, suggested possibilities for Sokoloff's metabolism studies. 2-deoxyglucose (DG), whose actions during metabolism, would make autoradiographic studies of local glucose utilization possible.

Beginning in 1967, Dr. Sokoloff collaborated with Dr. Reivich, who had relocated to the University of Pennsylvania, to develop a [14C]DG method to measure local cerebral glucose utilization. The first applications proved unsatisfactory, but while on sabbatical in 1968, at the College de France's Laboratory of General and Comparative Biochemistry, Sokoloff had an inspiration. He reformulated the [14C]DG method in terms of enzyme kinetics rather than blood flow. Work progressed through the early 1970s, and by 1976 the method was successfully used with monkeys.

The next development came in data representation. Using automated data techniques, NIMH's Charles Gouchee and Wayne Rasband reworked the autoradiographic images into colored displays representing metabolic rates.

For human application, Reivich collaborated with Dr. David Kuhl at the Department of Radiology at the University of Pennsylvania, who had constructed a section scanner which could measure concentrations of gamma-emitting isotopes in human brain cross sections. DG, however, was a poor candidate for gamma-emitting isotope evaluation. With the assistance of Brookhaven National Laboratory chemist Alfred Wolf, the [14C]DG formula was adapted to a fluorinated derivative, 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), which retained the properties of DG while producing positron-emitting isotopes. Dr. Kuhl, with Michael Phelps and Edward Hoffman, expanded on this method at UCLA with development of positron-emission tomographic (PET) scanning. This was an improvement over the initial single photon scanner at the University of Pennsylvania which provided better spatial resolution and accuracy.

Dr. Sokoloff received the Albert Lasker Clinical Medical Research Award in 1981 for his role in developing the vivid color images that map brain function. The technique measures the metabolism of its primary fuel, glucose, through a radioactive substitute that, unlike glucose, lingers long enough to undergo chemical analysis. The award citation stated that "the Sokoloff method has facilitated the diagnosis, understanding and possible future treatment of such disorders of the brain as schizophrenia, epilepsy, brain changes due to drug addiction and senile dementia."

Dr. Sokoloff continued his work at NIMH well into the 21st century, retiring in 2004. He was awarded Scientist Emeritus status and maintained an office at NIH until his death in 2015. Information about his life and research can be found in History of Neuroscience in Autobiography, vol. 1, edited by Larry R. Squire (1996), which contains a lengthy autobiographical essay by Dr. Sokoloff, Dr. Sokoloff describes his research in an interview available on Youtube entitled "History of Neuroscience: Louis Sokoloff."